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Developmental and epileptic encephalopathies (DEEs), a class of devastating neurological disorders characterized by recurrent seizures and exacerbated by disruptions to excitatory/inhibitory balance in the brain, are commonly caused by mutations in ion channels. Disruption of, or variants in, FGF13 were implicated as causal for a set of DEEs, but the underlying mechanisms were clouded because FGF13 is expressed in both excitatory and inhibitory neurons, FGF13 undergoes extensive alternative splicing producing multiple isoforms with distinct functions, and the overall roles of FGF13 in neurons are incompletely cataloged. To overcome these challenges, we generated a set of novel cell-type-specific conditional knockout mice. Interneuron-targeted deletion of Fgf13 led to perinatal mortality associated with extensive seizures and impaired the hippocampal inhibitory/excitatory balance while excitatory neuron-targeted deletion of Fgf13 caused no detectable seizures and no survival deficits. While best studied as a voltage-gated sodium channel (Nav) regulator, we observed no effect of Fgf13 ablation in interneurons on Navs but rather a marked reduction in K+ channel currents. Re-expressing different Fgf13 splice isoforms could partially rescue deficits in interneuron excitability and restore K+ channel current amplitude. These results enhance our understanding of the molecular mechanisms that drive the pathogenesis of Fgf13-related seizures and expand our understanding of FGF13 functions in different neuron subsets.

We provide a brief (and unabashedly biased) overview of the pre-transcriptomic history of somatostatin interneuron taxonomy, followed by a chronological summary of the large-scale, NIH-supported effort over the last ten years to generate a comprehensive, single-cell RNA-seq-based taxonomy of cortical neurons. Focusing on somatostatin interneurons, we present the perspective of experimental neuroscientists trying to incorporate the new classification schemes into their own research while struggling to keep up with the ever-increasing number of proposed cell types, which seems to double every two years. We suggest that for experimental analysis, the most useful taxonomic level is the subdivision of somatostatin interneurons into ten or so "supertypes," which closely agrees with their more traditional classification by morphological, electrophysiological and neurochemical features. We argue that finer subdivisions ("t-types" or "clusters"), based on slight variations in gene expression profiles but lacking clear phenotypic differences, are less useful to researchers and may actually defeat the purpose of classifying neurons to begin with. We end by stressing the need for generating novel tools (mouse lines, viral vectors) for genetically targeting distinct supertypes for expression of fluorescent reporters, calcium sensors and excitatory or inhibitory opsins, allowing neuroscientists to chart the input and output synaptic connections of each proposed subtype, reveal the position they occupy in the cortical network and examine experimentally their roles in sensorimotor behaviors and cognitive brain functions. [ABSTRACT FROM AUTHOR]

Motor learning is crucial for the survival of many animals. Acquiring a new motor skill involves complex alterations in both local neural circuits in many brain regions and long-range connections between them. Such changes can be observed anatomically and functionally. The primary motor cortex (M1) integrates information from diverse brain regions and plays a pivotal role in the acquisition and refinement of new motor skills. In this review, we discuss how motor learning affects the M1 at synaptic, cellular, and circuit levels. Wherever applicable, we attempt to relate and compare findings in humans, non-human primates, and rodents. Understanding the underlying principles shared by different species will deepen our understanding of the neurobiological and computational basis of motor learning.

We provide a brief (and unabashedly biased) overview of the pre-transcriptomic history of somatostatin interneuron taxonomy, followed by a chronological summary of the large-scale, NIH-supported effort over the last ten years to generate a comprehensive, single-cell RNA-seq-based taxonomy of cortical neurons. Focusing on somatostatin interneurons, we present the perspective of experimental neuroscientists trying to incorporate the new classification schemes into their own research while struggling to keep up with the ever-increasing number of proposed cell types, which seems to double every two years. We suggest that for experimental analysis, the most useful taxonomic level is the subdivision of somatostatin interneurons into ten or so “supertypes,” which closely agrees with their more traditional classification by morphological, electrophysiological and neurochemical features. We argue that finer subdivisions (“t-types” or “clusters”), based on slight variations in gene expression profiles but lacking clear phenotypic differences, are less useful to researchers and may actually defeat the purpose of classifying neurons to begin with. We end by stressing the need for generating novel tools (mouse lines, viral vectors) for genetically targeting distinct supertypes for expression of fluorescent reporters, calcium sensors and excitatory or inhibitory opsins, allowing neuroscientists to chart the input and output synaptic connections of each proposed subtype, reveal the position they occupy in the cortical network and examine experimentally their roles in sensorimotor behaviors and cognitive brain functions.

