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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]

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]

• 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]

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]

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. [Display omitted] [ABSTRACT FROM AUTHOR]

The cerebellum arguably constitutes one of the best characterized central nervous circuits, and its structure, cellular function, and histogenesis have been described in exceptional quantitative detail. A notable exception to this is the development of its inhibitory interneurons, and in particular the extensive migrations of future basket and stellate cells. Here, we used acute slices from 8-day-old mice to assess the migration of Pax2-EGFP-tagged precursors of these cells en route to the molecular layer during their transit through the nascent cerebellar cortex. We document that movement of these cells is highly directed. Their speed and directional persistence are larger in the nascent granule cell layer than in the molecular layer. And they migrate periodically, with periods of effective, directed translocation separated by bouts of rather local movement. Finally, we document that the arrangement of these cells in the adult molecular layer is characterized by clustering. These data are discussed with a focus on potential generative mechanisms for the developmental pattern observed. [ABSTRACT FROM AUTHOR]

Inhibition in thalamorecipient layer 4 simple cells of primary visual cortex is believed to play important roles in establishing visual response properties and integrating visual inputs across their receptive fields (RFs). Simple cell RFs are characterized by nonoverlapping, spatially restricted subregions in which visual stimuli can either increase or decrease the firing rate of the cell, depending on contrast. Inhibition is believed to be triggered exclusively from visual stimulation of individual RF subregions. However, this view is at odds with the known anatomy of layer 4 interneurons in visual cortex and differs from recent findings in mouse visual cortex. Here we show with in vivo intracellular recordings in cats that while excitation is restricted to RF subregions, inhibition spans the width of simple cell RFs. Consequently, excitatory stimuli within a subregion concomitantly drive excitation and inhibition. Furthermore, we found that the distribution of inhibition across the RF is stronger toward OFF subregions. This inhibitory OFF-subregion bias has a functional consequence on spatial integration of inputs across the RF. A model based on the known anatomy of layer 4 demonstrates that the known proportion and connectivity of inhibitory neurons in layer 4 of primary visual cortex is sufficient to explain broad inhibition with an OFF-subregion bias while generating a variety of phase relations, including antiphase, between excitation and inhibition in response to drifting gratings. [ABSTRACT FROM AUTHOR]

Around a quarter of neurons in laminae I–II of the dorsal horn are inhibitory interneurons. These play an important role in modulating somatosensory information, including that perceived as pain or itch. Previous studies in rat identified four largely non-overlapping neurochemical populations among these cells, defined by expression of galanin, neuropeptide Y (NPY), neuronal nitric oxide synthase (nNOS) or parvalbumin. The galanin cells were subsequently shown to coexpress dynorphin. Several recent studies have used genetically modified mice to investigate the function of different interneuron populations, and it is therefore important to determine whether the same pattern applies in mouse, and to estimate the relative sizes of these populations. We show that the neurochemical organization of inhibitory interneurons in mouse superficial dorsal horn is similar to that in the rat, although a larger proportion of these neurons (33%) express NPY. Between them, these four populations account for ∼75% of inhibitory cells in laminae I–II. Since ∼25% of inhibitory interneurons in this region belong to a novel calretinin-expressing type, our results suggest that virtually all inhibitory interneurons in superficial dorsal horn can be assigned to one of these five neurochemical populations. Although our main focus was inhibitory neurons, we also identified a population of excitatory dynorphin-expressing cells in laminae I–II that are largely restricted to the medial part of the mid-lumbar dorsal horn, corresponding to glabrous skin territory. These findings are important for interpretation of studies using molecular-genetic techniques to manipulate the functions of interneuron populations to investigate their roles in somatosensory processing. [ABSTRACT FROM AUTHOR]

Spiral waves were observed in the biological experiment on rat brain cortex with the application of carbachol and bicuculline which can block inhibitory coupling from interneurons to pyramidal neurons. To simulate the experimental spiral waves, a two-dimensional neuronal network composed of pyramidal neurons and inhibitory interneurons was built. By decreasing the percentage of active inhibitory interneurons, the random-like spatial patterns change to spiral waves and to random-like spatial patterns or nearly synchronous behaviors. The spiral waves appear at a low percentage of inhibitory interneurons, which matches the experimental condition that inhibitory couplings of the interneurons were blocked. The spiral waves exhibit a higher order or signal-to-noise ratio (SNR) characterized by spatial structure function than both random-like spatial patterns and nearly synchronous behaviors, which shows that changes of the percentage of active inhibitory interneurons can induce spatial coherence resonance-like behaviors. In addition, the relationship between the coherence degree and the spatial structures of the spiral waves is identified. The results not only present a possible and reasonable interpretation to the spiral waves observed in the biological experiment on the brain cortex with disinhibition, but also reveal that the spiral waves exhibit more ordered degree in spatial patterns. [ABSTRACT FROM AUTHOR]

