48 results on '"Castillo, Pablo"'
Search Results
2. Altered synaptic connectivity and brain function in mice lacking microglial adapter protein Iba1.
- Author
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Lituma PJ, Woo E, O'Hara BF, Castillo PE, Sibinga NES, and Nandi S
- Subjects
- Animals, Mice, Mice, Inbred C57BL, Neurogenesis physiology, Neuronal Plasticity physiology, Neurons metabolism, Phagocytosis physiology, Synaptic Transmission physiology, Calcium-Binding Proteins metabolism, Hippocampus metabolism, Microfilament Proteins metabolism, Microglia metabolism, Synapses metabolism
- Abstract
Growing evidence indicates that microglia impact brain function by regulating synaptic pruning and formation as well as synaptic transmission and plasticity. Iba1 (ionized Ca
+2 -binding adapter protein 1), encoded by the Allograft inflammatory factor 1 ( Aif1 ) gene, is an actin-interacting protein in microglia. Although Iba1 has long been used as a cellular marker for microglia, its functional role remains unknown. Here, we used global, Iba1-deficient ( Aif1-/- ) mice to characterize microglial activity, synaptic function, and behavior. Microglial imaging in acute hippocampal slices and fixed tissues from juvenile mice revealed that Aif1-/- microglia display reductions in ATP-induced motility and ramification, respectively. Biochemical assays further demonstrated that Aif1-/- brain tissues exhibit an altered expression of microglial-enriched proteins associated with synaptic pruning. Consistent with these changes, juvenile Aif1-/- mice displayed deficits in the excitatory synapse number and synaptic drive assessed by neuronal labeling and whole-cell patch-clamp recording in acute hippocampal slices. Unexpectedly, microglial synaptic engulfment capacity was diminished in juvenile Aif1-/- mice. During early postnatal development, when synapse formation is a predominant event in the hippocampus, the excitatory synapse number was still reduced in Aif1-/- mice. Together, these findings support an overall role of Iba1 in excitatory synaptic growth in juvenile mice. Lastly, postnatal synaptic deficits persisted in adulthood and correlated with significant behavioral changes in adult Aif1-/- mice, which exhibited impairments in object recognition memory and social interaction. These results suggest that Iba1 critically contributes to microglial activity underlying essential neuroglia developmental processes that may deeply influence behavior., Competing Interests: The authors declare no competing interest.- Published
- 2021
- Full Text
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3. Excitatory and inhibitory receptors utilize distinct post- and trans-synaptic mechanisms in vivo.
- Author
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Miyazaki T, Morimoto-Tomita M, Berthoux C, Konno K, Noam Y, Yamasaki T, Verhage M, Castillo PE, Watanabe M, and Tomita S
- Subjects
- Animals, Mice, Mice, Transgenic, Post-Synaptic Density metabolism, Presynaptic Terminals metabolism, Receptors, AMPA metabolism, Receptors, GABA-A metabolism, Synapses physiology, Synaptic Transmission physiology
- Abstract
Ionotropic neurotransmitter receptors at postsynapses mediate fast synaptic transmission upon binding of the neurotransmitter. Post- and trans-synaptic mechanisms through cytosolic, membrane, and secreted proteins have been proposed to localize neurotransmitter receptors at postsynapses. However, it remains unknown which mechanism is crucial to maintain neurotransmitter receptors at postsynapses. In this study, we ablated excitatory or inhibitory neurons in adult mouse brains in a cell-autonomous manner. Unexpectedly, we found that excitatory AMPA receptors remain at the postsynaptic density upon ablation of excitatory presynaptic terminals. In contrast, inhibitory GABA
A receptors required inhibitory presynaptic terminals for their postsynaptic localization. Consistent with this finding, ectopic expression at excitatory presynapses of neurexin-3 alpha, a putative trans-synaptic interactor with the native GABAA receptor complex, could recruit GABAA receptors to contacted postsynaptic sites. These results establish distinct mechanisms for the maintenance of excitatory and inhibitory postsynaptic receptors in the mature mammalian brain., Competing Interests: TM, MM, CB, KK, YN, TY, MV, PC, MW, ST No competing interests declared, (© 2021, Miyazaki et al.)- Published
- 2021
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4. Npas4 Is a Critical Regulator of Learning-Induced Plasticity at Mossy Fiber-CA3 Synapses during Contextual Memory Formation.
- Author
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Weng FJ, Garcia RI, Lutzu S, Alviña K, Zhang Y, Dushko M, Ku T, Zemoura K, Rich D, Garcia-Dominguez D, Hung M, Yelhekar TD, Sørensen AT, Xu W, Chung K, Castillo PE, and Lin Y
- Subjects
- Animals, Basic Helix-Loop-Helix Transcription Factors analysis, CA3 Region, Hippocampal chemistry, Excitatory Postsynaptic Potentials physiology, Female, Inhibitory Postsynaptic Potentials physiology, Learning physiology, Male, Mice, Mice, Inbred C57BL, Mice, Knockout, Mossy Fibers, Hippocampal chemistry, Synapses chemistry, Basic Helix-Loop-Helix Transcription Factors physiology, CA3 Region, Hippocampal physiology, Memory physiology, Mossy Fibers, Hippocampal physiology, Neuronal Plasticity physiology, Synapses physiology
- Abstract
Synaptic connections between hippocampal mossy fibers (MFs) and CA3 pyramidal neurons are essential for contextual memory encoding, but the molecular mechanisms regulating MF-CA3 synapses during memory formation and the exact nature of this regulation are poorly understood. Here we report that the activity-dependent transcription factor Npas4 selectively regulates the structure and strength of MF-CA3 synapses by restricting the number of their functional synaptic contacts without affecting the other synaptic inputs onto CA3 pyramidal neurons. Using an activity-dependent reporter, we identified CA3 pyramidal cells that were activated by contextual learning and found that MF inputs on these cells were selectively strengthened. Deletion of Npas4 prevented both contextual memory formation and this learning-induced synaptic modification. We further show that Npas4 regulates MF-CA3 synapses by controlling the expression of the polo-like kinase Plk2. Thus, Npas4 is a critical regulator of experience-dependent, structural, and functional plasticity at MF-CA3 synapses during contextual memory formation., (Copyright © 2018 Elsevier Inc. All rights reserved.)
- Published
- 2018
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5. Neurotrophin and FGF Signaling Adapter Proteins, FRS2 and FRS3, Regulate Dentate Granule Cell Maturation and Excitatory Synaptogenesis.
- Author
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Nandi S, Alviña K, Lituma PJ, Castillo PE, and Hébert JM
- Subjects
- Adaptor Proteins, Signal Transducing genetics, Animals, Excitatory Postsynaptic Potentials physiology, Hippocampus cytology, Hippocampus growth & development, Membrane Proteins genetics, Mice, Transgenic, Miniature Postsynaptic Potentials physiology, Neural Stem Cells cytology, Neural Stem Cells metabolism, Neurons cytology, Tissue Culture Techniques, Adaptor Proteins, Signal Transducing metabolism, Hippocampus metabolism, Membrane Proteins metabolism, Neurogenesis physiology, Neurons metabolism, Synapses metabolism
- Abstract
Dentate granule cells (DGCs) play important roles in cognitive processes. Knowledge about how growth factors such as FGFs and neurotrophins contribute to the maturation and synaptogenesis of DGCs is limited. Here, using brain-specific and germline mouse mutants we show that a module of neurotrophin and FGF signaling, the FGF Receptor Substrate (FRS) family of intracellular adapters, FRS2 and FRS3, are together required for postnatal brain development. In the hippocampus, FRS promotes dentate gyrus morphogenesis and DGC maturation during developmental neurogenesis, similar to previously published functions for both neurotrophins and FGFs. Consistent with a role in DGC maturation, two-photon imaging revealed that Frs2,3-double mutants have reduced numbers of dendritic branches and spines in DGCs. Functional analysis further showed that double-mutant mice exhibit fewer excitatory synaptic inputs onto DGCs. These observations reveal roles for FRS adapters in DGC maturation and synaptogenesis and suggest that FRS proteins may act as an important node for FGF and neurotrophin signaling in postnatal hippocampal development., (Copyright © 2017 IBRO. Published by Elsevier Ltd. All rights reserved.)
- Published
- 2018
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6. LTP at Hilar Mossy Cell-Dentate Granule Cell Synapses Modulates Dentate Gyrus Output by Increasing Excitation/Inhibition Balance.
