Cortical Interneurons Research Articles

Distinct invivo dynamics of excitatory synapses onto cortical pyramidal neurons and parvalbumin-positive interneurons.

SUMMARYCortical function relies on the balanced activation of excitatory and inhibitory neurons. However, little is known about the organization and dynamics of shaft excitatory synapses onto cortical inhibitory interneurons. Here, we use the excitatory postsynaptic marker PSD-95, fluorescently labeled at endogenous levels, as a proxy for excitatory synapses onto layer 2/3 pyramidal neurons and parvalbumin-positive (PV+) interneurons in the barrel cortex of adult mice. Longitudinal in vivo imaging under baseline conditions reveals that, although synaptic weights in both neuronal types are log-normally distributed, synapses onto PV+ neurons are less heterogeneous and more stable. Markov model analyses suggest that the synaptic weight distribution is set intrinsically by ongoing cell-type-specific dynamics, and substantial changes are due to accumulated gradual changes. Synaptic weight dynamics are multiplicative, i.e., changes scale with weights, although PV+ synapses also exhibit an additive component. These results reveal that cell-type-specific processes govern cortical synaptic strengths and dynamics.

The organization and development of cortical interneuron presynaptic circuits are area specific.

SUMMARYParvalbumin and somatostatin inhibitory interneurons gate information flow in discrete cortical areas that compute sensory and cognitive functions. Despite the considerable differences between areas, individual interneuron subtypes are genetically invariant and are thought to form canonical circuits regardless of which area they are embedded in. Here, we investigate whether this is achieved through selective and systematic variations in their afferent connectivity during development. To this end, we examined the development of their inputs within distinct cortical areas. We find that interneuron afferents show little evidence of being globally stereotyped. Rather, each subtype displays characteristic regional connectivity and distinct developmental dynamics by which this connectivity is achieved. Moreover, afferents dynamically regulated during development are disrupted by early sensory deprivation and in a model of fragile X syndrome. These data provide a comprehensive map of interneuron afferents across cortical areas and reveal the logic by which these circuits are established during development.

Reduction of cortical parvalbumin-expressing GABAergic interneurons in a rodent hyperoxia model of preterm birth brain injury with deficits in social behavior and cognition.

The inhibitory GABAergic system in the brain is involved in the etiology of various psychiatric problems, including autism spectrum disorders (ASD), attention deficit hyperactivity disorder (ADHD) and others. These disorders are influenced not only by genetic but also by environmental factors, such as preterm birth, although the underlying mechanisms are not known. In a translational hyperoxia model, exposing mice pups at P5 to 80% oxygen for 48 h to mimic a steep rise of oxygen exposure caused by preterm birth from in utero into room air, we documented a persistent reduction of cortical mature parvalbumin-expressing interneurons until adulthood. Developmental delay of cortical myelin was observed, together with decreased expression of oligodendroglial glial cell-derived neurotrophic factor (GDNF), a factor involved in interneuronal development. Electrophysiological and morphological properties of remaining interneurons were unaffected. Behavioral deficits were observed for social interaction, learning and attention. These results demonstrate that neonatal oxidative stress can lead to decreased interneuron density and to psychiatric symptoms. The obtained cortical myelin deficit and decreased oligodendroglial GDNF expression indicate that an impaired oligodendroglial-interneuronal interplay contributes to interneuronal damage.

Evaluation of the Activity of Choline Acetyltransferase From Different Synaptosomal Fractions at the Distinct Stages of Spatial Learning in the Morris Water Maze.