Signals with multiple oscillatory components may exhibit cross frequency coupling (CFC): a slow component modulating the amplitude and/or frequency of a fast one. CFC is ubiquitous in oscillatory brain signals but how it arises has remained unclear. We recently proposed a systematic approach to simulate CFC, in which all common modulations are generated by a Neural Mass Model [7]. A key mechanism in this approach is the dynamic self-feedback circuit of the fast inhibitory interneuron population that generates Gamma band oscillatory activity. Depending on noise-input level, the circuit switches between a limit cycle regime enabling amplitude modulation and a resonance regime enabling frequency modulation. In this study, we analyze the behavior of this circuit, using the describing function method for the limit cycle regime and root locus analysis for the resonance regime. The relationship between circuit parameters and behavior is investigated by bifurcation analysis. [ABSTRACT FROM AUTHOR]

Objective The present study aimed to investigate alterations in cortical function in amyotrophic lateral sclerosis (ALS) related to disease progression. Methods In total, clinical assessments were evaluated in 189 ALS patients, combined with assessment of cortical function utilising threshold tracking transcranial magnetic stimulation. Results were compared with disease stage. Disease stage was defined in three ways: (1) as a proportion of disease duration in deceased patients; (2) from the time of ALS onset; and (3) using the ALS rating scale-revised (ALSFRS-R). Results Prospective studies in ALS patients demonstrated decreased neurophysiological index ( p < 0.0001) and decreased compound muscle action potential (CMAP) ( p < 0.0001), combined with abnormalities of central function including prolonged central motor conduction time (CMCT) ( p < 0.05), increased motor evoked potential/CMAP amplitude ratio ( p < 0.0001) and decreased short interval intracortical inhibition (SICI) ( p < 0.001). SICI at 3 ms ( p < 0.05, β = −0.21) and averaged SICI ( p < 0.05, β = −0.21) decreased with disease progression, measured using proportion of disease duration. Alternatively, using time from disease onset, CMCT prolonged with disease progression ( p < 0.01, β = 0.25), while ALSFRS-R decline correlated with decreased SICI at 3 ms ( p < 0.01, β = 0.20). Conclusions Clinical measures combined with assessment of cortical function established that SICI decreased with disease progression. Significance These findings may suggest dysfunction of inhibitory interneurons with disease progression. [ABSTRACT FROM AUTHOR]

The multifaceted functions of the brain are borne through seemingly infinite spatiotemporal interactions between its resident neural elements. Using a combinatorial approach, Schuman and colleagues (J. Neurosci. 2018;39:125–139) recently identify four layer 1 cortical interneuron subtypes, including a hitherto uncharacterized neuron they term the 'canopy' cell. Properties unique to each of the subtypes likely endow them with distinct roles in top-down processing. [ABSTRACT FROM AUTHOR]

Inhibitory interneurons are the fundamental constituents of neural circuits that organize network outputs. The striatum as part of the basal ganglia is involved in reward-directed behaviors. However, the role of the inhibitory interneurons in this process remains unclear, especially in behaving monkeys. We recorded the striatal single neuron activity while monkeys performed reward-directed hand or eye movements. Presumed parvalbumin-containing GABAergic interneurons (fast-spiking neurons, FSNs) were identified based on narrow spike shapes in three independent experiments, though they were a small population (4.2%, 42/997). We found that FSNs are characterized by high-frequency and less-bursty discharges, which are distinct from the basic firing properties of the presumed projection neurons (phasically active neurons, PANs). Besides, the encoded information regarding actions and outcomes was similar between FSNs and PANs in terms of proportion of neurons, but the discharge selectivity was higher in PANs than that of FSNs. The coding of actions and outcomes in FSNs and PANs was consistently observed under various behavioral contexts in distinct parts of the striatum (caudate nucleus, putamen, and anterior striatum). Our results suggest that FSNs may enhance the discharge selectivity of postsynaptic output neurons (PANs) in encoding crucial variables for a reward-directed behavior. [ABSTRACT FROM AUTHOR]