- Author
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Hashimotodani Y, Nasrallah K, Jensen KR, Chávez AE, Carrera D, and Castillo PE
- Subjects
- Animals, Animals, Newborn, Brain-Derived Neurotrophic Factor pharmacology, Channelrhodopsins, Enzyme Inhibitors pharmacology, Female, Long-Term Potentiation drug effects, Long-Term Synaptic Depression drug effects, Male, Mice, Mice, Transgenic, Nerve Tissue Proteins metabolism, Neurotransmitter Agents pharmacology, Rats, Rats, Sprague-Dawley, Receptor, trkB genetics, Receptor, trkB metabolism, Receptors, Presynaptic metabolism, Signal Transduction drug effects, Dentate Gyrus cytology, Long-Term Potentiation physiology, Long-Term Synaptic Depression physiology, Mossy Fibers, Hippocampal physiology, Neurons physiology, Synapses physiology
- Abstract
Excitatory hilar mossy cells (MCs) in the dentate gyrus receive inputs from dentate granule cells (GCs) and project back to GCs locally, contralaterally, and along the longitudinal axis of the hippocampus, thereby establishing an associative positive-feedback loop and connecting functionally diverse hippocampal areas. MCs also synapse with GABAergic interneurons that mediate feed-forward inhibition onto GCs. Surprisingly, although these circuits have been implicated in both memory formation (e.g., pattern separation) and temporal lobe epilepsy, little is known about activity-dependent plasticity of their synaptic connections. Here, we report that MC-GC synapses undergo a presynaptic, NMDA-receptor-independent form of long-term potentiation (LTP) that requires postsynaptic brain-derived neurotrophic factor (BDNF)/TrkB and presynaptic cyclic AMP (cAMP)/PKA signaling. This LTP is input specific and selectively expressed at MC-GC synapses, but not at the disynaptic inhibitory loop. By increasing the excitation/inhibition balance, MC-GC LTP enhances GC output at the associative MC-GC recurrent circuit and may contribute to dentate-dependent forms of learning and epilepsy., (Copyright © 2017 Elsevier Inc. All rights reserved.)
- Published
- 2017
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7. De novo synaptogenesis induced by GABA in the developing mouse cortex.
- Author
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Oh WC, Lutzu S, Castillo PE, and Kwon HB
- Subjects
- Animals, Carrier Proteins metabolism, Cerebral Cortex cytology, Dendrites physiology, Dendritic Spines physiology, Female, Interneurons metabolism, Interneurons physiology, Male, Membrane Proteins metabolism, Mice, Pyramidal Cells metabolism, Receptors, GABA-A metabolism, Cerebral Cortex growth & development, Neurogenesis, Pyramidal Cells physiology, Synapses physiology, gamma-Aminobutyric Acid metabolism
- Abstract
Dendrites of cortical pyramidal neurons contain intermingled excitatory and inhibitory synapses. We studied the local mechanisms that regulate the formation and distribution of synapses. We found that local γ-aminobutyric acid (GABA) release on dendrites of mouse cortical layer 2/3 pyramidal neurons could induce gephyrin puncta and dendritic spine formation via GABA type A receptor activation and voltage-gated calcium channels during early postnatal development. Furthermore, the newly formed inhibitory and excitatory synaptic structures rapidly gained functions. Bidirectional manipulation of GABA release from somatostatin-positive interneurons increased and decreased the number of gephyrin puncta and dendritic spines, respectively. These results highlight a noncanonical function of GABA as a local synaptogenic element shaping the early establishment of neuronal circuitry in mouse cortex., (Copyright © 2016, American Association for the Advancement of Science.)
- Published
- 2016
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8. APP and APLP2 interact with the synaptic release machinery and facilitate transmitter release at hippocampal synapses.
- Author
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Fanutza T, Del Prete D, Ford MJ, Castillo PE, and D'Adamio L
- Subjects
- Amyloid beta-Protein Precursor genetics, Animals, Gene Deletion, Mice, Inbred C57BL, Protein Binding, Protein Interaction Mapping, Amyloid beta-Protein Precursor metabolism, Hippocampus physiology, Neurotransmitter Agents metabolism, Synapses physiology, Synaptic Transmission
- Abstract
The amyloid precursor protein (APP), whose mutations cause familial Alzheimer's disease, interacts with the synaptic release machinery, suggesting a role in neurotransmission. Here we mapped this interaction to the NH2-terminal region of the APP intracellular domain. A peptide encompassing this binding domain -named JCasp- is naturally produced by a γ-secretase/caspase double-cut of APP. JCasp interferes with the APP-presynaptic proteins interaction and, if linked to a cell-penetrating peptide, reduces glutamate release in acute hippocampal slices from wild-type but not APP deficient mice, indicating that JCasp inhibits APP function.The APP-like protein-2 (APLP2) also binds the synaptic release machinery. Deletion of APP and APLP2 produces synaptic deficits similar to those caused by JCasp. Our data support the notion that APP and APLP2 facilitate transmitter release, likely through the interaction with the neurotransmitter release machinery. Given the link of APP to Alzheimer's disease, alterations of this synaptic role of APP could contribute to dementia.
- Published
- 2015
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9. ANKS1B Gene Product AIDA-1 Controls Hippocampal Synaptic Transmission by Regulating GluN2B Subunit Localization.
- Author
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Tindi JO, Chávez AE, Cvejic S, Calvo-Ochoa E, Castillo PE, and Jordan BA
- Subjects
- Animals, Cells, Cultured, Endoplasmic Reticulum chemistry, Endoplasmic Reticulum physiology, Female, Hippocampus chemistry, Intracellular Signaling Peptides and Proteins, Male, Mice, Mice, 129 Strain, Mice, Inbred C57BL, Mice, Knockout, Protein Subunits analysis, Protein Subunits physiology, Rats, Rats, Sprague-Dawley, Receptors, N-Methyl-D-Aspartate analysis, Synapses chemistry, Carrier Proteins physiology, Hippocampus physiology, Receptors, N-Methyl-D-Aspartate physiology, Synapses physiology, Synaptic Transmission physiology
- Abstract
NMDA receptors (NMDARs) are key mediators of glutamatergic transmission and synaptic plasticity, and their dysregulation has been linked to diverse neuropsychiatric and neurodegenerative disorders. While normal NMDAR function requires regulated expression and trafficking of its different subunits, the molecular mechanisms underlying these processes are not fully understood. Here we report that the amyloid precursor protein intracellular domain associated-1 protein (AIDA-1), which associates with NMDARs and is encoded by ANKS1B, a gene recently linked to schizophrenia, regulates synaptic NMDAR subunit composition. Forebrain-specific AIDA-1 conditional knock-out (cKO) mice exhibit reduced GluN2B-mediated and increased GluN2A-mediated synaptic transmission, and biochemical analyses show AIDA-1 cKO mice have low GluN2B and high GluN2A protein levels at isolated hippocampal synaptic junctions compared with controls. These results are corroborated by immunocytochemical and electrophysiological analyses in primary neuronal cultures following acute lentiviral shRNA-mediated knockdown of AIDA-1. Moreover, hippocampal NMDAR-dependent but not metabotropic glutamate receptor-dependent plasticity is impaired in AIDA-1 cKO mice, further supporting a role for AIDA-1 in synaptic NMDAR function. We also demonstrate that AIDA-1 preferentially associates with GluN2B and with the adaptor protein Ca(2+)/calmodulin-dependent serine protein kinase and kinesin KIF17, which regulate the transport of GluN2B-containing NMDARs from the endoplasmic reticulum (ER) to synapses. Consistent with this function, GluN2B accumulates in ER-enriched fractions in AIDA-1 cKO mice. These findings suggest that AIDA-1 regulates NMDAR subunit composition at synapses by facilitating transport of GluN2B from the ER to synapses, which is critical for NMDAR plasticity. Our work provides an explanation for how AIDA-1 dysfunction might contribute to neuropsychiatric conditions, such as schizophrenia., (Copyright © 2015 the authors 0270-6474/15/358986-11$15.00/0.)
- Published
- 2015
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10. CA1 pyramidal cell theta-burst firing triggers endocannabinoid-mediated long-term depression at both somatic and dendritic inhibitory synapses.
- Author
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Younts TJ, Chevaleyre V, and Castillo PE
- Subjects
- Action Potentials drug effects, Action Potentials physiology, Animals, Animals, Newborn, Calcium Channel Blockers pharmacology, Electric Stimulation, Excitatory Amino Acid Agents pharmacology, Female, In Vitro Techniques, Long-Term Synaptic Depression physiology, Male, Mice, Mice, Inbred C57BL, Neural Inhibition drug effects, Neural Pathways drug effects, Neural Pathways physiology, Patch-Clamp Techniques, Piperidines pharmacology, Pyrazoles pharmacology, Rats, Rats, Wistar, Receptor, Cannabinoid, CB1 antagonists & inhibitors, Receptor, Cannabinoid, CB1 metabolism, Signal Transduction drug effects, Theta Rhythm drug effects, CA1 Region, Hippocampal cytology, Endocannabinoids pharmacology, Long-Term Synaptic Depression drug effects, Pyramidal Cells drug effects, Pyramidal Cells physiology, Synapses drug effects
- Abstract
Endocannabinoids (eCBs) are retrograde lipid messengers that, by targeting presynaptic type 1 cannabinoid receptors (CB1Rs), mediate short- and long-term synaptic depression of neurotransmitter release throughout the brain. Short-term depression is typically triggered by postsynaptic, depolarization-induced calcium rises, whereas long-term depression is induced by synaptic activation of Gq/11 protein-coupled receptors. Here we report that a physiologically relevant pattern of postsynaptic activity, in the form of theta-burst firing (TBF) of hippocampal CA1 pyramidal neurons, can trigger long-term depression of inhibitory transmission (iLTD) in rat hippocampal slices. Paired recordings between CA1 interneurons and pyramidal cells, followed by post hoc morphological reconstructions of the interneurons' axon, revealed that somatic and dendritic inhibitory synaptic inputs equally expressed TBF-induced iLTD. Simultaneous recordings from neighboring pyramidal cells demonstrated that eCB signaling triggered by TBF was highly restricted to only a single, active cell. Furthermore, pairing submaximal endogenous activation of metabotropic glutamate or muscarinic acetylcholine receptors with submaximal TBF unmasked associative iLTD. Although CB1Rs are also expressed at Schaffer-collateral excitatory terminals, long-term plasticity under various recording conditions was spared at these synapses. Consistent with this observation, TBF also shifted the balance of excitation and inhibition in favor of excitatory throughput, thereby altering information flow through the CA1 circuit. Given the near ubiquity of burst-firing activity patterns and CB1R expression in the brain, the properties described here may be a general means by which neurons fine tune the strength of their inputs in a cell-wide and cell-specific manner.