This brief review summarizes presentations at the Temporal Lobe Club Special Interest Group session held in December 2022 at the American Epilepsy Society meeting. The session addressed newer methods to treat temporal epilepsy, including methods currently in clinical use and techniques under investigation. Brief summaries are provided for each of 4 lectures. Dr Chengyuan Wu discussed ablative techniques such as laser interstitial thermal ablation, radiofrequency ablation, focused ultrasound; Dr Joon Kang reviewed neuromodulation techniques including electrical stimulation and focused ultrasound; Dr Julia Makhalova discussed network effects of the aforementioned techniques; and Dr Derek Southwell reviewed inhibitory interneuron transplantation. These summaries are intended to provide a brief overview and references are provided for the reader to learn more about each topic. [ABSTRACT FROM AUTHOR]

Layer 1 (L1) of the neocortex acts as a nexus for the collection and processing of widespread information. By integrating ascending inputs with extensive top-down activity, this layer likely provides critical information regulating how the perception of sensory inputs is reconciled with expectation. This is accomplished by sorting, directing, and integrating the complex network of excitatory inputs that converge onto L1. These signals are combined with neuromodulatory afferents and gated by the wealth of inhibitory interneurons that either are embedded within L1 or send axons from other cortical layers. Together, these interactions dynamically calibrate information flow throughout the neocortex. This review will primarily focus on L1 within the primary sensory cortex and will use these insights to understand L1 in other cortical areas. Huang et al. present a review of the structure, connectivity, and function of neocortex's layer 1, highlighting its critical role in gating and integrating diverse signals. [ABSTRACT FROM AUTHOR]

Motor learning is crucial for the survival of many animals. Acquiring a new motor skill involves complex alterations in both local neural circuits in many brain regions and long-range connections between them. Such changes can be observed anatomically and functionally. The primary motor cortex (M1) integrates information from diverse brain regions and plays a pivotal role in the acquisition and refinement of new motor skills. In this review, we discuss how motor learning affects the M1 at synaptic, cellular, and circuit levels. Wherever applicable, we attempt to relate and compare findings in humans, non-human primates, and rodents. Understanding the underlying principles shared by different species will deepen our understanding of the neurobiological and computational basis of motor learning. [ABSTRACT FROM AUTHOR]

Nicotinic acetylcholine receptors (nAChRs) play crucial roles in various human disorders, with the α7, α4, α6, and α3-containing nAChR subtypes extensively studied in relation to conditions such as Alzheimer's disease, Parkinson's disease, nicotine dependence, mood disorders, and stress disorders. In contrast, the α2-nAChR subunit has received less attention due to its more restricted expression and the scarcity of specific agonists and antagonists for studying its function. Nevertheless, recent research has shed light on the unique expression pattern of the Chrna2 gene, which encodes the α2-nAChR subunit, and its involvement in distinct populations of inhibitory interneurons. This review highlights the structure, pharmacology, localization, function, and disease associations of α2-containing nAChRs and points to the unique expression pattern of the Chrna2 gene and its role in different inhibitory interneuron populations. These populations, including the oriens lacunosum moleculare (OLM) cells in the hippocampus, Martinotti cells in the neocortex, and Renshaw cells in the spinal cord, share common features and contribute to recurrent inhibitory microcircuits. Thus, the α2-nAChR subunit's unique expression pattern in specific interneuron populations and its role in recurrent inhibitory microcircuits highlight its importance in various physiological processes. Further research is necessary to uncover the comprehensive functionality of α2-containing nAChRs, delineate their specific contributions to neuronal circuits, and investigate their potential as therapeutic targets for related disorders.

Opioids regulate circuits associated with motivation and reward across the brain. Of the opioid receptor types, delta opioid receptors (DORs) appear to have a unique role in regulating the activity of circuits related to reward without liability for abuse. In neocortex, DORs are expressed primarily in interneurons, including parvalbumin- and somatostatin-expressing interneurons that inhibit somatic and dendritic compartments of excitatory pyramidal cells, respectively. But how DORs regulate transmission from these key interneuron classes is unclear. We found that DORs regulate inhibition from these interneuron classes using different G-protein signaling pathways that both converge on presynaptic calcium channels but regulate distinct aspects of calcium channel function. This imposes different temporal filtering effects, via short-term plasticity, that depend on how calcium channels are regulated. Thus, DORs engage differential signaling cascades to regulate inhibition depending on the postsynaptic target compartment, with different effects on synaptic information transfer in somatic and dendritic domains., Competing Interests: Declaration of interests K.J.B. is on the scientific advisory board (SAB) for Regel Tx and receives research support from Regel Tx and BioMarin Pharmaceutical for projects not related to this work., (Copyright © 2025 The Authors. Published by Elsevier Inc. All rights reserved.)