ABSTRACT Hippocampal place cells that are activated sequentially during active waking get reactivated in a temporally compressed (5-20 times) manner during slow-wave-sleep and quiet waking. The two-stage model of the hippocampus suggests that neural activity during awaking supports encoding function while temporally compressed reactivation (replay) supports consolidation. However, the mechanisms supporting different neural activity with different temporal scales during encoding and consolidation remain unclear. Based on the idea that acetylcholine modulates functional transition between encoding and consolidation, we tested whether the cholinergic modulation may adjust intrinsic network dynamics to support different temporal scales for these two modes of operation. Simulations demonstrate that cholinergic modulation of the calcium activated non-specific cationic (CAN) current and the synaptic transmission may be sufficient to switch the network dynamics between encoding and consolidation modes. When the CAN current is active and the synaptic transmission is suppressed, mimicking the high acetylcholine condition during active waking, a slow propagation of multiple spikes is evident. This activity resembles the firing pattern of place cells and time cells during active waking. On the other hand, when CAN current is suppressed and the synaptic transmission is intact, mimicking the low acetylcholine condition during slow-wave-sleep, a time compressed fast (∼10 times) activity propagation of the same set of cells is evident. This activity resembles the time compressed firing pattern of place cells during replay and pre-play, achieving a temporal compression factor in the range observed in vivo (5-20 times). These observations suggest that cholinergic system could adjust intrinsic network dynamics suitable for encoding and consolidation through the modulation of the CAN current and synaptic conductance in the hippocampus. © 2015 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

While the dopamine hypothesis has dominated schizophrenia research for several decades, more recent studies have highlighted the role of fast synaptic transmitters and their receptors in schizophrenia etiology. Here we review evidence that schizophrenia is associated with a reduction in N-methyl-d-aspartate receptor (NMDAR) function. By highlighting postmortem, neuroimaging and electrophysiological studies, we provide evidence for preferential disruption of GABAergic circuits in the context of NMDAR hypo-activity states. The functional relationship between NMDARs and GABAergic neurons is realized at the molecular, cellular, microcircuit and systems levels. A synthesis of findings across these levels explains how NMDA-mediated inhibitory dysfunction may lead to aberrant interactions among brain regions, accounting for key clinical features of schizophrenia. This synthesis of schizophrenia unifies observations from diverse fields and may help chart pathways for developing novel diagnostics and therapeutics. [ABSTRACT FROM AUTHOR]

The intracellular transcriptional milieu wields considerable influence over the induction of neuronal identity. The transcription factor Ptf1a has been proposed to act as an identity "switch" between developmentally related precursors in the spinal cord (Glasgow et al., 2005; Huang et al., 2008), retina (Fujitani et al., 2006; Dullin et al., 2007; Nakhai et al., 2007; Lelièvre et al., 2011), and cerebellum (Hoshino et al., 2005; Pascual et al., 2007; Yamada et al., 2014), where it promotes an inhibitory over an excitatory neuronal identity. In this study, we investigate the potency of Ptf1a to cell autonomously confer a specific neuronal identity outside of its endogenous environment, using mouse in utero electroporation and a conditional genetic strategy to misexpress Ptf1a exclusively in developing cortical pyramidal cells. Transcriptome profiling of Ptf1a-misexpressing cells using RNA-seq reveals that Ptf1a significantly alters pyramidal cell gene expression, upregulating numerous Ptf1a-dependent inhibitory interneuron markers and ultimately generating a gene expression profile that resembles the transcriptomes of both Ptf1a-expressing spinal interneurons and endogenous cortical interneurons. Using RNA-seq and in situ hybridization analyses, we also show that Ptf1a induces expression of the peptidergic neurotransmitter nociceptin, while minimally affecting the expression of genes linked to other neurotransmitter systems. Moreover, Ptf1a alters neuronal morphology, inducing the radial redistribution and branching of neurites in cortical pyramidal cells. Thus Ptf1a is sufficient, even in a dramatically different neuronal precursor, to cell autonomously promote characteristics of an inhibitory peptidergic identity, providing the first example of a single transcription factor that can direct an inhibitory peptidergic fate. [ABSTRACT FROM AUTHOR]

Cortical spike trains are highly irregular both during ongoing, spontaneous activity and when driven at high firing rates. There is uncertainty about the source of this irregularity, ranging from intrinsic noise sources in neurons to collective effects in large-scale cortical networks. Cortical interneurons display highly irregular spike times (coefficient of variation of the interspike intervals >1) in response to dc-current injection in vitro. This is in marked contrast to cortical pyramidal cells, which spike highly irregularly in vivo, but regularly in vitro. We show with in vitro recordings and computational models that this is due to the fast activation kinetics of interneuronal K+ currents. This explanation holds over a wide parameter range and with Gaussian white, power-law, and Ornstein-Uhlenbeck noise. The intrinsically irregular spiking of interneurons could contribute to the irregularity of the cortical network. [ABSTRACT FROM AUTHOR]