Accumulated data have evidenced that brain cholinergic circuits play a crucial role in learning and memory; however, our knowledge about the participation of neocortical and hippocampal cholinergic systems in spatial learning needs to be refined. The aim of this study was to evaluate the association of the activity of membrane-bound and soluble choline acetyltransferase (ChAT) in the synaptosomal sub-fractions of the neocortex and hippocampus with performance of the spatial navigation task in the Morris water maze at different temporal stages of memory trace formation. To identify distinct stages of memory formation, rats were trained using a 5-day protocol with four trials per day. The mean escape latency for each trial was collected, and the entire dataset was subjected to principal component analysis. Based on the Morris water maze protocol, there were three relatively distinct stages of memory formation: days 1–2, day 3, and days 4–5. The remotely stored memory trace tested in repeated and reversal learning beginning on day 19 (14 days after the end of initial learning) was associated at the individual level mainly with performance during the second trial on day 21 (the third day or repeated or reversal learning). The ChAT activity data suggest the participation of cortical cholinergic projections mainly in the first stage of spatial learning (automatic sensory processing) and the involvement of hippocampal interneurons in the second stage (error-corrected learning). Cholinergic cortical interneurons participated mainly in the stage of asymptotic performance (days 4–5). It is advisable to evaluate other signalling pathways at the identified stages of memory formation.

Exploration of alcohol use disorder-associated brain miRNA\u2013mRNA regulatory networks

Transcriptomic changes in specific brain regions can influence the risk of alcohol use disorder (AUD), but the underlying mechanism is not fully understood. We investigated AUD-associated miRNA–mRNA regulatory networks in multiple brain regions by analyzing transcriptomic changes in two sets of postmortem brain tissue samples and ethanol-exposed human embryonic stem cell (hESC)-derived cortical interneurons. miRNA and mRNA transcriptomes were profiled in 192 tissue samples (Set 1) from eight brain regions (amygdala, caudate nucleus, cerebellum, hippocampus, nucleus accumbens, prefrontal cortex, putamen, and ventral tegmental area) of 12 AUD and 12 control European Australians. Nineteen differentially expressed miRNAs (fold-change>2.0 & P < 0.05) and 97 differentially expressed mRNAs (fold-change>2.0 & P < 0.001) were identified in one or multiple brain regions of AUD subjects. AUD-associated miRNA–mRNA regulatory networks in each brain region were constructed using differentially expressed and negatively correlated miRNA–mRNA pairs. AUD-relevant pathways (including CREB Signaling, IL-8 Signaling, and Axonal Guidance Signaling) were potentially regulated by AUD-associated brain miRNA–mRNA pairs. Moreover, miRNA and mRNA transcriptomes were mapped in additional 96 tissue samples (Set 2) from six of the above eight brain regions of eight AUD and eight control European Australians. Some of the AUD-associated miRNA–mRNA regulatory networks were confirmed. In addition, miRNA and mRNA transcriptomes were analyzed in hESC-derived cortical interneurons with or without ethanol exposure, and ethanol-influenced miRNA–mRNA regulatory networks were constructed. This study provided evidence that alcohol could induce concerted miRNA and mRNA expression changes in reward-related or alcohol-responsive brain regions. We concluded that altered brain miRNA–mRNA regulatory networks might contribute to AUD development.

Maternal immune activation downregulates schizophrenia genes in the foetal mouse brain.

Susceptibility to schizophrenia is mediated by genetic and environmental risk factors. Maternal immune activation by infections during pregnancy is hypothesized to be a key environmental risk factor. However, little is known about how maternal immune activation contributes to schizophrenia pathogenesis. In this study, we investigated if maternal immune activation influences the expression of genes associated with schizophrenia in foetal mouse brains. We found that two sets of schizophrenia genes were downregulated more than expected by chance in the foetal mouse brain following maternal immune activation, namely those genes associated with schizophrenia through genome-wide association study (fold change = 1.93, false discovery rate = 4 × 10−4) and downregulated genes in adult schizophrenia brains (fold change = 1.51, false discovery rate = 4 × 10−10). We found that these genes mapped to key biological processes, such as neuronal cell adhesion. We also identified cortical excitatory neurons and inhibitory interneurons as the most vulnerable cell types to the deleterious effects of this interaction. Subsequently, we used gene expression information from herpes simplex virus 1 infection of neuronal precursor cells as orthogonal evidence to support our findings and to demonstrate that schizophrenia-associated cell adhesion genes, PCDHA2, PCDHA3 and PCDHA5, were downregulated following herpes simplex virus 1 infection. Collectively, our results provide novel evidence for a link between genetic and environmental risk factors in schizophrenia pathogenesis. These findings carry important implications for early preventative strategies in schizophrenia.