- Published
- 2013
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11. Neuroligin1 drives synaptic and behavioral maturation through intracellular interactions.
- Author
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Hoy JL, Haeger PA, Constable JR, Arias RJ, McCallum R, Kyweriga M, Davis L, Schnell E, Wehr M, Castillo PE, and Washbourne P
- Subjects
- Animals, Auditory Cortex growth & development, Auditory Cortex physiology, Blotting, Western, Cell Adhesion Molecules, Neuronal genetics, Dendritic Spines physiology, Dendritic Spines ultrastructure, Doxycycline pharmacology, Electrophysiological Phenomena, Green Fluorescent Proteins, Humans, Image Processing, Computer-Assisted, Immunohistochemistry, Learning Disabilities genetics, Learning Disabilities psychology, Maze Learning physiology, Mice, Mice, Transgenic, Microscopy, Confocal, Psychomotor Performance drug effects, Psychomotor Performance physiology, Recognition, Psychology, Social Behavior, Social Dominance, Synaptosomes physiology, Behavior, Animal physiology, Cell Adhesion Molecules, Neuronal physiology, Second Messenger Systems physiology, Synapses physiology
- Abstract
In vitro studies suggest that the intracellular C terminus of Neuroligin1 (NL1) could play a central role in the maturation of excitatory synapses. However, it is unknown how this activity affects synapses in vivo, and whether it may impact the development of complex behaviors. To determine how NL1 influences the state of glutamatergic synapses in vivo, we compared the synaptic and behavioral phenotypes of mice overexpressing a full-length version of NL1 (NL1FL) with mice overexpressing a version missing part of the intracellular domain (NL1ΔC). We show that overexpression of full-length NL1 yielded an increase in the proportion of synapses with mature characteristics and impaired learning and flexibility. In contrast, the overexpression of NL1ΔC increased the number of excitatory postsynaptic structures and led to enhanced flexibility in mnemonic and social behaviors. Transient overexpression of NL1FL revealed that elevated levels are not necessary to maintain synaptic and behavioral states altered earlier in development. In contrast, overexpression of NL1FL in the fully mature adult was able to impair normal learning behavior after 1 month of expression. These results provide the first evidence that NL1 significantly impacts key developmental processes that permanently shape circuit function and behavior, as well as the function of fully developed neural circuits. Overall, these manipulations of NL1 function illuminate the significance of NL1 intracellular signaling in vivo, and enhance our understanding of the factors that gate the maturation of glutamatergic synapses and complex behavior. This has significant implications for our ability to address disorders such as autism spectrum disorders.
- Published
- 2013
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12. RNA-binding protein Sam68 controls synapse number and local β-actin mRNA metabolism in dendrites.
- Author
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Klein ME, Younts TJ, Castillo PE, and Jordan BA
- Subjects
- Adaptor Proteins, Signal Transducing genetics, Animals, Mice, Mice, Knockout, RNA-Binding Proteins genetics, Rats, Rats, Sprague-Dawley, Actins genetics, Adaptor Proteins, Signal Transducing physiology, Dendrites metabolism, RNA, Messenger metabolism, RNA-Binding Proteins physiology, Synapses
- Abstract
Proper synaptic function requires the spatial and temporal compartmentalization of RNA metabolism via transacting RNA-binding proteins (RBPs). Loss of RBP activity leads to abnormal posttranscriptional regulation and results in diverse neurological disorders with underlying deficits in synaptic morphology and transmission. Functional loss of the 68-kDa RBP Src associated in mitosis (Sam68) is associated with the pathogenesis of the neurological disorder fragile X tremor/ataxia syndrome. Sam68 binds to the mRNA of β-actin (actb), an integral cytoskeletal component of dendritic spines. We show that Sam68 knockdown or disruption of the binding between Sam68 and its actb mRNA cargo in primary hippocampal cultures decreases the amount of actb mRNA in the synaptodendritic compartment and results in fewer dendritic spines. Consistent with these observations, we find that Sam68-KO mice have reduced levels of actb mRNA associated with synaptic polysomes and diminished levels of synaptic actb protein, suggesting that Sam68 promotes the translation of actb mRNA at synapses in vivo. Moreover, genetic knockout of Sam68 or acute knockdown in vivo results in fewer excitatory synapses in the hippocampal formation as assessed morphologically and functionally. Therefore, we propose that Sam68 regulates synapse number in a cell-autonomous manner through control of postsynaptic actb mRNA metabolism. Our research identifies a role for Sam68 in synaptodendritic posttranscriptional regulation of actb and may provide insight into the pathophysiology of fragile X tremor/ataxia syndrome.
- Published
- 2013
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13. REST-dependent epigenetic remodeling promotes the developmental switch in synaptic NMDA receptors.
- Author
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Rodenas-Ruano A, Chávez AE, Cossio MJ, Castillo PE, and Zukin RS
- Subjects
- Animals, Gene Knockdown Techniques, Hippocampus metabolism, Maternal Deprivation, Phenotype, Rats, Receptors, N-Methyl-D-Aspartate genetics, Repressor Proteins genetics, Synapses genetics, Epigenetic Repression genetics, Hippocampus growth & development, Receptors, N-Methyl-D-Aspartate metabolism, Repressor Proteins metabolism, Synapses metabolism
- Abstract
NMDA receptors (NMDARs) are critical to synaptogenesis, neural circuitry and higher cognitive functions. A hallmark feature of NMDARs is an early postnatal developmental switch from those containing primarily GluN2B to primarily GluN2A subunits. Although the switch in phenotype has been an area of intense interest for two decades, the mechanisms that trigger it and the link between experience and the switch are unclear. Here we show a new role for the transcriptional repressor REST in the developmental switch of synaptic NMDARs. REST is activated at a critical window of time and acts via epigenetic remodeling to repress Grin2b expression and alter NMDAR properties at rat hippocampal synapses. Knockdown of REST in vivo prevented the decline in GluN2B and developmental switch in NMDARs. Maternal deprivation impaired REST activation and acquisition of the mature NMDAR phenotype. Thus, REST is essential for experience-dependent fine-tuning of genes involved in synaptic plasticity.
- Published
- 2012
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14. Synaptic plasticity of NMDA receptors: mechanisms and functional implications.
- Author
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Hunt DL and Castillo PE
- Subjects
- Animals, Biophysics, Synaptic Transmission physiology, Neuronal Plasticity physiology, Receptors, N-Methyl-D-Aspartate physiology, Synapses physiology
- Abstract
Beyond their well-established role as triggers for LTP and LTD of fast synaptic transmission mediated by AMPA receptors, an expanding body of evidence indicates that NMDA receptors (NMDARs) themselves are also dynamically regulated and subject to activity-dependent long-term plasticity. NMDARs can significantly contribute to information transfer at synapses particularly during periods of repetitive activity. It is also increasingly recognized that NMDARs participate in dendritic synaptic integration and are critical for generating persistent activity of neural assemblies. Here we review recent advances on the mechanisms and functional consequences of NMDAR plasticity. Given the unique biophysical properties of NMDARs, synaptic plasticity of NMDAR-mediated transmission emerges as a particularly powerful mechanism for the fine tuning of information encoding and storage throughout the brain., (Copyright © 2012 Elsevier Ltd. All rights reserved.)
- Published
- 2012
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15. Presynaptic LTP and LTD of excitatory and inhibitory synapses.
- Author
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Castillo PE
- Subjects
- Animals, Learning physiology, Mice, Long-Term Potentiation physiology, Long-Term Synaptic Depression physiology, Neurotransmitter Agents physiology, Synapses physiology, Synaptic Transmission physiology
- Abstract
Ubiquitous forms of long-term potentiation (LTP) and depression (LTD) are caused by enduring increases or decreases in neurotransmitter release. Such forms or presynaptic plasticity are equally observed at excitatory and inhibitory synapses and the list of locations expressing presynaptic LTP and LTD continues to grow. In addition to the mechanistically distinct forms of postsynaptic plasticity, presynaptic plasticity offers a powerful means to modify neural circuits. A wide range of induction mechanisms has been identified, some of which occur entirely in the presynaptic terminal, whereas others require retrograde signaling from the postsynaptic to presynaptic terminals. In spite of this diversity of induction mechanisms, some common induction rules can be identified across synapses. Although the precise molecular mechanism underlying long-term changes in transmitter release in most cases remains unclear, increasing evidence indicates that presynaptic LTP and LTD can occur in vivo and likely mediate some forms of learning.
- Published
- 2012
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16. Rab3B protein is required for long-term depression of hippocampal inhibitory synapses and for normal reversal learning.