During neuronal synaptic transmission, the exocytotic release of neurotransmitters from synaptic vesicles in the presynaptic neuron evokes a change in conductance for one or more types of ligand-gated ion channels in the postsynaptic neuron. The standard method of investigation uses electrophysiological recordings of the postsynaptic response. However, electrophysiological recordings can directly quantify the presynaptic release of neurotransmitters with high temporal resolution by measuring the membrane capacitance before and after exocytosis, as fusion of the membrane of presynaptic vesicles with the plasma membrane increases the total capacitance. While the standard technique for capacitance measurement assumes that the presynaptic cell is unbranched and can be represented as a simple resistance-capacitance (RC) circuit, neuronal exocytosis typically occurs at a distance from the soma. Even in such cases, however, it can be possible to detect a depolarization-evoked increase in capacitance. Here, we provide a detailed, step-by-step protocol that describes how "Sine + DC" (direct current) capacitance measurements can quantify the exocytotic release of neurotransmitters from AII amacrine cells in rat retinal slices. The AII is an important inhibitory interneuron of the mammalian retina that plays an important role in integrating rod and cone pathway signals. AII amacrines release glycine from their presynaptic dendrites, and capacitance measurements have been important for understanding the release properties of these dendrites. When the goal is to directly quantify the presynaptic release, there is currently no other competing method available. This protocol includes procedures for measuring depolarization-evoked exocytosis, using both standard square-wave pulses, arbitrary stimulus waveforms, and synaptic input. Key features • Quantification of exocytosis with the Sine + DC technique for visually targeted AII amacrines in retinal slices, using voltage-clamp and whole-cell patch-clamp recording. • Because exocytosis occurs away from the somatic recording electrode, the sine wave frequency must be lower than for the standard Sine + DC technique. • Because AII amacrines are electrically coupled, the sine wave frequency must be sufficiently high to avoid interference from other cells in the electrically coupled network. • The protocol includes procedures for measuring depolarization-evoked exocytosis using standard square-wave pulses, stimulation with arbitrary and prerecorded stimulus waveforms, and activation of synaptic inputs., Competing Interests: Competing interestsThe authors declare no competing interests., (©Copyright : © 2025 The Authors; This is an open access article under the CC BY license.)

Amacrine cells, inhibitory interneurons of the retina, feature synaptic inputs and outputs in close proximity throughout their dendritic trees, making them notable exceptions to prototypical somato-dendritic integration with output transmitted via axonal action potentials. The extent of dendritic compartmentalization in amacrine cells with widely differing dendritic tree morphology, however, is largely unexplored. Combining compartmental modeling, dendritic Ca2+ imaging, targeted microiontophoresis and multielectrode patch-clamp recording (voltage and current clamp, capacitance measurement of exocytosis), we investigated integration in the AII amacrine cell, a narrow-field electrically coupled interneuron that participates in multiple, distinct microcircuits. Physiological experiments were performed with in vitro slices prepared from retinas of both male and female rats. We found that the morphology of the AII enables simultaneous local and global integration of inputs targeted to different dendritic regions. Local integration occurs within spatially restricted dendritic subunits and narrow time windows and is largely unaffected by the strength of electrical coupling. In contrast, global integration across the dendritic tree occurs over longer time periods and is markedly influenced by the strength of electrical coupling. These integrative properties enable AII amacrines to combine local control of synaptic plasticity with location-independent global integration. Dynamic inhibitory control of dendritic subunits is likely to be of general importance for amacrine cells, including cells with small dendritic trees, as well as for inhibitory interneurons in other regions of the CNS. [ABSTRACT FROM AUTHOR]

The prevalent use of antibiotics in pregnant women and neonates raises concerns about long-term risks for children's health, but their effects on the central nervous system is not well understood. We studied the effects of perinatal penicillin exposure (PPE) on brain structure and function in mice with a therapeutically relevant regimen. We used a battery of behavioral tests to evaluate anxiety, working memory, and sensory processing, and immunohistochemistry to quantify changes in parvalbumin-expressing inhibitory interneurons (PV+ INs), perineuronal nets (PNNs), as well as microglia density and morphology. In addition, we performed mesoscale calcium imaging to study neural activity and functional connectivity across cortical regions, and two-photon imaging to monitor dendritic spine and microglial dynamics. We found that adolescent PPE mice have abnormal sensory processing, including impaired texture discrimination and altered prepulse inhibition. Such behavioral changes are associated with increased spontaneous neural activities in various cortical regions, and delayed maturation of PV+ INs in the somatosensory cortex. Furthermore, adolescent PPE mice have elevated elimination of dendritic spines on the apical dendrites of layer 5 pyramidal neurons, as well as increased ramifications and spatial coverage of cortical microglia. Finally, while synaptic defects are transient during adolescence, behavioral abnormalities persist into adulthood. Our study demonstrates that early-life exposure to antibiotics affects cortical development, leaving a lasting effect on brain functions. [ABSTRACT FROM AUTHOR]