Involvement of central sensory pathways in subjects with restless legs syndrome: A neurophysiological study

In patients with restless legs syndrome (RLS) a motor cortical disinhibition has been reported in transcranial magnetic stimulation (TMS) studies, but the neuronal excitability in other cortical areas has been poorly explored. The aim of this study was the functional evaluation of thalamo-cortical circuits and inhibitory cortical responses in the sensory cortex in RLS.We assessed the high-frequency somatosensory evoked potentials (HF-SEP) in sixteen subjects suffering from RLS of different degrees of severity.In patients with severe or very severe RLS we found a significant desynchronization with amplitude reduction of both pre- and post-synaptic HF-SEP bursts, which suggest an impairment in the thalamo-cortical projections and in the cortical inhibitory interneurons activity, respectively.The assessment of the central sensory pathways by means of HF-SEP may shed light on the pathophysiological mechanisms of RLS.

Extensive Structural Remodeling of the Axonal Arbors of Parvalbumin Basket Cells during Development in Mouse Neocortex.

Parvalbumin-containing (PV+) basket cells are specialized cortical interneurons that regulate the activity of local neuronal circuits with high temporal precision and reliability. To understand how the PV+ interneuron connectivity underlying these functional properties is established during development, we used array tomography to map pairs of synaptically connected PV+ interneurons and postsynaptic neurons from the neocortex of mice of both sexes. We focused on the axon-myelin unit of the PV+ interneuron and quantified the number of synapses onto the postsynaptic neuron, length of connecting axonal paths, and their myelination at different time points between 2 weeks and 7 months of age. We find that myelination of the proximal axon occurs very rapidly during the third and, to a lesser extent, fourth postnatal weeks. The number of synaptic contacts made by the PV+ interneuron on its postsynaptic partner meanwhile is significantly reduced to about one-third by the end of the first postnatal month. The number of autapses, the synapses that PV+ interneurons form on themselves, however, remains constant throughout the examined period. Axon reorganizations continue beyond postnatal month 2, with the postsynaptic targets of PV+ interneurons gradually shifting to more proximal locations, and the length of axonal paths and their myelin becoming conspicuously uniform per connection. These continued microcircuit refinements likely provide the structural substrate for the robust inhibitory effects and fine temporal precision of adult PV+ basket cells.SIGNIFICANCE STATEMENT The axon of adult parvalbumin-containing (PV+) interneurons is highly specialized for fast and reliable neurotransmission. It is myelinated and forms synapses mostly onto the cell bodies and proximal dendrites of postsynaptic neurons for maximal impact. In this study, we follow the development of the PV+ interneuron axon, its myelination and synapse formation, revealing a rapid sequence of axonal reorganization, myelination of the PV+ interneuron proximal axon, and pruning of almost two-thirds of the synapses in an individual connection. This is followed by a prolonged period of axon refinement and additional myelination leading to a remarkable precision of connections in the adult mouse cortex, consistent with the temporal precision and fidelity of PV+ interneuron action.

Identification of Vulnerable Interneuron Subtypes in 15q13.3 Microdeletion Syndrome Using Single-Cell Transcriptomics