- Author
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Tsetsenis T, Younts TJ, Chiu CQ, Kaeser PS, Castillo PE, and Südhof TC
- Subjects
- Animals, CA1 Region, Hippocampal cytology, CA1 Region, Hippocampal physiology, Excitatory Postsynaptic Potentials physiology, Extinction, Psychological physiology, Fear physiology, Gene Deletion, Hippocampus cytology, Inhibitory Postsynaptic Potentials physiology, Mice, Mice, Knockout, Models, Neurological, Synaptic Transmission physiology, rab3 GTP-Binding Proteins deficiency, Hippocampus physiology, Long-Term Synaptic Depression physiology, Reversal Learning physiology, Synapses physiology, rab3 GTP-Binding Proteins metabolism
- Abstract
Rab3B, similar to other Rab3 isoforms, is a synaptic vesicle protein that interacts with the Rab3-interacting molecule (RIM) isoforms RIM1α and RIM2α as effector proteins in a GTP-dependent manner. Previous studies showed that at excitatory synapses, Rab3A and RIM1α are essential for presynaptically expressed long-term potentiation (LTP), whereas at inhibitory synapses RIM1α is required for endocannabinoid-dependent long-term depression (referred to as "i-LTD"). However, it remained unknown whether i-LTD also involves a Rab3 isoform and whether i-LTD, similar to other forms of long-term plasticity, is important for learning and memory. Here we show that Rab3B is highly enriched in inhibitory synapses in the CA1 region of the hippocampus. Using electrophysiological recordings in acute slices, we demonstrate that knockout (KO) of Rab3B does not alter the strength or short-term plasticity of excitatory or inhibitory synapses but does impair i-LTD significantly without changing classical NMDA receptor-dependent LTP. Behaviorally, we found that Rab3B KO mice exhibit no detectable changes in all basic parameters tested, including the initial phase of learning and memory. However, Rab3B KO mice did display a selective enhancement in reversal learning, as measured using Morris water-maze and fear-conditioning assays. Our data support the notion that presynaptic forms of long-term plasticity at excitatory and inhibitory synapses generally are mediated by a common Rab3/RIM-dependent pathway, with various types of synapses using distinct Rab3 isoforms. Moreover, our results suggest that i-LTD contributes to learning and memory, presumably by stabilizing circuits established in previous learning processes.
- Published
- 2011
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17. Long-term plasticity at inhibitory synapses.
- Author
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Castillo PE, Chiu CQ, and Carroll RC
- Subjects
- Animals, Humans, Neuronal Plasticity physiology, Synapses physiology
- Abstract
Experience-dependent modifications of neural circuits and function are believed to heavily depend on changes in synaptic efficacy such as LTP/LTD. Hence, much effort has been devoted to elucidating the mechanisms underlying these forms of synaptic plasticity. Although most of this work has focused on excitatory synapses, it is now clear that diverse mechanisms of long-term inhibitory plasticity have evolved to provide additional flexibility to neural circuits. By changing the excitatory/inhibitory balance, GABAergic plasticity can regulate excitability, neural circuit function and ultimately, contribute to learning and memory, and neural circuit refinement. Here we discuss recent advancements in our understanding of the mechanisms and functional relevance of GABAergic inhibitory synaptic plasticity., (Copyright © 2011 Elsevier Ltd. All rights reserved.)
- Published
- 2011
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18. αβγ-Synuclein triple knockout mice reveal age-dependent neuronal dysfunction.
- Author
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Greten-Harrison B, Polydoro M, Morimoto-Tomita M, Diao L, Williams AM, Nie EH, Makani S, Tian N, Castillo PE, Buchman VL, and Chandra SS
- Subjects
- Age Factors, Animals, Gene Deletion, Mice, Mice, Knockout, Nerve Tissue Proteins analysis, Parkinson Disease etiology, Phenotype, Synucleins deficiency, alpha-Synuclein deficiency, alpha-Synuclein genetics, beta-Synuclein deficiency, beta-Synuclein genetics, gamma-Synuclein deficiency, gamma-Synuclein genetics, Neurons physiology, Synapses pathology, Synaptic Transmission genetics, Synucleins genetics, Synucleins physiology
- Abstract
Synucleins are a vertebrate-specific family of abundant neuronal proteins. They comprise three closely related members, α-, β-, and γ-synuclein. α-Synuclein has been the focus of intense attention since mutations in it were identified as a cause for familial Parkinson's disease. Despite their disease relevance, the normal physiological function of synucleins has remained elusive. To address this, we generated and characterized αβγ-synuclein knockout mice, which lack all members of this protein family. Deletion of synucleins causes alterations in synaptic structure and transmission, age-dependent neuronal dysfunction, as well as diminished survival. Abrogation of synuclein expression decreased excitatory synapse size by ∼30% both in vivo and in vitro, revealing that synucleins are important determinants of presynaptic terminal size. Young synuclein null mice show improved basic transmission, whereas older mice show a pronounced decrement. The late onset phenotypes in synuclein null mice were not due to a loss of synapses or neurons but rather reflect specific changes in synaptic protein composition and axonal structure. Our results demonstrate that synucleins contribute importantly to the long-term operation of the nervous system and that alterations in their physiological function could contribute to the development of Parkinson's disease.
- Published
- 2010
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19. ELKS2alpha/CAST deletion selectively increases neurotransmitter release at inhibitory synapses.
- Author
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Kaeser PS, Deng L, Chávez AE, Liu X, Castillo PE, and Südhof TC
- Subjects
- Animals, Animals, Newborn, Behavior, Animal physiology, Brain metabolism, Brain ultrastructure, Calcium metabolism, Carrier Proteins genetics, Cells, Cultured, Electric Stimulation methods, GTP-Binding Proteins metabolism, Green Fluorescent Proteins genetics, Hippocampus cytology, Hippocampus physiology, In Vitro Techniques, Inhibitory Postsynaptic Potentials physiology, Mice, Mice, Knockout, Microscopy, Electron, Transmission, Models, Neurological, Movement physiology, Nerve Tissue Proteins genetics, Neurons physiology, Neurons ultrastructure, Patch-Clamp Techniques methods, Protein Isoforms genetics, Protein Isoforms metabolism, Synapses ultrastructure, Synaptosomes metabolism, Synaptosomes ultrastructure, rab GTP-Binding Proteins, Gene Deletion, Inhibitory Postsynaptic Potentials genetics, Nerve Tissue Proteins deficiency, Neurotransmitter Agents metabolism, Synapses metabolism
- Abstract
The presynaptic active zone is composed of a protein network that contains ELKS2alpha (a.k.a. CAST) as a central component. Here we demonstrate that in mice, deletion of ELKS2alpha caused a large increase in inhibitory, but not excitatory, neurotransmitter release, and potentiated the size, but not the properties, of the readily-releasable pool of vesicles at inhibitory synapses. Quantitative electron microscopy revealed that the ELKS2alpha deletion did not change the number of docked vesicles or other ultrastructural parameters of synapses, except for a small decrease in synaptic vesicle numbers. The ELKS2alpha deletion did, however, alter the excitatory/inhibitory balance and exploratory behaviors, possibly as a result of the increased synaptic inhibition. Thus, as opposed to previous studies indicating that ELKS2alpha is essential for mediating neurotransmitter release, our results suggest that ELKS2alpha normally restricts release and limits the size of the readily-releasable pool of synaptic vesicles at the active zone of inhibitory synapses.
- Published
- 2009
- Full Text
- View/download PDF
20. Age-dependent impairment of cognitive and synaptic function in the htau mouse model of tau pathology.
- Author
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Polydoro M, Acker CM, Duff K, Castillo PE, and Davies P
- Subjects
- Age Factors, Analysis of Variance, Animals, Disease Models, Animal, Dual Specificity Phosphatase 2, Electric Stimulation methods, Excitatory Postsynaptic Potentials genetics, Exploratory Behavior physiology, Hippocampus cytology, In Vitro Techniques, Long-Term Potentiation physiology, Maze Learning physiology, Mice, Mice, Inbred C57BL, Mice, Knockout, Neuropsychological Tests, Pyramidal Cells physiopathology, Recognition, Psychology physiology, Synapses physiology, tau Proteins deficiency, Aging, Cognition Disorders etiology, Neurofibrillary Tangles pathology, Synapses pathology, Tauopathies complications, Tauopathies pathology
- Abstract
A hallmark feature of Alzheimer's disease pathology is the presence of neurofibrillary tangles (NFTs), which are intracellular aggregates of conformationally abnormal and hyperphosphorylated tau. The presence of NFTs in the forebrain is associated with impairments of cognitive function, supporting a central role for tau in dementia. The significance of the accumulation of NFTs for neuronal and cognitive function is still obscure. It is possible that NFTs disrupt synaptic transmission and plasticity, leading to memory deficits and cognitive malfunction. To elucidate the relationship between the development of tau pathology and synaptic and cognitive functions, we performed behavioral tests and electrophysiological experiments in the htau mouse. Here we report age-dependent cognitive and physiological impairments in htau mice that preceded neurodegeneration. Twelve-month-old htau mice with moderate tau pathology, but not 4-month-old mice with early-stage tau pathology, presented cognitive deficits in an object recognition memory task in which the visual recognition memory of a novel object was disrupted. Moreover, only 12-month-old htau mice exhibit spatial memory deficits, as indicated by the impaired performance in the Morris water maze. In addition, we report that basal synaptic transmission and induction of long-term potentiation with high-frequency stimulation, but not theta burst stimulation, is perturbed in hippocampal CA1 region of old but not young htau mice. Our results suggest that tau pathology may underlie an age-dependent learning impairment through disruption of synaptic function.