The prevalent use of antibiotics in pregnant women and neonates raises concerns about long-term risks for children’s health, but their effects on the central nervous system is not well understood. We studied the effects of perinatal penicillin exposure (PPE) on brain structure and function in mice with a therapeutically relevant regimen. We used a battery of behavioral tests to evaluate anxiety, working memory, and sensory processing, and immunohistochemistry to quantify changes in parvalbumin-expressing inhibitory interneurons (PV+ INs), perineuronal nets (PNNs), as well as microglia density and morphology. In addition, we performed mesoscale calcium imaging to study neural activity and functional connectivity across cortical regions, and two-photon imaging to monitor dendritic spine and microglial dynamics. We found that adolescent PPE mice have abnormal sensory processing, including impaired texture discrimination and altered prepulse inhibition. Such behavioral changes are associated with increased spontaneous neural activities in various cortical regions, and delayed maturation of PV+ INs in the somatosensory cortex. Furthermore, adolescent PPE mice have elevated elimination of dendritic spines on the apical dendrites of layer 5 pyramidal neurons, as well as increased ramifications and spatial coverage of cortical microglia. Finally, while synaptic defects are transient during adolescence, behavioral abnormalities persist into adulthood. Our study demonstrates that early-life exposure to antibiotics affects cortical development, leaving a lasting effect on brain functions.

The cerebral cortex contains numerous neuronal cell types, distinguished by their molecular identity as well as their electrophysiological and morphological properties. Cortical function is reliant on stereotyped patterns of synaptic connectivity and synaptic function among these neuron types, but how these patterns are established during development remains poorly understood. Selective targeting not only of different cell types but also of distinct postsynaptic neuronal domains occurs in many brain circuits and is directed by multiple mechanisms. These mechanisms include the regulation of axonal and dendritic guidance and fine-scale morphogenesis of pre- and postsynaptic processes, lineage relationships, activity dependent mechanisms and intercellular molecular determinants such as transmembrane and secreted molecules, many of which have also been implicated in neurodevelopmental disorders. However, many studies of synaptic targeting have focused on circuits in which neuronal processes target different lamina, such that cell-type-biased connectivity may be confounded with mechanisms of laminar specificity. In the cerebral cortex, each cortical layer contains cell bodies and processes from intermingled neuronal cell types, an arrangement that presents a challenge for the development of target-selective synapse formation. Here, we address progress and future directions in the study of cell-type-biased synaptic targeting in the cerebral cortex. We highlight challenges to identifying developmental mechanisms generating stereotyped patterns of intracortical connectivity, recent developments in uncovering the determinants of synaptic target selection during cortical synapse formation, and current gaps in the understanding of cortical synapse specificity.

The cerebral cortex contains numerous neuronal cell types, distinguished by their molecular identity as well as their electrophysiological and morphological properties. Cortical function is reliant on stereotyped patterns of synaptic connectivity and synaptic function among these neuron types, but how these patterns are established during development remains poorly understood. Selective targeting not only of different cell types but also of distinct postsynaptic neuronal domains occurs in many brain circuits and is directed by multiple mechanisms. These mechanisms include the regulation of axonal and dendritic guidance and fine-scale morphogenesis of pre- and postsynaptic processes, lineage relationships, activity dependent mechanisms and intercellular molecular determinants such as transmembrane and secreted molecules, many of which have also been implicated in neurodevelopmental disorders. However, many studies of synaptic targeting have focused on circuits in which neuronal processes target different lamina, such that cell-type-biased connectivity may be confounded with mechanisms of laminar specificity. In the cerebral cortex, each cortical layer contains cell bodies and processes from intermingled neuronal cell types, an arrangement that presents a challenge for the development of target-selective synapse formation. Here, we address progress and future directions in the study of cell-type-biased synaptic targeting in the cerebral cortex. We highlight challenges to identifying developmental mechanisms generating stereotyped patterns of intracortical connectivity, recent developments in uncovering the determinants of synaptic target selection during cortical synapse formation, and current gaps in the understanding of cortical synapse specificity. [ABSTRACT FROM AUTHOR]

Dynamic causal modeling (DCM) is a method for analyzing functional magnetic resonance imaging (fMRI) and other functional neuroimaging data that provides information about directionality of connectivity between brain regions. A review of the neuropsychiatric fMRI DCM literature suggests that there may be a historical trend to under-report self-connectivity (within brain regions) compared to between brain region connectivity findings. These findings are an integral part of the neurologic model represented by DCM and serve an important neurobiological function in regulating excitatory and inhibitory activity between regions. We reviewed the literature on the topic as well as the past 13 years of available neuropsychiatric DCM literature to find an increasing (but still, perhaps, and inadequate) trend in reporting these results. The focus of this review is fMRI as the majority of published DCM studies utilized fMRI and the interpretation of the self-connectivity findings may vary across imaging methodologies. About 25% of articles published between 2007 and 2019 made any mention of self-connectivity findings. We recommend increased attention toward the inclusion and interpretation of self-connectivity findings in DCM analyses in the neuropsychiatric literature, particularly in forthcoming effective connectivity studies of substance use disorders.