BackgroundA number of rare copy number variants (CNVs) have been linked to neurodevelopmental disorders. However, because CNVs encompass many genes, it is often difficult to identify the mechanisms that lead to developmental perturbations. MethodsWe used 15q13.3 microdeletion to propose and validate a novel strategy to predict the impact of CNV genes on brain development that could further guide functional studies. We analyzed single-cell transcriptomics datasets containing cortical interneurons to identify their developmental vulnerability to 15q13.3 microdeletion, which was validated in mouse models. ResultsWe found that Klf13—but not other 15q13.3 genes—is expressed by precursors and neuroblasts in the medial and caudal ganglionic eminences during development, with a peak of expression at embryonic day (E)13.5 and E18.5, respectively. In contrast, in the adult mouse brain, Klf13 expression is negligible. Using Df(h15q13.3)/+ and Klf13+/− embryos, we observed a precursor subtype-specific impairment in proliferation in the medial ganglionic eminence and caudal ganglionic eminence at E13.5 and E17.5, respectively, corresponding to vulnerability predicted by Klf13 expression patterns. Finally, Klf13+/− mice showed a layer-specific decrease in parvalbumin and somatostatin cortical interneurons accompanied by changes in locomotor and anxiety-related behavior. ConclusionsWe show that the impact of 15q13.3 microdeletion on precursor proliferation is grounded in a reduction in Klf13 expression. The lack of Klf13 in Df(h15q13.3)/+ cortex might be the major reason for perturbed density of cortical interneurons. Thus, the behavioral defects seen in 15q13.3 microdeletion could stem from a developmental perturbation owing to selective vulnerability of cortical interneurons during sensitive stages of their development.

Genetic and epigenetic coordination of cortical interneuron development.

One of the hallmarks of the cerebral cortex is the extreme diversity of interneurons1-3. The two largest subtypes of cortical interneurons, parvalbumin- and somatostatin-positive cells, are morphologically and functionally distinct in adulthood but arise from common lineages within the medial ganglionic eminence4-11. This makes them an attractive model for studying the generation of cell diversity. Here we examine how developmental changes in transcription and chromatin structure enable these cells to acquire distinct identities in the mouse cortex. Generic interneuron features are first detected upon cell cycle exit through the opening of chromatin at distal elements. By constructing cell-type-specific gene regulatory networks, we observed that parvalbumin- and somatostatin-positive cells initiate distinct programs upon settling within the cortex. We used these networks to model the differential transcriptional requirement of a shared regulator, Mef2c, and confirmed the accuracy of our predictions through experimental loss-of-function experiments. We therefore reveal how a common molecular program diverges to enable these neuronal subtypes to acquire highly specialized properties by adulthood. Our methods provide a framework for examining the emergence of cellular diversity, as well as for quantifying and predicting the effect of candidate genes on cell-type-specific development.

NMDARs Drive the Expression of Neuropsychiatric Disorder Risk Genes Within GABAergic Interneuron Subtypes in the Juvenile Brain.

Medial ganglionic eminence (MGE)-derived parvalbumin (PV)+, somatostatin (SST)+and Neurogliaform (NGFC)-type cortical and hippocampal interneurons, have distinct molecular, anatomical, and physiological properties. However, the molecular mechanisms regulating their maturation remain poorly understood. Here, via single-cell transcriptomics, we show that the obligate NMDA-type glutamate receptor (NMDAR) subunit gene Grin1 mediates transcriptional regulation of gene expression in specific subtypes of MGE-derived interneurons, leading to altered subtype abundances. Notably, MGE-specific early developmental Grin1 loss results in a broad downregulation of diverse transcriptional, synaptogenic and membrane excitability regulatory programs in the juvenile brain. These widespread gene expression abnormalities mirror aberrations that are typically associated with neurodevelopmental disorders. Our study hence provides a road map for the systematic examination of NMDAR signaling in interneuron subtypes, revealing potential MGE-specific genetic targets that could instruct future therapies of psychiatric disorders.

A functional cerebral endothelium is necessary to protect against cognitive decline

A vascular insult occurring early in disease onset may initiate cognitive decline leading to dementia, while pharmacological and lifestyle interventions can prevent this progression. Mice with a selective, tamoxifen-inducible deletion of NF-κB essential modulator (Nemo) in brain endothelial cells were studied as a model of vascular cognitive impairment. Groups included NemoFl controls and three NemobeKO groups: One untreated, and two treated with simvastatin or exercise. Social preference and nesting were impaired in NemobeKO mice and were not countered by treatments. Cerebrovascular function was compromised in NemobeKO groups regardless of treatment, with decreased changes in sensory-evoked cerebral blood flow and total hemoglobin levels, and impaired endothelium-dependent vasodilation. NemobeKO mice had increased string vessel pathology, blood-brain barrier disruption, neuroinflammation, and reduced cortical somatostatin-containing interneurons. These alterations were reversed when endothelial function was recovered. Findings strongly suggest that damage to the cerebral endothelium can trigger pathologies associated with dementia and its functional integrity should be an effective target in future therapeutic efforts.