- Published
- 2009
- Full Text
- View/download PDF
21. Endocannabinoid signaling and long-term synaptic plasticity.
- Author
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Heifets BD and Castillo PE
- Subjects
- Animals, Humans, Long-Term Synaptic Depression physiology, Signal Transduction physiology, Synaptic Transmission physiology, Cannabinoid Receptor Modulators physiology, Endocannabinoids, Neuronal Plasticity physiology, Synapses physiology
- Abstract
Endocannabinoids (eCBs) are key activity-dependent signals regulating synaptic transmission throughout the central nervous system. Accordingly, eCBs are involved in neural functions ranging from feeding homeostasis to cognition. There is great interest in understanding how exogenous (e.g., cannabis) and endogenous cannabinoids affect behavior. Because behavioral adaptations are widely considered to rely on changes in synaptic strength, the prevalence of eCB-mediated long-term depression (eCB-LTD) at synapses throughout the brain merits close attention. The induction and expression of eCB-LTD, although remarkably similar at various synapses, are controlled by an array of regulatory influences that we are just beginning to uncover. This complexity endows eCB-LTD with important computational properties, such as coincidence detection and input specificity, critical for higher CNS functions like learning and memory. In this article, we review the major molecular and cellular mechanisms underlying eCB-LTD, as well as the potential physiological relevance of this widespread form of synaptic plasticity.
- Published
- 2009
- Full Text
- View/download PDF
22. Role of glutamate autoreceptors at hippocampal mossy fiber synapses.
- Author
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Kwon HB and Castillo PE
- Subjects
- Animals, Animals, Newborn, Biophysics, Calcium pharmacology, Cyclopropanes pharmacology, Electric Stimulation methods, Excitatory Amino Acid Agonists pharmacology, Excitatory Amino Acid Antagonists pharmacology, Excitatory Postsynaptic Potentials drug effects, Excitatory Postsynaptic Potentials genetics, Excitatory Postsynaptic Potentials physiology, Glycine analogs & derivatives, Glycine pharmacology, In Vitro Techniques, Kainic Acid pharmacology, Mice, Mice, Knockout, Patch-Clamp Techniques methods, Presynaptic Terminals physiology, Rats, Receptors, Glutamate deficiency, Sodium Channel Blockers pharmacology, Synapses drug effects, Tetrodotoxin pharmacology, Autoreceptors physiology, Hippocampus cytology, Mossy Fibers, Hippocampal physiology, Neurons physiology, Receptors, Glutamate physiology, Synapses physiology
- Abstract
Presynaptic autoreceptors modulate transmitter release at many synapses. At the mossy fiber to CA3 pyramidal cell (mf-CA3) synapse, two types of glutamatergic autoreceptors have been identified: transmitter release is reportedly suppressed by metabotropic glutamate receptors (mGluRs) and augmented by kainate receptors (KARs). However, the net effect of these autoreceptors when activated by endogenous glutamate is unknown. Here, we show that during low-frequency mossy fiber stimulation, glutamate acting through presynaptic mGluRs substantially suppresses transmitter release. However, using similar recording conditions, we find that presynaptic KARs are insufficient to facilitate transmitter release over a wide range of mossy fiber stimulus frequencies, indicating that the uniquely robust mf-CA3 short-term plasticity is KAR independent. Furthermore, we report that actions generally attributed to presynaptic KARs are likely due to activation of recurrent CA3 network activity. Thus, negative feedback via presynaptic mGluRs is the dominant mode of glutamatergic autoregulation at the mf-CA3 synapse.
- Published
- 2008
- Full Text
- View/download PDF
23. RIM1alpha and RIM1beta are synthesized from distinct promoters of the RIM1 gene to mediate differential but overlapping synaptic functions.
- Author
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Kaeser PS, Kwon HB, Chiu CQ, Deng L, Castillo PE, and Südhof TC
- Subjects
- Animals, Excitatory Postsynaptic Potentials physiology, Mice, Mice, Knockout, Neurotransmitter Agents metabolism, Organ Culture Techniques, Patch-Clamp Techniques, Presynaptic Terminals metabolism, Promoter Regions, Genetic, Protein Isoforms genetics, Protein Isoforms metabolism, Reverse Transcriptase Polymerase Chain Reaction, Synaptic Vesicles metabolism, GTP-Binding Proteins genetics, GTP-Binding Proteins metabolism, Hippocampus physiology, Neuronal Plasticity physiology, Synapses physiology, Synaptic Transmission physiology
- Abstract
At a synapse, presynaptic terminals form a specialized area of the plasma membrane called the active zone that mediates neurotransmitter release. RIM1alpha is a multidomain protein that constitutes a central component of the active zone by binding to other active zone proteins such as Munc13 s, alpha-liprins, and ELKS, and to synaptic vesicle proteins such as Rab3 and synaptotagmin-1. In mice, knockout of RIM1alpha significantly impairs synaptic vesicle priming and presynaptic long-term plasticity, but is not lethal. We now find that the RIM1 gene encodes a second, previously unknown RIM1 isoform called RIM1beta that is upregulated in RIM1alpha knock-out mice. RIM1beta is identical to RIM1alpha except for the N terminus where RIM1beta lacks the N-terminal Rab3-binding sequence of RIM1alpha. Using newly generated knock-out mice lacking both RIM1alpha and RIM1beta, we demonstrate that different from the deletion of only RIM1alpha, deletion of both RIM1alpha and RIM1beta severely impairs mouse survival. Electrophysiological analyses show that the RIM1alphabeta deletion abolishes long-term presynaptic plasticity, as does RIM1alpha deletion alone. In contrast, the impairment in synaptic strength and short-term synaptic plasticity that is caused by the RIM1alpha deletion is aggravated by the deletion of both RIM1alpha and RIM1beta. Thus, our data indicate that the RIM1 gene encodes two different isoforms that perform overlapping but distinct functions in neurotransmitter release.
- Published
- 2008
- Full Text
- View/download PDF
24. Protein kinase A regulates calcium permeability of NMDA receptors.
- Author
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Skeberdis VA, Chevaleyre V, Lau CG, Goldberg JH, Pettit DL, Suadicani SO, Lin Y, Bennett MV, Yuste R, Castillo PE, and Zukin RS
- Subjects
- Animals, Barium metabolism, Cell Membrane Permeability, Cells, Cultured, Cyclic AMP metabolism, Cyclic AMP-Dependent Protein Kinases antagonists & inhibitors, Hippocampus cytology, Humans, In Vitro Techniques, Long-Term Potentiation physiology, Neurons cytology, Rats, Rats, Sprague-Dawley, Signal Transduction physiology, Calcium metabolism, Cyclic AMP-Dependent Protein Kinases metabolism, Neurons metabolism, Receptors, N-Methyl-D-Aspartate metabolism, Synapses metabolism
- Abstract
Calcium (Ca2+) influx through NMDA receptors (NMDARs) is essential for synaptogenesis, experience-dependent synaptic remodeling and plasticity. The NMDAR-mediated rise in postsynaptic Ca2+ activates a network of kinases and phosphatases that promote persistent changes in synaptic strength, such as long-term potentiation (LTP). Here we show that the Ca2+ permeability of neuronal NMDARs is under the control of the cyclic AMP-protein kinase A (cAMP-PKA) signaling cascade. PKA blockers reduced the relative fractional Ca2+ influx through NMDARs as determined by reversal potential shift analysis and by a combination of electrical recording and Ca2+ influx measurements in rat hippocampal neurons in culture and hippocampal slices from mice. In slices, PKA blockers markedly inhibited NMDAR-mediated Ca2+ rises in activated dendritic spines, with no significant effect on synaptic current. Consistent with this, PKA blockers depressed the early phase of NMDAR-dependent LTP at hippocampal Schaffer collateral-CA1 (Sch-CA1) synapses. Our data link PKA-dependent synaptic plasticity to Ca2+ signaling in spines and thus provide a new mechanism whereby PKA regulates the induction of LTP.
- Published
- 2006
- Full Text
- View/download PDF
25. Endocannabinoid-mediated synaptic plasticity in the CNS.
- Author
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Chevaleyre V, Takahashi KA, and Castillo PE
- Subjects
- Animals, Models, Neurological, Neural Inhibition physiology, Receptors, Cannabinoid physiology, Synaptic Transmission physiology, Cannabinoid Receptor Modulators metabolism, Central Nervous System cytology, Central Nervous System physiology, Endocannabinoids, Neuronal Plasticity physiology, Synapses physiology
- Abstract
Changes in synaptic efficacy are thought to be crucial to experience-dependent modifications of neural function. The diversity of mechanisms underlying these changes is far greater than previously expected. In the last five years, a new class of use-dependent synaptic plasticity that requires retrograde signaling by endocannabinoids (eCB) and presynaptic CB1 receptor activation has been identified in several brain structures. eCB-mediated plasticity encompasses many forms of transient and long-lasting synaptic depression and is found at both excitatory and inhibitory synapses. In addition, eCBs can modify the inducibility of non-eCB-mediated forms of plasticity. Thus, the eCB system is emerging as a major player in synaptic plasticity. Given the wide distribution of CB1 receptors in the CNS, the list of brain structures and synapses expressing eCB-mediated plasticity is likely to expand.