Background: Endocannabinoids provide control over cortical neurotransmission. We investigated the developmental expression of key genes in the endocannabinoid system across human postnatal life and determined whether they correspond to the development of markers for inhibitory interneurons, which shape cortical development. We used microarray with qPCR validation and in situ hybridisation to quantify mRNA for the central endocannabinoid receptor CB1R, endocannabinoid synthetic enzymes (DAGLα for 2-arachidonylglycerol [2-AG] and NAPE-PLD for anandamide), and inactivating enzymes (MGL and ABHD6 for 2-AG and FAAH for anandamide) in human dorsolateral prefrontal cortex (39 days - 49 years). Results: CB1R mRNA decreases until adulthood, particularly in layer II, after peaking between neonates and toddlers. DAGLα mRNA expression is lowest in early life and adulthood, peaking between school age and young adulthood. MGL expression declines after peaking in infancy, while ABHD6 increases from neonatal age. NAPE-PLD and FAAH expression increase steadily after infancy, peaking in adulthood. Conclusions: Stronger endocannabinoid regulation of presynaptic neurotransmission in both supragranular and infragranular cortical layers as indexed through higher CB1R mRNA may occur within the first few years of human life. After adolescence, higher mRNA levels of the anandamide synthetic and inactivating enzymes NAPE-PLD and FAAH suggest that a late developmental switch may occur where anandamide is more strongly regulated after adolescence than earlier in life. Thus, expression of key genes in the endocannabinoid system changes with maturation of cortical function. [ABSTRACT FROM AUTHOR]

Abstract: In the hippocampus, activation of nicotinic receptors that include α4 and β2 subunits (α4β2*) facilitates memory formation. α4β2* receptors may also play a role in nicotine withdrawal, and their loss may contribute to cognitive decline in aging and Alzheimer’s disease (AD). However, little is known about their cellular function in the hippocampus. Therefore, using optogenetics, whole cell patch clamping and voltage-sensitive dye (VSD) imaging, we measured nicotinic excitatory postsynaptic potentials (EPSPs) in hippocampal CA1. In a subpopulation of inhibitory interneurons, release of ACh resulted in slow depolarizations (rise time constant 33.2 ± 6.5 ms, decay time constant 138.6 ± 27.2 ms) mediated by the activation of α4β2* nicotinic receptors. These interneurons had somata and dendrites located in the stratum oriens (SO) and stratum lacunosum-moleculare (SLM). Furthermore, α4β2* nicotinic EPSPs were largest in the SLM. Thus, our data suggest that nicotinic EPSPs in hippocampal CA1 interneurons are predominantly mediated by α4β2* nicotinic receptors and their activation may preferentially affect extrahippocampal inputs in SLM of hippocampal CA1. [Copyright &y& Elsevier]

Abstract: A brief review of previous studies is presented on high frequency oscillations (HFOs)>300Hz overlying the cortical response in the somatosensory evoked potential (SEP) or magnetic field (SEF) in humans as well as other mammals. The characteristics of somatosensory HFOs are described about reproducibility and origin (area 3b and 1) of the HFOs, changes during a wake-sleep cycle, effects of stimulus rate or tactile interference, and pharmacological effects. Also, several hypotheses on the neural mechanisms of the HFOs are reconsidered; the early HFO burst is probably generated from action potentials of thalamocortical fibers at the time when they arrive at the area 3b (and 1), since this component is resistant to higher stimulus rate >10Hz, general anesthesia, or application of glutamatergic receptor antagonist: by contrast, the late HFO burst is sensitive to higher stimulus rate and eliminated after application of glutamatergic receptor antagonist, reflecting activities of a postsynaptic neural network in areas 3b and 1 of the somatosensory cortex. In view of physiological features of the somatosensory HFOs and their pathological or pharmacological changes, possible mechanisms of the late HFO burst genesis are discussed: a fast-spiking interneuron hypothesis, a fast pyramidal cell IPSP hypothesis and a chattering cell hypothesis. [Copyright &y& Elsevier]