Development, Diversity, and Death of MGE-Derived Cortical Interneurons.

In the mammalian brain, cortical interneurons (INs) are a highly diverse group of cells. A key neurophysiological question concerns how each class of INs contributes to cortical circuit function and whether specific roles can be attributed to a selective cell type. To address this question, researchers are integrating knowledge derived from transcriptomic, histological, electrophysiological, developmental, and functional experiments to extensively characterise the different classes of INs. Our hope is that such knowledge permits the selective targeting of cell types for therapeutic endeavours. This review will focus on two of the main types of INs, namely the parvalbumin (PV+) or somatostatin (SOM+)-containing cells, and summarise the research to date on these classes.

Chemogenetic Activation of Cortical Parvalbumin-Positive Interneurons Reverses Noise-Induced Impairments in Gap Detection.

Exposure to loud noises not only leads to trauma and loss of output from the ear but also alters downstream central auditory circuits. A perceptual consequence of noise-induced central auditory disruption is impairment in gap-induced prepulse inhibition, also known as gap detection. Recent studies have implicated cortical parvalbumin (PV)-positive inhibitory interneurons in gap detection and prepulse inhibition. Here, we show that exposure to loud noises specifically reduces the density of cortical PV but not somatostatin (SOM)-positive interneurons in the primary auditory cortex in mice (C57BL/6) of both sexes. Optogenetic activation of PV neurons produced less cortical inhibition in noise-exposed than sham-exposed animals, indicative of reduced PV neuron function. Activation of SOM neurons resulted in similar levels of cortical inhibition in noise- and sham-exposed groups. Furthermore, chemogenetic activation of PV neurons with the hM3-based designer receptor exclusively activated by designer drugs completely reversed the impairments in gap detection for noise-exposed animals. These results support the notions that cortical PV neurons encode gap in sound and that PV neuron dysfunction contributes to noise-induced impairment in gap detection.SIGNIFICANCE STATEMENT Noise-induced hearing loss contributes to a range of central auditory processing deficits (CAPDs). The mechanisms underlying noise-induced CAPDs are still poorly understood. Here we show that exposure to loud noises results in dysfunction of PV-positive but not somatostatin-positive inhibitory interneurons in the primary auditory cortex. In addition, cortical PV inhibitory neurons in noise-exposed animals had reduced expression of glutamic acid decarboxylases and weakened inhibition on cortical activity. Noise exposure resulted in impaired gap detection, indicative of disrupted temporal sound processing and possibly tinnitus. We found that chemogenetic activation of cortical PV inhibitory interneurons alleviated the deficits in gap detection. These results implicate PV neuron dysfunction as a mechanism for noise-induced CAPDs.

Postmitotic Prox1 Expression Controls the Final Specification of Cortical VIP Interneuron Subtypes.

Throughout development, neuronal identity is controlled by key transcription factors that determine the unique properties of a cell. During embryogenesis, the transcription factor Prox1 regulates VIP-positive cortical interneuron migration, survival, and connectivity. Here, we explore the role of Prox1 as a regulator of genetic programs that guide the final specification of VIP interneuron subtypes in early postnatal life. Synaptic in vitro electrophysiology in male and female mice shows that postnatal Prox1 removal differentially affects the dynamics of excitatory inputs onto VIP bipolar and multipolar subtypes. RNA sequencing reveals that one of the downstream targets of Prox1 is the postsynaptic protein Elfn1, a constitutive regulator of presynaptic release probability. Further genetic, pharmacological, and electrophysiological experiments demonstrate that removing Prox1 reduces Elfn1 function in VIP multipolar but not in bipolar cells. Finally, overexpression experiments and analysis of native Elfn1 mRNA expression reveal that Elfn1 levels are differentially controlled at the post-transcriptional stage. Thus, in addition to activity-dependent processes that contribute to the developmental trajectory of VIP cells, genetic programs engaged by Prox1 control the final differentiation of multipolar and bipolar subtypes.SIGNIFICANCE STATEMENT The transcription factor Prox1 generates functional diversification of cortical VIP interneuron subtypes in early postnatal life, thus expanding the inhibitory repertoire of the cortex.