A distinctive feature of the hippocampal structure is the diversity of inhibitory interneurons. These complex inhibitory interconnections largely contribute to the tight modulation of hippocampal circuitry, as well as to the formation and coordination of neuronal assemblies underlying learning and memory. Inhibitory interneurons provide more than a simple transitory inhibition of hippocampal principal cells (PCs). The synaptic plasticity of inhibitory neurons provides long-lasting changes in the hippocampal network and is a key component of memory formation. The dendrite targeting interneurons expressing the peptide somatostatin (SOM) are particularly interesting in this regard because they display unique long-lasting synaptic changes leading to metaplastic regulation of hippocampal networks. In this article, we examine the actions of the neuropeptide SOM on hippocampal cells, synaptic plasticity, learning, and memory. We address the different subtypes of hippocampal SOM interneurons. We describe the long-term synaptic plasticity that takes place at the excitatory synapses of SOM interneurons, its singular induction and expression mechanisms, as well as the consequences of these changes on the hippocampal network, learning, and memory. We also review evidence that astrocytes provide cell-specific dynamic regulation of inhibition of PC dendrites by SOM interneurons. Finally, we cover how, in mouse models of Alzheimer’s disease (AD), dysfunction of plasticity of SOM interneuron excitatory synapses may also contribute to cognitive impairments in brain disorders.

Dynamic causal modeling (DCM) is a method for analyzing functional magnetic resonance imaging (fMRI) and other functional neuroimaging data that provides information about directionality of connectivity between brain regions. A review of the neuropsychiatric fMRI DCM literature suggests that there may be a historical trend to under-report self-connectivity (within brain regions) compared to between brain region connectivity findings. These findings are an integral part of the neurologic model represented by DCM and serve an important neurobiological function in regulating excitatory and inhibitory activity between regions. We reviewed the literature on the topic as well as the past 13 years of available neuropsychiatric DCM literature to find an increasing (but still, perhaps, and inadequate) trend in reporting these results. The focus of this review is fMRI as the majority of published DCM studies utilized fMRI and the interpretation of the self-connectivity findings may vary across imaging methodologies. About 25% of articles published between 2007 and 2019 made any mention of self-connectivity findings. We recommend increased attention toward the inclusion and interpretation of self-connectivity findings in DCM analyses in the neuropsychiatric literature, particularly in forthcoming effective connectivity studies of substance use disorders. [ABSTRACT FROM AUTHOR]

A distinctive feature of the hippocampal structure is the diversity of inhibitory interneurons. These complex inhibitory interconnections largely contribute to the tight modulation of hippocampal circuitry, as well as to the formation and coordination of neuronal assemblies underlying learning and memory. Inhibitory interneurons provide more than a simple transitory inhibition of hippocampal principal cells (PCs). The synaptic plasticity of inhibitory neurons provides long-lasting changes in the hippocampal network and is a key component of memory formation. The dendrite targeting interneurons expressing the peptide somatostatin (SOM) are particularly interesting in this regard because they display unique long-lasting synaptic changes leading to metaplastic regulation of hippocampal networks. In this article, we examine the actions of the neuropeptide SOM on hippocampal cells, synaptic plasticity, learning, and memory. We address the different subtypes of hippocampal SOM interneurons. We describe the long-term synaptic plasticity that takes place at the excitatory synapses of SOM interneurons, its singular induction and expression mechanisms, as well as the consequences of these changes on the hippocampal network, learning, and memory. We also review evidence that astrocytes provide cell-specific dynamic regulation of inhibition of PC dendrites by SOM interneurons. Finally, we cover how, in mouse models of Alzheimer's disease (AD), dysfunction of plasticity of SOM interneuron excitatory synapses may also contribute to cognitive impairments in brain disorders. [ABSTRACT FROM AUTHOR]

Synapse formation and regulation require signaling interactions between pre- and postsynaptic proteins, notably cell adhesion molecules (CAMs). It has been proposed that the functions of neuroligins (Nlgns), postsynaptic CAMs, rely on the formation of trans-synaptic complexes with neurexins (Nrxns), presynaptic CAMs. Nlgn3 is a unique Nlgn isoform that localizes at both excitatory and inhibitory synapses. However, Nlgn3 function mediated via Nrxn interactions is unknown. Here we demonstrate that Nlgn3 localizes at postsynaptic sites apposing vesicular glutamate transporter 3-expressing (VGT3+) inhibitory terminals and regulates VGT3+ inhibitory interneuron-mediated synaptic transmission in mouse organotypic slice cultures. Gene expression analysis of interneurons revealed that the αNrxn1+AS4 splice isoform is highly expressed in VGT3+ interneurons as compared with other interneurons. Most importantly, postsynaptic Nlgn3 requires presynaptic αNrxn1+AS4 expressed in VGT3+ interneurons to regulate inhibitory synaptic transmission. Our results indicate that specific Nlgn–Nrxn signaling generates distinct functional properties at synapses.