Abstract: Long-term sensory memories are considered to be stored in the relevant cortical region subserving the given modality. We and others have recently identified a series of molecular alterations in the gustatory cortex (GC) of the rat at different time intervals following novel taste learning. Some of these correlative modifications were also necessary for taste memory acquisition and/or consolidation. However, very little is known about the localization of these molecular modifications within the GC or about the functional activation of the GC hours after novel taste learning. Here, we hypothesize that inhibitory interneurons are activated in the GC on a scale of hours following learning and used c-Fos expression and confocal microscopy with different markers to test this hypothesis. We found that GABAergic interneurons are activated in the GC in correlation with novel taste learning. The activation was evident in the deep but not superficial layers of the dysgranular insular cortex. These results suggest that the GABAergic machinery in the deep layers of the GC participates in the processing of taste information hours after learning, and provide evidence for the involvement of a local cortical circuit not only during acquisition of new information but also during off-line processing and consolidation of taste information. [Copyright &y& Elsevier]

We mined the Allen Mouse Brain Atlas for genes expressed in cerebellar cortical inhibitory interneurons that would allow identification and possibly distinction of these cells. We identified some 90 genes that are highly expressed in specific subsets of cerebellar cortical inhibitory interneurons or various combinations thereof. Four genes are exclusively expressed, within the cerebellar cortex, in molecular layer interneurons, and ten genes label exclusively inhibitory interneurons in the granule cell layer or subsets thereof. Differential expression of many of these genes in cells residing in the lower versus the upper molecular layer provides evidence that these cells, traditionally referred to as basket and stellate cells, are indeed molecularly distinct. Two genes could be identified as novel markers for unipolar brush cells. Intersection of these data with embryonic expression patterns as documented in the genepaint repository does not support a hierarchical model of cerebellar interneuron development, but may be more easily reconciled with the view that cerebellar inhibitory interneurons derive from a common precursor pool from which they are specified only late into their development. The novel markers identified here should prove useful for probing the timing and mechanisms supporting cerebellar cortical interneuron specification and diversification. [ABSTRACT FROM AUTHOR]

Neurovascular coupling, or the tight coupling between neuronal activity and regional cerebral blood flow (CBF), seems largely driven by the local processing of incoming afferent signals within the activated area. To test if cortical γ-aminobutyric acid (GABA) interneurons—the local integrators of cortical activity—are involved in this coupling, we stimulated the basalocortical pathway in vivo, monitored cortical CBF, and identified the activated interneurons (c-Fos-immunopositive) and the neuromediators involved in this response. Basal forebrain (BF) stimulation induced ipsilateral increases in CBF and selective activation of layers II to VI somatostatin- and/or neuropeptide Y-containing, as well as layer I GABA interneurons. Nitric oxide synthase interneurons displayed weak bilateral activation, whereas vasoactive intestinal polypeptide- or acetylcholine (ACh)-containing GABA interneurons were not activated. Selective cholinergic deafferentation indicated that ACh released from stimulated BF afferents triggered the CBF response, but the latter was mediated, in part, by the local release of GABA from cholinoceptive cortical interneurons, and through GABA-A receptor-mediated transmission. These data show that activation of specific subsets of GABA interneurons and their GABA-A-mediated effects on neuronal, vascular, and/or astroglial targets are necessary for the full expression of the hemodynamic response to BF stimulation. Further, these findings highlight the importance of understanding the cellular networks and circuitry that underlie hemodynamic signals, as only specific subsets of neurons may be activated by a given stimulus, depending on the afferent inputs they receive and integrate.Journal of Cerebral Blood Flow & Metabolism (2008) 28, 221–231; doi:10.1038/sj.jcbfm.9600558; published online 26 September 2007 [ABSTRACT FROM AUTHOR]

In this paper, we present a network of silicon interneurons that synchronize in the gamma frequency range (20-80 Hz). The gamma rhythm strongly influences neuronal spike timing within many brain regions, potentially playing a crucial role in computation. Yet it has largely been ignored in neuromorphic systems, which use mixed analog and digital circuits to model neurobiology in silicon. Our neurons synchronize by using shunting inhibition (conductance based) with a synaptic rise time. Synaptic rise time promotes synchrony by delaying the effect of inhibition, providing an opportune period for interneurons to spike together. Shunting inhibition, through its voltage dependence, inhibits interneurons that spike out of phase more strongly (delaying the spike further), pushing them into phase (in the next cycle). We characterize the interneuron, which consists of soma (cell body) and synapse circuits, fabricated in a 0.25-pm complementary metal-oxide-semiconductor (CMOS). Further, we show that synchronized interneurons (population of 256) spike with a period that is proportional to the synaptic rise time. We use these interneurons to entrain model excitatory principal neurons and to implement a form of object binding. [ABSTRACT FROM AUTHOR]