Thyroid Hormone Transporter Deficiency in Mice Impacts Multiple Stages of GABAergic Interneuron Development.

Cortical interneuron neurogenesis is strictly regulated and depends on the presence of thyroid hormone (TH). In particular, inhibitory interneurons expressing the calcium binding protein Parvalbumin are highly sensitive toward developmental hypothyroidism. Reduced numbers of Parvalbumin-positive interneurons are observed in mice due to the combined absence of the TH transporters Mct8 and Oatp1c1. To unravel if cortical Parvalbumin-positive interneurons depend on cell-autonomous action of Mct8/Oatp1c1, we compared Mct8/Oatp1c1 double knockout (dko) mice to conditional knockouts with abolished TH transporter expression in progenitors of Parvalbumin-positive interneurons. These conditional knockouts exhibited a transient delay in the appearance of Parvalbumin-positive interneurons in the early postnatal somatosensory cortex while cell numbers remained permanently reduced in Mct8/Oatp1c1 dko mice. Using fluorescence in situ hybridization on E12.5 embryonic brains, we detected reduced expression of sonic hedgehog signaling components in Mct8/Oatp1c1 dko embryos only. Moreover, we revealed spatially distinct expression patterns of both TH transporters at brain barriers at E12.5 by immunofluorescence. At later developmental stages, we uncovered a sequential expression of first Oatp1c1 in individual interneurons and then Mct8 in Parvalbumin-positive subtypes. Together, our results point to multiple cell-autonomous and noncell-autonomous mechanisms that depend on proper TH transport during cortical interneuron development.

FLRT2 and FLRT3 Cooperate in Maintaining the Tangential Migratory Streams of Cortical Interneurons during Development.

Neuron migration is a hallmark of nervous system development that allows gathering of neurons from different origins for assembling of functional neuronal circuits. Cortical inhibitory interneurons arise in the ventral telencephalon and migrate tangentially forming three transient migratory streams in the cortex before reaching the final laminar destination. Although migration defects lead to the disruption of inhibitory circuits and are linked to aspects of psychiatric disorders such as autism and schizophrenia, the molecular mechanisms controlling cortical interneuron development and final layer positioning are incompletely understood. Here, we show that mouse embryos with a double deletion of FLRT2 and FLRT3 genes encoding cell adhesion molecules exhibit an abnormal distribution of interneurons within the streams during development, which in turn, affect the layering of somatostatin+ interneurons postnatally. Mechanistically, FLRT2 and FLRT3 proteins act in a noncell-autonomous manner, possibly through a repulsive mechanism. In support of such a conclusion, double knockouts deficient in the repulsive receptors for FLRTs, Unc5B and Unc5D, also display interneuron defects during development, similar to the FLRT2/FLRT3 mutants. Moreover, FLRT proteins are chemorepellent ligands for developing interneurons in vitro, an effect that is in part dependent on FLRT-Unc5 interaction. Together, we propose that FLRTs act through Unc5 receptors to control cortical interneuron distribution in a mechanism that involves cell repulsion.SIGNIFICANCE STATEMENT Disruption of inhibitory cortical circuits is responsible for some aspects of psychiatric disorders such as schizophrenia or autism. These defects include interneuron migration during development. A crucial step during this process is the formation of three transient migratory streams within the developing cortex that determine the timing of interneuron final positioning and the formation of functional cortical circuits in the adult. We report that FLRT proteins are required for the proper distribution of interneurons within the cortical migratory streams and for the final laminar allocation in the postnatal cortex. These results expand the multifunctional role of FLRTs during nervous system development in addition to the role of FLRTs in axon guidance and the migration of excitatory cortical neurons.