- Published
- 2006
- Full Text
- View/download PDF
26. Double-knockout mice for alpha- and beta-synucleins: effect on synaptic functions.
- Author
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Chandra S, Fornai F, Kwon HB, Yazdani U, Atasoy D, Liu X, Hammer RE, Battaglia G, German DC, Castillo PE, and Südhof TC
- Subjects
- Animals, Base Sequence, Biological Transport, DNA Primers, Dopamine metabolism, Electrophysiology, Mice, Mice, Knockout, Nerve Tissue Proteins deficiency, Nerve Tissue Proteins genetics, Neurons cytology, Neurons ultrastructure, Synaptic Vesicles physiology, Synaptic Vesicles ultrastructure, Synucleins, alpha-Synuclein, beta-Synuclein, Corpus Striatum physiology, Hippocampus physiology, Nerve Tissue Proteins physiology, Neurons physiology, Synapses physiology
- Abstract
An abundant presynaptic protein, alpha-synuclein, is centrally involved in the pathogenesis of Parkinson's disease. However, conflicting data exist about the normal function of alpha-synuclein, possibly because alpha-synuclein is redundant with the very similar beta-synuclein. To investigate the functions of synucleins systematically, we have now generated single- and double-knockout (KO) mice that lack alpha- and/or beta-synuclein. We find that deletion of synucleins in mice does not impair basic brain functions or survival. We detected no significant changes in the ultrastructure of synuclein-deficient synapses, in short- or long-term synaptic plasticity, or in the pool size or replenishment of recycling synaptic vesicles. However, protein quantitations revealed that KO of synucleins caused selective changes in two small synaptic signaling proteins, complexins and 14-3-3 proteins. Moreover, we found that dopamine levels in the brains of double-KO but not single-KO mice were decreased by approximately 20%. In contrast, serotonin levels were unchanged, and dopamine uptake and release from isolated nerve terminals were normal. These results show that synucleins are not essential components of the basic machinery for neurotransmitter release but may contribute to the long-term regulation and/or maintenance of presynaptic function.
- Published
- 2004
- Full Text
- View/download PDF
27. A single in-vivo exposure to delta 9THC blocks endocannabinoid-mediated synaptic plasticity.
- Author
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Mato S, Chevaleyre V, Robbe D, Pazos A, Castillo PE, and Manzoni OJ
- Subjects
- Animals, Cannabinoid Receptor Modulators physiology, Dose-Response Relationship, Drug, Hippocampus drug effects, Hippocampus physiology, In Vitro Techniques, Mice, Neuronal Plasticity physiology, Nucleus Accumbens drug effects, Nucleus Accumbens physiology, Synapses physiology, Cannabinoid Receptor Modulators antagonists & inhibitors, Dronabinol administration & dosage, Endocannabinoids, Neuronal Plasticity drug effects, Synapses drug effects
- Abstract
Endogenous cannabinoids (eCB) mediate synaptic plasticity in brain regions involved in learning and reward. Here we show that in mice, a single in-vivo exposure to Delta 9-tetrahydrocannabinol (THC) abolishes the retrograde signaling that underlies eCB-mediated synaptic plasticity in both nucleus accumbens (NAc) and hippocampus in vitro. This effect is reversible within 3 days and is associated with a transient modification in the functional properties of cannabinoid receptors.
- Published
- 2004
- Full Text
- View/download PDF
28. Heterosynaptic LTD of hippocampal GABAergic synapses: a novel role of endocannabinoids in regulating excitability.
- Author
-
Chevaleyre V and Castillo PE
- Subjects
- Animals, Cannabinoid Receptor Modulators, Cannabinoids pharmacology, Chelating Agents pharmacology, Electric Stimulation, Endocannabinoids, Enzyme Inhibitors pharmacology, Excitatory Amino Acid Agonists pharmacology, Fatty Acids, Unsaturated agonists, Hippocampus cytology, Hippocampus drug effects, Long-Term Synaptic Depression drug effects, Methoxyhydroxyphenylglycol pharmacology, Neural Inhibition drug effects, Neural Inhibition physiology, Organ Culture Techniques, Presynaptic Terminals drug effects, Presynaptic Terminals metabolism, Pyramidal Cells cytology, Pyramidal Cells drug effects, Rats, Rats, Sprague-Dawley, Receptors, Cannabinoid, Receptors, Drug agonists, Receptors, Drug metabolism, Receptors, Metabotropic Glutamate drug effects, Synapses drug effects, Synaptic Transmission drug effects, Synaptic Transmission physiology, Fatty Acids, Unsaturated metabolism, Hippocampus metabolism, Long-Term Synaptic Depression physiology, Methoxyhydroxyphenylglycol analogs & derivatives, Pyramidal Cells metabolism, Receptors, Metabotropic Glutamate metabolism, Synapses metabolism, gamma-Aminobutyric Acid metabolism
- Abstract
Neuronal excitability and long-term synaptic plasticity at excitatory synapses are critically dependent on the level of inhibition, and accordingly, changes of inhibitory synaptic efficacy should have great impact on neuronal function and neural network processing. We describe here a form of activity-dependent long-term depression at hippocampal inhibitory synapses that is triggered postsynaptically via glutamate receptor activation but is expressed presynaptically. That is, glutamate released by repetitive activation of Schaffer collaterals activates group I metabotropic glutamate receptors at CA1 pyramidal cells, triggering a persistent reduction of GABA release that is mediated by endocannabinoids. This heterosynaptic form of plasticity is involved in changes of pyramidal cell excitability associated with long-term potentiation at excitatory synapses and could account for the effects of cannabinoids on learning and memory.
- Published
- 2003
- Full Text
- View/download PDF
29. Double-Knockout Mice for α- and β-Synucleins: Effect on Synaptic Functions
- Author
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Chandra, Sreeganga, Fornai, Francesco, Kwon, Hyung-Bae, Yazdani, Umar, Atasoy, Deniz, Liu, Xinran, Hammer, Robert E., Battaglia, Giuseppe, German, Dwight C., Castillo, Pablo E., and Südhof, Thomas C.
- Published
- 2004
30. Assessing the Role of Ih Channels in Synaptic Transmission and Mossy Fiber LTP
- Author
-
Chevaleyre, Vivien and Castillo, Pablo E.
- Published
- 2002
31. Presenilin-ryanodine receptor connection
- Author
-
D'Adamio, Luciano and Castillo, Pablo E.
- Published
- 2013
32. Piccolo and bassoon maintain synaptic vesicle clustering without directly participating in vesicle exocytosis
- Author
-
Mukherjee, Konark, Yang, Xiaofei, Gerber, Stefan H., Kwon, Hyung-Bae, Ho, Angela, Castillo, Pablo E., Liu, Xinran, and Südhof, Thomas C.
- Published
- 2010
33. RIM1α Phosphorylation at Serine-413 by Protein Kinase A Is Not Required for Presynaptic Long-Term Plasticity or Learning
- Author
-
Kaeser, Pascal S., Kwon, Hyung-Bae, Blundell, Jacqueline, Chevaleyre, Vivien, Morishita, Wade, Malenka, Robert C., Powell, Craig M., Castillo, Pablo E., and Südhof, Thomas C.
- Published
- 2008
- Full Text
- View/download PDF
34. Interneuron Activity Controls Endocannabinoid-Mediated Presynaptic Plasticity through Calcineurin
- Author
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Heifets, Boris D., Chevaleyre, Vivien, and Castillo, Pablo E.
- Published
- 2008
- Full Text
- View/download PDF
35. Mediation of Hippocampal Mossy Fiber Long-Term Potentiation by Cyclic AMP
- Author
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Weisskopf, Marc G., Castillo, Pablo E., Zalutsky, Robert A., and Nicoll, Roger A.
- Published
- 1994
36. REST-dependent epigenetic remodeling promotes the in vivo developmental switch in NMDA receptors
- Author
-
Rodenas-Ruano, Alma, Chávez, Andrés E., Cossio, Maria J., Castillo, Pablo E., and Zukin, R. Suzanne
- Subjects
Repressor Proteins ,Phenotype ,nervous system ,Gene Knockdown Techniques ,Maternal Deprivation ,Synapses ,Animals ,Epigenetic Repression ,Hippocampus ,Receptors, N-Methyl-D-Aspartate ,Article ,Rats - Abstract
N-methyl-D-aspartate receptors (NMDARs) are critical to synaptogenesis, neural circuitry and higher cognitive functions such as learning and memory. A hallmark feature of NMDARs is an early postnatal developmental switch from primarily GluN2B- to GluN2A-containing. Although the switch in phenotype has been an area of intense interest for two decades, the mechanisms that trigger it, and the link between experience and the switch are unclear. Here we show a novel role for the transcriptional repressor REST in the developmental switch of synaptic NMDARs. REST is activated at a critical window of time and acts via epigenetic remodeling to repress grin2b expression and properties at rat hippocampal synapses. Knockdown of REST in vivo prevented the decline in GluN2B and developmental switch in NMDARs. Notably, maternal deprivation impaired REST activation and acquisition of the mature NMDAR phenotype. Thus, REST is essential for experience-dependent fine-tuning of genes involved in synaptic plasticity.