• Loss of V1 inhibitory neurons in the SODG93A mouse model of ALS. • V1 loss occurs after motor and excitatory V2a neuron loss during disease progression. • Developmental markers of V1 inhibitory neuron subpopulations are maintained to adult stages. • Identification of ALS-susceptible and ALS-resistant V1 inhibitory subpopulations at late stages of disease. • V1 to motor neuron synaptic contacts increase at early ALS stages. Amyotrophic lateral sclerosis (ALS) leads to a loss of specific motor neuron populations in the spinal cord and cortex. Emerging evidence suggests that interneurons may also be affected, but a detailed characterization of interneuron loss and its potential impacts on motor neuron loss and disease progression is lacking. To examine this issue, the fate of V1 inhibitory neurons during ALS was assessed in the ventral spinal cord using the SODG93A mouse model. The V1 population makes up ∼30% of all ventral inhibitory neurons, ∼50% of direct inhibitory synaptic contacts onto motor neuron cell bodies, and is thought to play a key role in modulating motor output, in part through recurrent and reciprocal inhibitory circuits. We find that approximately half of V1 inhibitory neurons are lost in SODG93A mice at late disease stages, but that this loss is delayed relative to the loss of motor neurons and V2a excitatory neurons. We further identify V1 subpopulations based on transcription factor expression that are differentially susceptible to degeneration in SODG93A mice. At an early disease stage, we show that V1 synaptic contacts with motor neuron cell bodies increase, suggesting an upregulation of inhibition before V1 neurons are lost in substantial numbers. These data support a model in which progressive changes in V1 synaptic contacts early in disease, and in select V1 subpopulations at later stages, represent a compensatory upregulation and then deleterious breakdown of specific interneuron circuits within the spinal cord. [ABSTRACT FROM AUTHOR]

Delineation of functional synaptic connections is fundamental to understanding sensory processing. Olfactory signals are synaptically processed initially in the olfactory bulb (OB) where neural circuits are formed among inhibitory' interneurons and the output neurons mitral cells (MCs) and tufted cells (TCs). TCs function in parallel with but differently from MCs and are further classified into multiple subpopulations based on their anatomic and functional heterogeneities. Here, we combined optogenetics with electrophysiology' to characterize the synaptic transmission from a subpopulation of TCs, which exclusively express the neuropeptide choleq'stokinin (CCK), to two groups of spatially segregated GABAergic interneurons, granule cells (GCs) and glomerular interneurons in mice of both sexes with four major findings. First, CCKergic TCs receive direct input from the olfactory sensory' neurons (OSNs). This monosynaptic transmission exhibits high fidelity in response to repetitive OSN input. Second, CCKergic TCs drive GCs through two functionally distinct types of monosynaptic connections: (1) dendrodendritic synapses onto GC distal dendrites via their lateral dendrites in the superficial external plexiform layer (EPL); (2) axodendritic synapses onto GC proximal dendrites via their axon collaterals or terminals in the internal plexiform layer (IPL) on both sides of each bulb. Third, CCKergic TCs monosynaptically excite two subpopulations of inhibitory' glomerular interneurons via dendrodendritic synapses. Finally, sniff-like patterned activation of CCKergic TCs induces robust frequency-dependent depression of the dendrodendritic synapses but facilitation of the axodendritic synapses. These results demonstrated important roles of the CCKergic TCs in olfactory processing by orchestrating OB inhibitory' activities. [ABSTRACT FROM AUTHOR]

Spinal interneurons are critical modulators of motor circuit function. In the dorsal spinal cord, a set of interneurons called GABApre presynaptically inhibits proprioceptive sensory afferent terminals, thus negatively regulating sensory-motor signaling. Although deficits in presynaptic inhibition have been inferred in human motor diseases, including dystonia, it remains unclear whether GABApre circuit components are altered in these conditions. Here, we use developmental timing to show that GABApre neurons are a late Ptf1a-expressing subclass and localize to the intermediate spinal cord. Using a microarray screen to identify genes expressed in this intermediate population, we find the kelch-like family member Klhl14, implicated in dystonia through its direct binding with torsion-dystonia-related protein Tor1a. Furthermore, in Tor1a mutant mice in which Klhl14 and Tor1a binding is disrupted, formation of GABApre sensory afferent synapses is impaired. Our findings suggest a potential contribution of GABApre neurons to the deficits in presynaptic inhibition observed in dystonia.

Abstract Exocytotic release of neurotransmitter can be quantified by electrophysiological recording from postsynaptic neurons. Alternatively, fusion of synaptic vesicles with the cell membrane can be measured as increased capacitance by recording directly from a presynaptic neuron. The “Sine + DC” technique is based on recording from an unbranched cell, represented by an electrically equivalent RC‐circuit. It is challenging to extend such measurements to branching neurons where exocytosis occurs at a distance from a somatic recording electrode. The AII amacrine is an important inhibitory interneuron of the mammalian retina and there is evidence that exocytosis at presynaptic lobular dendrites increases the capacitance. Here, we combined electrophysiological recording and computer simulations with realistic compartmental models to explore capacitance measurements of rat AII amacrine cells. First, we verified the ability of the “Sine + DC” technique to detect depolarization‐evoked exocytosis in physiological recordings. Next, we used compartmental modeling to demonstrate that capacitance measurements can detect increased membrane surface area at lobular dendrites. However, the accuracy declines for lobular dendrites located further from the soma due to frequency‐dependent signal attenuation. For sine wave frequencies ≥1 kHz, the magnitude of the total releasable pool of synaptic vesicles will be significantly underestimated. Reducing the sine wave frequency increases overall accuracy, but when the frequency is sufficiently low that exocytosis can be detected with high accuracy from all lobular dendrites (~100 Hz), strong electrical coupling between AII amacrines compromises the measurements. These results need to be taken into account in studies with capacitance measurements from these and other electrically coupled neurons.