Early impairment of thalamocortical circuit activity and coherence in a mouse model of Huntington's disease

Huntington's disease (HD) is a progressive, fatal neurodegenerative disorder characterized by motor, cognitive, and psychiatric disturbances. There is no known cure for HD, but its progressive nature allows for early therapeutic intervention. Currently, much of the research has focused on the striatum, however, there is evidence suggesting that disruption of thalamocortical circuits could underlie some of the early symptoms of HD. Loss of both cortical pyramidal neurons (CPNs) and thalamic neurons occurs in HD patients, and cognitive, somatosensory, and attention deficits precede motor abnormalities. However, the role of thalamocortical pathways in HD progression has been understudied. Here, we measured single unit activity and local field potentials (LFPs) from electrode arrays implanted in the thalamus and primary motor cortex of 4–5 month-old male and female Q175 mice. We assessed neuronal activity under baseline conditions as well as during presentation of rewards delivered via actuation of an audible solenoid valve. HD mice showed a significantly delayed licking response to the reward stimulus. At the same time, neuronal activation to the reward was delayed in thalamic neurons, CPNs and fast-spiking cortical interneurons (FSIs) of HD mice. In addition, thalamocortical coherence increased at lower frequencies in HD relative to wildtype mice. Together, these data provide evidence that impaired cortical and thalamic responses to reward stimuli, and impaired thalamocortical coherence, may play an important early role in motor, cognitive, and learning deficits in HD patients.

Prefrontal GABAergic Interneurons Gate Long-Range Afferents to Regulate Prefrontal Cortex-Associated Complex Behaviors.

Prefrontal cortical GABAergic interneurons (INs) and their innervations are essential for the execution of complex behaviors such as working memory, social behavior, and fear expression. These behavior regulations are highly dependent on primary long-range afferents originating from the subcortical structures such as mediodorsal thalamus (MD), ventral hippocampus (vHPC), and basolateral amygdala (BLA). In turn, the regulatory effects of these inputs are mediated by activation of parvalbumin-expressing (PV) and/or somatostatin expressing (SST) INs within the prefrontal cortex (PFC). Here we review how each of these long-range afferents from the MD, vHPC, or BLA recruits a subset of the prefrontal interneuron population to exert precise control of specific PFC-dependent behaviors. Specifically, we first summarize the anatomical connections of different long-range inputs formed on prefrontal GABAergic INs, focusing on PV versus SST cells. Next, we elaborate on the role of prefrontal PV- and SST- INs in regulating MD afferents-mediated cognitive behaviors. We also examine how prefrontal PV- and SST- INs gate vHPC afferents in spatial working memory and fear expression. Finally, we discuss the possibility that prefrontal PV-INs mediate fear conditioning, predominantly driven by the BLA-mPFC pathway. This review will provide a broad view of how multiple long-range inputs converge on prefrontal interneurons to regulate complex behaviors and novel future directions to understand how PFC controls different behaviors.

Characterization and Stage-Dependent Lineage Analysis of Intermediate Progenitors of Cortical GABAergic Interneurons.

Intermediate progenitors of both excitatory and inhibitory neurons, which can replenish neurons in the adult brain, were recently identified. However, the generation of intermediate progenitors of GABAergic inhibitory neurons (IPGNs) has not been studied in detail. Here, we characterized the spatiotemporal distribution of IPGNs in mouse cerebral cortex. IPGNs generated neurons during both embryonic and postnatal stages, but the embryonic IPGNs were more proliferative. Our lineage tracing analyses showed that the embryonically proliferating IPGNs tended to localize to the superficial layers rather than the deep cortical layers at 3 weeks after birth. We also found that embryonic IPGNs derived from the medial and caudal ganglionic eminence (CGE) but more than half of the embryonic IPGNs were derived from the CGE and broadly distributed in the cerebral cortex. Taken together, our data indicate that the broadly located IPGNs during embryonic and postnatal stages exhibit a different proliferative property and layer distribution.