- Published
- 2012
37. Neto1 and Neto2: auxiliary subunits that determine key properties of native kainate receptors
- Author
-
Tomita, Susumu and Castillo, Pablo E
- Subjects
Lipoproteins, LDL ,Protein Subunits ,Symposium Section Reviews: Synaptic Mechanisms in the CNS ,Receptors, Kainic Acid ,Synapses ,Animals ,Membrane Proteins ,Receptors, N-Methyl-D-Aspartate ,LDL-Receptor Related Proteins - Abstract
Kainate receptors (KARs) are a subfamily of ionotropic glutamate receptors (iGluRs) that mediate excitatory synaptic transmission, regulate neurotransmitter release, and show a remarkably selective distribution in the brain. Compared to other iGluRs, the precise contribution of KARs to brain function is less understood. Unlike recombinant KARs, native KARs exhibit characteristically slow channel kinetics. The underlying explanation for this dissimilar kinetics has remained elusive until recently. New research has identified Neto1 and Neto2 as KAR auxiliary subunits that determine unique properties of synaptic KARs, including their slow kinetics and high affinity for agonist. Whether these auxiliary subunits regulate KAR trafficking and targeting at the synapse is less clear. By regulating channel gating, Neto1 and Neto2 can increase the diversity of KAR functional properties. These auxiliary subunits may represent a starting point for a better understanding of the role played by neuronal KARs under normal and pathological conditions, but also, they may provide an alternative target for the development of new drugs regulating KARs and brain function.
- Published
- 2012
38. Endocannabinoid Signaling and Synaptic Function
- Author
-
Castillo, Pablo E., Younts, Thomas J., Chávez, Andrés E., and Hashimotodani, Yuki
- Subjects
- *
CELLULAR signal transduction , *CANNABINOID receptors , *SYNAPSES , *CENTRAL nervous system physiology , *NEUROPLASTICITY , *NEURAL physiology - Abstract
Endocannabinoids are key modulators of synaptic function. By activating cannabinoid receptors expressed in the central nervous system, these lipid messengers can regulate several neural functions and behaviors. As experimental tools advance, the repertoire of known endocannabinoid-mediated effects at the synapse, and their underlying mechanism, continues to expand. Retrograde signaling is the principal mode by which endocannabinoids mediate short- and long-term forms of plasticity at both excitatory and inhibitory synapses. However, growing evidence suggests that endocannabinoids can also signal in a nonretrograde manner. In addition to mediating synaptic plasticity, the endocannabinoid system is itself subject to plastic changes. Multiple points of interaction with other neuromodulatory and signaling systems have now been identified. In this Review, we focus on new advances in synaptic endocannabinoid signaling in the mammalian brain. The emerging picture not only reinforces endocannabinoids as potent regulators of synaptic function but also reveals that endocannabinoid signaling is mechanistically more complex and diverse than originally thought. [Copyright &y& Elsevier]
- Published
- 2012
- Full Text
- View/download PDF
39. Distinct functions of kainate receptors in the brain are determined by the auxiliary subunit Neto1.
- Author
-
Straub, Christoph, Hunt, David L., Yamasaki, Miwako, Kim, Kwang S., Watanabe, Masahiko, Castillo, Pablo E., and Tomita, Susumu
- Subjects
GLUTAMIC acid ,NEURAL transmission ,SYNAPSES ,HIPPOCAMPUS (Brain) ,BRAIN - Abstract
Ionotropic glutamate receptors principally mediate fast excitatory transmission in the brain. Among the three classes of ionotropic glutamate receptors, kainate receptors (KARs) have a unique brain distribution, which has been historically defined by
3 H-radiolabeled kainate binding. Compared with recombinant KARs expressed in heterologous cells, synaptic KARs exhibit characteristically slow rise-time and decay kinetics. However, the mechanisms responsible for these distinct KAR properties remain unclear. We found that both the high-affinity binding pattern in the mouse brain and the channel properties of native KARs are determined by the KAR auxiliary subunit Neto1. Through modulation of agonist binding affinity and off-kinetics of KARs, but not trafficking of KARs, Neto1 determined both the KAR high-affinity binding pattern and the distinctively slow kinetics of postsynaptic KARs. By regulating KAR excitatory postsynaptic current kinetics, Neto1 can control synaptic temporal summation, spike generation and fidelity. [ABSTRACT FROM AUTHOR]- Published
- 2011
- Full Text
- View/download PDF
40. The extent and strength of electrical coupling between inferior olivary neurons is heterogeneous.
- Author
-
Hoge, Gregory J., Davidson, Kimberly G. V., Yasumura, Thomas, Castillo, Pablo E., Rash, John E., and Pereda, Alberto E.
- Subjects
OLIVARY nucleus ,GAP junctions (Cell biology) ,CEREBELLAR cortex ,ELECTROPHYSIOLOGY ,NEURONS ,SYNAPSES - Abstract
Gap junctions constitute the only form of synaptic communication between neurons in the inferior olive (IO), which gives rise to the climbing fibers innervating the cerebellar cortex. Although its exact functional role remains undetermined, electrical coupling was shown to be necessary for the transient formation of functional compartments of IO neurons and to underlie the precise timing of climbing fibers required for cerebellar learning. So far, most functional considerations assume the existence of a network of permanently and homogeneously coupled IO neurons. Contrasting this notion, our results indicate that coupling within the IO is highly variable. By combining tracer-coupling analysis and paired electrophysiological recordings, we found that individual IO neurons could be coupled to a highly variable number of neighboring neurons. Furthermore, a given neuron could be coupled at remarkably different strengths with each of its partners. Freeze-fracture analysis of IO glomeruli revealed the close proximity of glutamatergic postsynaptic densities to connexin 36-containing gap junctions, at distances comparable to separations between chemical transmitting domains and gap junctions in goldfish mixed contacts, where electrical coupling was shown to be modulated by the activity of glutamatergic synapses. On the basis of structural and molecular similarities with goldfish mixed synapses, we speculate that, rather than being hardwired, variations in coupling could result from glomerulus-specific long-term modulation of gap junctions. This striking heterogeneity of coupling might act to finely influence the synchronization of IO neurons, adding an unexpected degree of complexity to olivary networks. [ABSTRACT FROM AUTHOR]
- Published
- 2011
- Full Text
- View/download PDF
41. TRPV1 activation by endogenous anandamide triggers postsynaptic long-term depression in dentate gyrus.
- Author
-
Chávez, Andrés E, Chiu, Chiayu Q., and Castillo, Pablo E.
- Subjects
DENTATE gyrus ,SENSORY neurons ,PERIPHERAL nervous system ,NEUROTRANSMITTERS ,CANNABINOIDS ,SYNAPSES - Abstract
The transient receptor potential TRPV1 is a nonselective cation channel that mediates pain sensations and is commonly activated by a wide variety of exogenous and endogenous, physical and chemical stimuli. Although TRPV1 receptors are mainly found in nociceptive neurons of the peripheral nervous system, these receptors have also been found in the brain, where their role is far less understood. Activation of TRPV1 reportedly regulates neurotransmitter release at several central synapses. However, we found that TRPV1 suppressed excitatory transmission in rat and mouse dentate gyrus by regulating postsynaptic function in an input-specific manner. This suppression was a result of Ca
2+ -calcineurin and clathrin-dependent internalization of AMPA receptors. Moreover, synaptic activation of TRPV1 triggered a form of long-term depression (TRPV1-LTD) mediated by the endocannabinoid anandamide in a type 1 cannabinoid receptor-independent manner. Thus, our findings reveal a previously unknown form of endocannabinoid- and TRPV1-mediated regulation of synaptic strength at central synapses. [ABSTRACT FROM AUTHOR]- Published
- 2010
- Full Text
- View/download PDF
42. Dopaminergic Modulation of Endocannabinoid-Mediated Plasticity at GABAergic Synapses in the Prefrontal Cortex.
- Author
-
Chiu, Chiayu Q., Puente, Nagore, Grandes, Pedro, and Castillo, Pablo E.
- Subjects
DOPAMINE ,NEUROPLASTICITY ,SYNAPSES ,CANNABINOIDS ,NEUROTRANSMITTERS - Abstract
Similar to dopamine (DA), cannabinoids strongly influence prefrontal cortical functions, such as working memory, emotional learning, and sensory perception. Although endogenous cannabinoid receptors (CB
1 Rs) are abundantly expressed in the prefrontal cortex (PFC), very little is known about endocannabinoid (eCB) signaling in this brain region. Recent behavioral and electrophysiological evidence has suggested a functional interplay between the dopamine and cannabinoid receptor systems, although the cellular mechanisms underlying this interaction remain to be elucidated. We examined this issue by combining neuroanatomical and electrophysiological techniques in PFC of rats and mice (both genders). Using immunoelectron microscopy, we show that CB1 Rs and dopamine type 2 receptors (D2 Rs) colocalize at terminals of symmetrical, presumably GABAergic, synapses in the PFC. Indeed, activation of either receptor can suppress GABA release onto layer 5 pyramidal cells. Furthermore, coactivation of both receptors via repetitive afferent stimulation triggers eCB-mediated long-term depression of inhibitory transmission (I-LTD). This I-LTD is heterosynaptic in nature, requiring glutamate release to activate group I metabotropic glutamate receptors.D2Rs most likely facilitate eCB signaling at the presynaptic site as disrupting postsynaptic D2 R signaling does not diminish I-LTD. Facilitation of eCB--LTD may be one mechanism by which DA modulates neuronal activity in the PFC and regulates PFC-mediated behavior in vivo. [ABSTRACT FROM AUTHOR]- Published
- 2010
- Full Text
- View/download PDF
43. Long-Term Potentiation Selectively Expressed by NMDA Receptors at Hippocampal Mossy Fiber Synapses
- Author
-
Kwon, Hyung-Bae and Castillo, Pablo E.