Repetitive correlated spiking can induce long-term potentiation (LTP) and long-term depression (LTD) of many excitatory synapses on glutamatergic neurons, in a manner that depends on the timing of presynaptic and postsynaptic spiking. However, it is mostly unknown whether and how such spike-timing-dependent plasticity (STDP) operates at neocortical excitatory synapses on inhibitory interneurons, which have diverse physiological and morphological characteristics. In this study, we found that these synapses exhibit target-cell-dependent STDP. In layer 2/3 of the somatosensory cortex, the pyramidal cell (PC) forms divergent synapses on fast spiking (FS) and low-threshold spiking (LTS) interneurons that exhibit short-term synaptic depression and facilitation in response to high-frequency stimulation, respectively. At PC-LTS synapses, repetitive correlated spiking induced LTP or LTD, depending on the timing of presynaptic and postsynaptic spiking. However, regardless of the timing and frequency of spiking, correlated activity induced only LTD at PC-FS synapses. This target-cell-specific STDP was not caused by the difference in the short-term plasticity between these two types of synapses. Activation of postsynaptic NMDA subtype of glutamate receptors (NMDARs) was required for LTP induction at PC-LTS synapses, whereas activation of metabotropic glutamate receptors was required for LTD induction at both PC-LTS and PC-FS synapses. Additional analysis of synaptic currents suggests that LTP and LTD of PC-LTS synapses, but not LTD of PC-FS synapses, involves presynaptic modifications. Such dependence of both the induction and expression of STDP on the type of postsynaptic interneurons may contribute to differential processing and storage of information in cortical local circuits. [ABSTRACT FROM AUTHOR]

Abstract: In sensory cortices, synaptic plasticities such as long-term potentiation (LTP) and long-term depression (LTD) have important roles in the development of neural circuits and sensory information processing. However, the differential roles and mechanisms of the various types of LTP and LTD are not clear. In the present study, we investigated LTP and two types of LTD in slices obtained from the rat auditory cortex. Supragranular field potentials elicited by layer VI stimulation were recorded through a metal electrode. Transsynaptic field potentials exhibited marked LTP after tetanic stimulation (TS, 100 Hz for 1 s) was applied to layer VI. The same field potential components exhibited LTD after low-frequency stimulation (LFS, 1 Hz for 900 s) was applied to layer VI. LTD of supragranular field potentials was also induced by local TS applied to supragranular layers 0.3 mm from the recording site. Neither LTP nor LTD of either type was induced in the presence of 50 μM d-(−)-2-amino-5-phosphonovalerate (APV), an NMDA receptor antagonist. However, 500 μM (+)-α-methyl-4-carboxyphenylglycine (MCPG), an antagonist of metabotropic glutamate receptors, had no effect. LTD induced by LFS and that induced by local TS were suppressed in the presence of 3 μM bicuculline, an antagonist of GABAA receptors. Each of these forms of LTD occluded the other. These results and intracellular recordings in supragranular pyramidal neurons during LFS and local TS strongly suggest that the two types of LTD share common neural circuits for their induction. [Copyright &y& Elsevier]

The cerebellar cortex consists of a small set of neuronal cell types interconnected in a highly stereotyped way. While the development of cerebellar cortical projection neurons, i.e. Purkinje cells, and that of granule cells has been elucidated in considerable detail, that of cerebellar cortical inhibitory interneurons is still rather fragmentarily understood. Here, we use mice expressing green fluorescent protein (GFP) from the Pax2 locus to analyse the ontogenesis of these cells. Numbers of Pax2-positive inhibitory interneuronal precursors increase following a classical sigmoidal growth curve to yield a total of some 905.000 ± 77.000 cells. Maximal cell increase occurs at about postnatal day (P)5.4, and some 75% of all inhibitory interneurons are generated prior to P7. Conjoint analysis of the developmental accruement of Pax2-GFP-positive cells and their cell cycle distribution reveals that, at least at P0 and P3, the numerical increase of these cells results primarily from proliferation of a Pax2-negative precursor population and suggests that Pax2 expression begins at or around the final mitosis. Following their terminal mitosis, inhibitory cerebellar cortical interneurons go through a protracted quiescent phase in which they maintain expression of the cell cycle marker Ki-67. During this phase, they translocate into the nascent molecular layer, where they stall next to premigratory granule cell precursors without penetrating this population of cells. These observations provide a quantitative description of cerebellar cortical inhibitory interneuron genesis and early differentiation, and define Pax2 as a marker expressed in basket and stellate cells, from around their final mitosis to their incipient histogenetic integration. [ABSTRACT FROM AUTHOR]