Diabetic peripheral neuropathic pain (DPNP) is a common manifestation of diabetic peripheral neuropathy (DPN). Although the pathogenesis of DPNP remains unclear, the disinhibition of spinal dorsal horn neuronal circuitry mediated by endoplasmic reticulum stress (ERS) is an important mechanism underlying neuropathic pain (NP). Tanshinone II A is mainly used to treat cardiovascular diseases but has also been shown to relieve various types of neuralgia, including DPNP. This study investigated the effects of tanshinone II A in DPNP model rats. We divided animals into two groups: 1) the model (diabetic) group and 2) the tanshinone II A-treatment group. Our results demonstrated that diabetic rats exhibited a decrease in the mechanical withdrawal threshold (MWT) and thermal withdrawal latency (TWL), and that NMT is increased and TWL is prolonged in rats treated with tanshinone II A. Additionally, the levels of ERS-signaling pathway factors in the spinal dorsal horns of rats were lower in the tanshinone II A-treated group than in the diabetic group. Overall, our study demonstrated that the disinhibition of spinal dorsal horn neuronal circuitry mediated by endoplasmic reticulum stress underlies DPNP and is modulated by tanshinone II A treatment. [ABSTRACT FROM AUTHOR]

To detect the effects of AMPA receptor (琢-amino-3-hydroxy-5-methyl-4-isoxazole propionate receptor) and NMDA receptor (N-methyl-D-aspartic acid receptor), two of ionotropic glutamate receptors, on the morphological development of inhibitory interneurons and excitatory neurons. Primary cultured cortical neurons were treated with drugs to interfere with AMPA receptors and/or NMDA receptors, to block neuronal ionotropic glutamate receptors. Neurons of each group were observed, and the inhibitory neurons were displayed by green fluorescence in GAD67-GFP transgenic mice while the excitatory neurons were showed by CaMKII immunofluorescence staining. When AMPA and/or NMDA receptors were blocked, the density of the neural network decreased when observed under light microscope, and the degree of decreasing became even more obvious with the increase of drug concentration. For GFP-positive inhibitory interneurons, when AMPA receptors were blocked, the number of neuronal branches decreased to 65% (low concentration) and 55% (high concentration) of the control group, and the length of processes was shortened to 43% (low concentration) and 36% (high concentration) of the control. When NMDA receptors were blocked, the number of branches decreased to 70% (low concentration) and 45% (high concentration), and the length decreased to 43% (low concentration) and 31% (high concentration). And when AMPA and NMDA receptors were blocked together, the number of branches decreased to 42% and the length decreased to 38%. For CaMKII-positive excitatory neurons, although the degree was weaker, the neurons showed similar changes in morphology, with reduced number of branches and shortened length of processes. When AMPA receptors were blocked, the number of branches decreased to 64% (high concentration), and the length didn't vary too much. When NMDA receptors were blocked, the number of branches decreased to 50% (high concentration), and the length decreased to 77% (low concentration) and 71% (high concentration). And when AMPA and NMDA receptors were blocked together, the number of branches decreased to 69% and the length decreased to 62%. During neuronal development, the excitatory synaptic afferent signal mediated by ionic glutamate receptors showed effects on the morphological development of inhibitory interneurons and excitatory neurons, and finally plays an important regulatory role in the formation of neural circuits. [ABSTRACT FROM AUTHOR]

During development of the mammalian cerebral neocortex, postmitotic excitatory neurons migrate toward the outermost region of the neocortex. We previously reported that this outermost region is composed of densely packed relatively immature neurons; we named this region, which is observed during the late stage of mouse neocortical development, the "primitive cortical zone (PCZ)." Here, we report that postmigratory immature neurons spend about 1–1.5 days in the PCZ. An electron microscopic analysis showed that the neurons in the PCZ tend to be in direct contact with each other, mostly in a radial direction, forming "primitive neuronal clusters" with a height of 3–7 cells and a width of 1–2 cells. A time‐course analysis of fluorescently labeled neurons revealed that the neurons took their positions within the primitive clusters in an inside‐out manner. The neurons initially participated in the superficial part of the clusters, gradually shifted their relative positions downward, and then left the clusters at the bottom of this structure. GABAergic inhibitory interneurons were also found within the primitive clusters in the developing mouse neocortex, suggesting that some clusters are composed of both excitatory neurons and inhibitory interneurons. Similar clusters were also observed in the outermost region of embryonic day (E) 78 cynomolgus monkey occipital cortex and 23 gestational week (GW) human neocortices. In the primate neocortices, including human, the presumptive primitive clusters seemed to expand in the radial direction more than that observed in mice, which might contribute to the functional integrity of the primate neocortex. [ABSTRACT FROM AUTHOR]