- Subjects
- *
NEURAL transmission , *SYNAPSES , *HIPPOCAMPUS (Brain) , *NEURONS - Abstract
Summary: The mossy fiber to CA3 pyramidal cell synapse (mf-CA3) provides a major source of excitation to the hippocampus. Thus far, these glutamatergic synapses are well recognized for showing a presynaptic, NMDA receptor-independent form of LTP that is expressed as a long-lasting increase of transmitter release. Here, we show that in addition to this “classical” LTP, mf-CA3 synapses can undergo a form of LTP characterized by a selective enhancement of NMDA receptor-mediated transmission. This potentiation requires coactivation of NMDA and mGlu5 receptors and a postsynaptic calcium rise. Unlike classical LTP, expression of this mossy fiber LTP is due to a PKC-dependent recruitment of NMDA receptors specifically to the mf-CA3 synapse via a SNARE-dependent process. Having two mechanistically different forms of LTP may allow mf-CA3 synapses to respond with more flexibility to the changing demands of the hippocampal network. [Copyright &y& Elsevier]
- Published
- 2008
- Full Text
- View/download PDF
44. Input-specific plasticity at excitatory synapses mediated by endocannabinoids in the dentate gyrus
- Author
-
Chiu, Chiayu Q. and Castillo, Pablo E.
- Subjects
- *
NEURAL transmission , *NEURAL circuitry , *SYNAPSES , *NERVE endings - Abstract
Abstract: Endocannabinoids (eCBs) mediate transient and long-lasting synaptic plasticity in several brain structures. In the dentate gyrus, activation of the type 1 cannabinoid receptor (CB1R) by exogenous ligands reportedly depresses excitatory synaptic transmission. However, direct evidence of eCB signaling at excitatory synapses in this region has been lacking. Here, we demonstrate that eCB release can be induced by a brief postsynaptic depolarization of dentate granule cells (DGCs), which potently and transiently suppresses glutamatergic inputs from mossy cell interneurons (MCs) but not from entorhinal cortex via the lateral and medial perforant paths. This input-specific depolarization-induced suppression of excitation (DSE) is calcium-dependent and can be modulated by agonists of cholinergic and group I metabotropic glutamate receptors. Inhibiting the synthesis of 2-arachidonoyl glycerol (2-AG), one of the most abundant eCBs in the brain, by diacyglycerol lipase (DGL) does not abolish DSE. Moreover, preventing the breakdown of anandamide, the other main eCB, does not potentiate DSE. Thus, eCB signaling underlying DSE in the dentate does not require DGL activity and is unlikely to be mediated by anandamide. Finally, we find that manipulations known to induce eCB-LTD at other central synapses do not trigger LTD at MCF-DGC synapses. [Copyright &y& Elsevier]
- Published
- 2008
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45. Redundant functions of RIM1α and RIM2α in Ca2+-triggered neurotransmitter release.
- Author
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Schoch, Susanne, Mittelstaedt, Tobias, Kaeser, Pascal S., Padgett, Daniel, Feldmann, Nicole, Chevaleyre, Vivien, Castillo, Pablo E., Hammer, Robert E., Weiping Han, Schmitz, Frank, Weichun Lin, and Südhof, Thomas C.
- Subjects
NEUROSCIENCES ,NEUROTRANSMITTERS ,SYNAPSES ,NERVE endings ,NEUROPLASTICITY ,PROTEINS - Abstract
α-RIMs (RIM1α and RIM2α) are multidomain active zone proteins of presynaptic terminals. α-RIMs bind to Rab3 on synaptic vesicles and to Munc13 on the active zone via their N-terminal region, and interact with other synaptic proteins via their central and C-terminal regions. Although RIM1α has been well characterized, nothing is known about the function of RIM2α. We now show that RIM1α and RIM2α are expressed in overlapping but distinct patterns throughout the brain. To examine and compare their functions, we generated knockout mice lacking RIM2α, and crossed them with previously produced RIM1α knockout mice. We found that deletion of either RIM1α or RIM2α is not lethal, but ablation of both α-RIMs causes postnatal death. This lethality is not due to a loss of synapse structure or a developmental change, but to a defect in neurotransmitter release. Synapses without α-RIMs still contain active zones and release neurotransmitters, but are unable to mediate normal Ca
2+ -triggered release. Our data thus demonstrate that α-RIMs are not essential for synapse formation or synaptic exocytosis, but are required for normal Ca2+ -triggering of exocytosis. [ABSTRACT FROM AUTHOR]- Published
- 2006
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46. Blockade of calcium-permeable AMPA receptors protects hippocampal neurons against global ischemia-induced death.
- Author
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Kyung-Min Noh, Yokota, Hidenori, Mashiko, Toshihiro, Castillo, Pablo E., Zukin, R. Suzanne, and Bennett, Michael V. L.
- Subjects
HIPPOCAMPUS (Brain) ,CEREBRAL cortex ,ISCHEMIA ,NERVOUS system ,CELL death ,SYNAPSES - Abstract
Transient global or forebrain ischemia induced experimentally in animals can cause selective, delayed neuronal death of hippocampal CA1 pyramidal neurons. A striking feature is a delayed rise in intracellular free Zn
2+ in CA1 neurons just before the onset of histologically detectable cell death. Here we show that a-amino- 3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)-type glutamate receptors (AMPARs) at Schaffer collateral to CA1 synapses in postischemic hippocampus exhibit properties of Ca2+ /Zn2+ -permeable, Glu receptor 2 (GluR2)-lacking AMPARs before the rise in Zn2+ and cell death. At 42 h after ischemia, AMPA excitatory postsynaptic currents exhibited pronounced inward rectification and marked sensitivity to 1-naphthyl acetyl spermine (Naspm), a selective channel blocker of GluR2-lacking AMPARs. In control hippocampus, AMPA excitatory postsynaptic currents were electrically linear and relatively insensitive to Naspm. Naspm injected intrahippocampally at 9-40 h after insult greatly reduced the late rise in intracellular free Zn2+ in postischemic CA1 neurons and afforded partial protection against ischemia-induced cell death. These results implicate GluR2-lacking AMPA receptors in the ischemia-induced rise in free Zn2+ and death of CA1 neurons, although a direct action at the time of the rise in Zn2+ is unproven. This receptor subtype appears to be an important therapeutic target for intervention in ischemia-induced neuronal death in humans. [ABSTRACT FROM AUTHOR]- Published
- 2005
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47. Endocannabinoid-Mediated Metaplasticity in the Hippocampus
- Author
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Chevaleyre, Vivien and Castillo, Pablo E.
- Subjects
- *
SYNAPSES , *FIBERS , *NEURAL transmission , *HIPPOCAMPUS (Brain) - Abstract
Repetitive activation of glutamatergic fibers that normally induces long-term potentiation (LTP) at excitatory synapses in the hippocampus also triggers long-term depression at inhibitory synapses (I-LTD) via retrograde endocannabinoid signaling. Little is known, however, about the physiological significance of I-LTD. Here, we show that synaptic-driven release of endocannabinoids is a highly localized and efficient process that strongly depresses cannabinoid-sensitive inhibitory inputs within the dendritic compartment of CA1 pyramidal cells. By removing synaptic inhibition in a restricted area of the dendritic tree, endocannabinoids selectively “primed” nearby excitatory synapses, thereby facilitating subsequent induction of LTP. This induction of local metaplasticity is a novel mechanism by which endocannabinoids can contribute to the storage of information in the brain. [Copyright &y& Elsevier]
- Published
- 2004
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48. A single in-vivo exposure to ?9THC blocks endocannabinoid-mediated synaptic plasticity.
- Author
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Mato, Susana, Chevaleyre, Vivien, Robbe, David, Pazos, Angel, Castillo, Pablo E., and Manzoni, Olivier J.
- Subjects
CANNABINOIDS ,NEUROPLASTICITY ,ANIMAL models in research ,COGNITIVE learning ,REWARD (Psychology) ,SYNAPSES ,NEURAL transmission ,LIMBIC system - Abstract
Endogenous cannabinoids (eCB) mediate synaptic plasticity in brain regions involved in learning and reward. Here we show that in mice, a single in-vivo exposure to ?9-tetrahydrocannabinol (THC) abolishes the retrograde signaling that underlies eCB-mediated synaptic plasticity in both nucleus accumbens (NAc) and hippocampus in vitro. This effect is reversible within 3 days and is associated with a transient modification in the functional properties of cannabinoid receptors. [ABSTRACT FROM AUTHOR]
- Published
- 2004
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