GABA-releasing inhibitory interneurons in the cerebral cortex can be classified by their neurochemical content, firing patterns, or axonal targets, to name the most common criteria, but whether classifications using different criteria converge on the same neuronal subtypes, and how many such subtypes exist, is a matter of much current interest and considerable debate. To address these issues, we generated transgenic mice expressing green fluorescent protein (GFP) under control of the GAD67 promoter. In two of these lines, named X94 and X98, GFP expression in the barrel cortex was restricted to subsets of somatostatin-containing (SOM+) GABAergic interneurons, similar to the previously reported "GIN" line (Oliva et al., 2000), but the laminar distributions of GFP-expressing (GFP+) cell bodies in the X94, X98, and GIN lines were distinct and nearly complementary. We compared neurochemical content and axonal distribution patterns of GFP+ neurons among the three lines and analyzed in detail electrophysiological properties in a dataset of 150 neurons recorded in whole-cell, current-clamp mode. By all criteria, there was nearly perfect segregation of X94 and X98 GFP+ neurons, whereas GIN GFP+ neurons exhibited intermediate properties. In the X98 line, GFP expression was found in infragranular, calbindin-containing, layer 1-targeting ("Martinotti") cells that had a propensity to fire low-threshold calcium spikes, whereas X94 GFP+ cells were stuttering interneurons with quasi fast-spiking properties, residing in and targeting the thalamo-recipient neocortical layers. We conclude that much of the variability previously attributed to neocortical SOM+ interneurons can be accounted for by their natural grouping into distinct subtypes. [ABSTRACT FROM AUTHOR]

Group I metabotropic glutamate receptors (mGluRs) are important for hippocampal interneuron function. We used whole-cell recording and confocal imaging to characterize group I mGluR actions in CA1 oriens/alveus interneurons in slices. In tetrodotoxin and ionotropic glutamate receptor antagonists, the group I mGluR specific agonist DHPG increased intradendritic Ca2+ levels and depolarized interneurons, whereas the group II mGluR specific agonist DCG-IV and the group III mGluR specific agonist L-AP4 did not. DHPG-induced depolarizing and Ca2+ responses were antagonized by the group I mGluR antagonist 4CPG, but only Ca2+ responses were significantly inhibited by the mGluR1 antagonist CPCCOEt. DHPG-induced depolarizing responses were not blocked by the inositol-1,4,5-trisphosphate (IP3) receptor inhibitor heparin, the protein kinase C (PKC) antagonists GF-109203X, or the inhibitor of phospholipase C (PLC) U73122. Thus, these responses to DHPG may not be transduced by the PLC→IP3/diacylglycerol (DAG) pathway classically linked to group I mGluRs. DHPG-induced depolarizations were not blocked by intracellular GDPβS or bath-application of N-ethylmaleimide (NEM), suggesting the involvement of a G protein-independent pathway. Our findings indicate that group I mGluRs induce a depolarization of oriens/alveus interneurons via a G protein-independent mechanism different from their classic signalling pathway. Since depolarizations are associated with intracellular Ca2+ rises, these actions may be important for their synaptic plasticity and vulnerability to excitotoxicity. [Copyright &y& Elsevier]

Sensory cues in the natural environment predict reward or punishment, important for survival. For example, the ability to detect attractive tastes indicating palatable food is essential for foraging while the recognition of inedible substrates prevents harm. While some of these sensory responses are innate, they can undergo fundamental changes due to prior experience associated with the stimulus. However, the mechanisms underlying such behavioral switching of an innate sensory response at the neuron and network levels require further investigation. We used the model learning system of Lymnaea stagnalis 1-3 to address the question of how an anticipated aversive outcome reverses the behavioral response to a previously effective feeding stimulus, sucrose. Key to the switching mechanism is an extrinsic inhibitory interneuron of the feeding network, PlB (pleural buccal 4,5), which is inhibited by sucrose to allow a feeding response. After multi-trial aversive associative conditioning, pairing sucrose with strong tactile stimuli to the head, PlB's firing rate increases in response to sucrose application to the lips and the feeding response is suppressed; this learned response is reversed by the photoinactivation of a single PlB. A learning-induced persistent change in the cellular properties of PlB that results in an increase rather than a decrease in its firing rate in response to sucrose provides a neurophysiological mechanism for this behavioral switch. A key interneuron, PeD12 (Pedal-Dorsal 12), of the defensive withdrawal network 5,6 does not mediate the conditioned suppression of feeding, but its facilitated output contributes to the sensitization of the withdrawal response. [Display omitted] • Anticipation of an aversive outcome reverses the behavioral response to food. • The switching mechanism relies on an interneuron extrinsic to the feeding network. • Aversive learning causes persistent physiological change in this interneuron. Pirger et al. demonstrate that persistent modulation of an inhibitory interneuron extrinsic to the feeding system can switch the behavioral response so that a previously salient food stimulus elicits an aversive response. Anticipation of punishment associated with food induces excitation of an interneuron that inhibits the feeding network. [ABSTRACT FROM AUTHOR]