Highlights • Hippocampal DG-CA3 is important for pattern separation and completion. • DG-CA3 dynamics is coordinated differently during waking and non-REM sleep. • Granule cells and mossy cells in DG have distinct spatial representations. • Granule cells show weaker pattern separation compared to downstream targets. • Contribution of DG to pattern separation in CA3 needs to be reevaluated. Abstract Anatomical observations, theoretical work and lesioning experiments have supported the idea that the CA3 in the hippocampus is important for encoding, storage and retrieval of memory while the dentate gyrus (DG) is important for the pattern separation of the incoming inputs from the entorhinal cortex. Study of the presumed function of the dentate gyrus in pattern separation has been hampered by the lack of reliable methods to identify different excitatory cell types in the DG. Recent papers have identified different cell types in the DG, in awake behaving animals, with more reliable methods. These studies have revealed each cell type's spatial representation as well as their involvement in pattern separation. Moreover, chronic electrophysiological recording from sleeping and waking animals also provided more insights into the operation of the DG-CA3 system for memory encoding and retrieval. This article will review the local circuit architectures and physiological properties of the DG-CA3 system and discuss how the local circuit in the DG-CA3 may function, incorporating recent physiological findings in the DG-CA3 system. [ABSTRACT FROM AUTHOR]

Highlights • Neonatal rat rostral thoracic ventral roots showed greater inspiratory motor activity than caudal thoracic ventral roots. • The rostral thoracic interneurons showed greater inspiratory activity than caudal thoracic interneurons. • The glycinergic and GABAergic inhibitory thoracic interneurons are not involved in these rostro-caudal gradients. • Glycinergic or GABAergic inhibition is involved in adjusting the thoracic inspiratory motor outputs. Abstract The inspiratory motor activities are greater in the intercostal muscles positioned at more rostral thoracic segments. This rostro-caudal gradient of the thoracic inspiratory motor activity is thought to be generated by the spinal interneurons. To clarify the involvement of the inhibitory thoracic interneurons in this rostro-caudal gradient, we examined the effects of 10 μM strychnine, an antagonist of glycine and GABA A receptors, applied to the neonatal rat thoracic spinal cord. The respiratory-related interneuron activities were optically recorded from thoracic segments in the isolated neonatal rat brainstem-spinal cord preparations stained with voltage-sensitive dye, and the electrical inspiratory motor activities were obtained from the third and eleventh thoracic ventral roots (T3VR, T11VR). Although strychnine caused seizure-like activities in all of the ventral roots recorded, the inspiratory motor activities continued. The inspiratory optical signals in the rostral thoracic segments (T2–T5) were significantly larger than those in the caudal thoracic segments (T9–T11) regardless of the existence of strychnine. Similarly, the percent ratio of the amplitude of the inspiratory electrical activity in the T3VR under control and strychnine was significantly larger than that in the T11VR regardless of the existence of strychnine. Strychnine significantly increased the inspiratory activity in both the T3VR and T11VR. These results suggest that the glycinergic and GABAergic inhibitory interneurons are not essential to generate the rostro-caudal gradient in the neonatal rat thoracic inspiratory motor outputs, but these interneurons are likely to play a role in the inhibitory control of inspiratory motor output. [ABSTRACT FROM AUTHOR]

The accumulation of unfolded or misfolded proteins in the endoplasmic reticulum (ER) lumen leads to ER stress, which is related to cellular reactive oxygen species production. Neuropathic pain may result from spinal dorsal horn (SDH) ER stress. In this study, we examined the cause-effect relationship between ER stress and neuropathic pain using the spinal nerve ligation (SNL) rat model. We showed that ER stress was mutually promotive with oxidative stress during the process. We also tested the hypothesis that spinal sensitization arose from reduced activities of GABA-ergic interneurons and that spinal sensitization was mediated by SDH ER stress. Other important findings in this study including the following: (1) nociceptive behavior was alleviated in SNL rat as long as tauroursodeoxycholic acid injections were repeated to inhibit ER stress; (2) inducing SDH ER stress in healthy rat resulted in mechanical hyperalgesia; (3) blocking protein disulfide isomerase pharmacologically reduced ER stress and nociceptive behavior in SNL rat; (4) cells in the dorsal horn with elevated ER stress were mainly neurons; and (5) whole-cell recordings made in slide preparations revealed significant inhibition of GABA-ergic interneuron activity in the dorsal horn with ER stress vs in the healthy dorsal horn. Taken together, results of the current study demonstrate that coregulation of ER stress and oxidative stress played an important role in neuropathic pain process. Inhibiting SDH ER stress could be a potential novel strategy to manage neuropathic pain. [ABSTRACT FROM AUTHOR]