Abstract: This simulation study shows that with a simple network model the background function of a central pattern generator (CPG) network can be understood easily. The network model connects units consisting of two excitatory and one inhibitory population. An example of the lamprey demonstrates that a sufficient inhibition activity is necessary to produce CPG like patterns. [Copyright &y& Elsevier]

Melanopsin-expressing, intrinsically photosensitive retinal ganglion cells (ipRGCs) synchronize our biological clocks with the external light/dark cycle [ 1 ]. In addition to photoentrainment, they mediate the effects of light experience as a central modulator of mood, learning, and health [ 2 ]. This makes a complete account of the circuity responsible for ipRGCs' light responses essential to understanding their diverse roles in our well-being. Considerable progress has been made in understanding ipRGCs' melanopsin-mediated responses in rodents [ 3–5 ]. However, in primates, ipRGCs also have a rare blue-OFF response mediated by an unknown short-wavelength-sensitive (S)-cone circuit [ 6 ]. Identifying this S-cone circuit is particularly important because ipRGCs mediate many of the wide-ranging effects of short-wavelength light on human biology. These effects are often attributed to melanopsin, but there is evidence for an S-cone contribution as well [ 7 , 8 ]. Here, we tested the hypothesis that the S-OFF response is mediated by the S-ON pathway through inhibitory input from an undiscovered S-cone amacrine cell. Using serial electron microscopy in the macaque retina, we reconstructed the neurons and synapses of the S-cone connectome, revealing a novel inhibitory interneuron, an amacrine cell, receiving excitatory glutamatergic input exclusively from S-ON bipolar cells. This S-cone amacrine cell makes highly selective inhibitory synapses onto ipRGCs, resulting in a blue-OFF response. Identification of the S-cone amacrine cell provides the missing component of an evolutionarily ancient circuit using spectral information for non-image forming visual functions. • 3D reconstruction of the S-cone connectome revealed S-cone selective amacrine cells • S-cone amacrine cells receive excitatory input from only S-cone ON bipolar cells • S-cone amacrine cells make targeted inhibitory synapses onto ipRGCs • Resulting short-wavelength sensitivity is distinct from that mediated by melanopsin Patterson et al. identify a new amacrine cell type in the primate retina with "blue" S-cone circuit input and targeted output to intrinsically photosensitive retinal ganglion cells (ipRGCs). This circuit may contribute to the effects of short-wavelength light on ipRGC downstream non-image-forming visual functions such as sleep, mood, and learning. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Summary Oxytocin is an important neuromodulator in the mammalian brain that increases information salience and circuit plasticity, but its signaling mechanisms and circuit effect are not fully understood. Here we report robust oxytocinergic modulation of intrinsic properties and circuit operations in hippocampal area CA2, a region of emerging importance for hippocampal function and social behavior. Upon oxytocin receptor activation, CA2 pyramidal cells depolarize and fire bursts of action potentials, a consequence of phospholipase C signaling to modify two separate voltage-dependent ionic processes. A reduction of potassium current carried by KCNQ-based M channels depolarizes the cell; protein kinase C activity attenuates spike rate of rise and overshoot, dampening after-hyperpolarizations. These actions, in concert with activation of fast-spiking interneurons, promote repetitive firing and CA2 bursting; bursting then governs short-term plasticity of CA2 synaptic transmission onto CA1 and, thus, efficacy of information transfer in the hippocampal network. Highlights • Oxytocin alters intrinsic properties of CA2 pyramidal cells to induce burst firing • OXT-driven PIP 2 hydrolysis reduces M-current and spike overshoot and undershoot • These actions and activation of fast-spiking interneurons promote CA2 bursts • CA2 bursts shape short-term plasticity and E:I ratio of feedforward drive onto CA1 Tirko et al. show that activation of oxytocin receptors drives pyramidal cells in hippocampal area CA2 to fire bursts. They deconstruct the cellular mechanism, oxytocin receptor-driven modulation of K+, and spike-generating currents and reveal the circuit consequences for neurotransmission to CA1. [ABSTRACT FROM AUTHOR]