FXR1 regulation of parvalbumin interneurons in the prefrontal cortex is critical for schizophrenia-like behaviors.

Parvalbumin interneurons (PVIs) are affected in many psychiatric disorders including schizophrenia (SCZ), however the mechanism remains unclear. FXR1, a high confident risk gene for SCZ, is indispensable but its role in the brain is largely unknown. We show that deleting FXR1 from PVIs of medial prefrontal cortex (mPFC) leads to reduced PVI excitability, impaired mPFC gamma oscillation, and SCZ-like behaviors. PVI-specific translational profiling reveals that FXR1 regulates the expression of Cacna1h/Cav3.2 a T-type calcium channel implicated in autism and epilepsy. Inhibition of Cav3.2 in PVIs of mPFC phenocopies whereas elevation of Cav3.2 in PVIs of mPFC rescues behavioral deficits resulted from FXR1 deficiency. Stimulation of PVIs using a gamma oscillation-enhancing light flicker rescues behavioral abnormalities caused by FXR1 deficiency in PVIs. This work unveils the function of a newly identified SCZ risk gene in SCZ-relevant neurons and identifies a therapeutic target and a potential noninvasive treatment for psychiatric disorders.

Medial Prefrontal Cortex-Pontine Nuclei Projections Modulate Suboptimal Cue-Induced Associative Motor Learning.

Diverse and powerful mechanisms have evolved to enable organisms to modulate learning and memory under a variety of survival conditions. Cumulative evidence has shown that the prefrontal cortex (PFC) is closely involved in many higher-order cognitive functions. However, when and how the medial PFC (mPFC) modulates associative motor learning remains largely unknown. Here, we show that delay eyeblink conditioning (DEC) with the weak conditioned stimulus (wCS) but not the strong CS (sCS) elicited a significant increase in the levels of c-Fos expression in caudal mPFC. Both optogenetic inhibition and activation of the bilateral caudal mPFC, or its axon terminals at the pontine nucleus (PN) contralateral to the training eye, significantly impaired the acquisition, recent and remote retrieval of DEC with the wCS but not the sCS. However, direct optogenetic activation of the contralateral PN had no significant effect on the acquisition, recent and remote retrieval of DEC. These results are of great importance in understanding the elusive role of the mPFC and its projection to PN in subserving the associative motor learning under suboptimal learning cue.

Continuous spike-waves during slow-wave sleep in a mouse model of focal cortical dysplasia.

OBJECTIVE: To examine if mice with focal cortical dysplasia (FCD) develop spontaneous epileptic seizures and, if so, determine the key electroencephalography (EEG) features. METHODS: Unilateral single freeze lesions to the S1 region (SFLS1R) were made in postnatal day 0-1 pups to induce a neocortical microgyrus in the right cortical hemisphere. Continuous 24-h recordings with intracranial EEG electrodes and behavioral tests were performed in adult SFLS1R and sham-control mice to assess neurologic status. RESULTS: A high percentage of adult SFLS1R animals (89%, 40/45) exhibited at least one or more spontaneous nonconvulsive seizure events over the course of 24 h. Of these animals, 60% (27/45) presented with a chronic seizure state that was persistent throughout the recording session, consisting of bursts of rhythmic high-amplitude spike-wave activities and primarily occurring during periods of slow-wave sleep. In comparison, none of the control, age-matched, mice (0/12) developed seizures. The epileptic discharge pattern closely resembled a pattern of continuous spike-waves during slow-wave sleep (CSWS) of the human syndrome described as an electrical status epilepticus during slow-wave sleep (ESES). Key findings in the SFLS1R model indicated that the observed CSWS (1) were more prevalent in female (18/23) versus male (9/22, p < 0.05), (2) were strongest in the right S1 region although generalized to other brain regions, (3) were associated with significant cognitive and behavioral deficits, (4) were temporarily alleviated by ethosuximide treatment or optogenetic activation of cortical γ-aminobutyric acid (GABA)ergic neurons, and (5) theta and alpha band rhythms may play a key role in the generalization of spike-wave activities. SIGNIFICANCE: This is the first report of an in vivo animal FCD model that induces chronic spontaneous electrographic brain seizures. Further characterization of the abnormal oscillations in this mouse model may lead to a better understanding of the mechanisms of CSWS/ESES.

Thorough GABAergic innervation of the entire axon initial segment revealed by an optogenetic 'laserspritzer'.

GABAergic terminals of chandelier cells exclusively innervate the axon initial segment (AIS) of excitatory neurons. Although the anatomy of these synapses has been well-studied in several brain areas, relatively little is known about their physiological properties. Using vesicular γ-aminobutyric acid transporter-channelrhodopsin 2-enhanced yellow fluorescence protein (VGAT-ChR2-YFP)-expressing mice and a novel fibreoptic 'laserspritzer' approach that we developed, we investigated the physiological properties of axo-axonic synapses (AASs) in brain slices from the piriform cortex (PC) of mice. AASs were in close proximity to voltage-gated Na(+) (NaV) channels located at the AIS. AASs were selectively activated by a 5 µm laserspritzer placed in close proximity to the AIS. Under a minimal laser stimulation condition and using whole-cell somatic voltage-clamp recordings, the amplitudes and kinetics of IPSCs mediated by AASs were similar to those mediated by perisomatic inhibitions. Results were further validated with channelrhodopsin 2-assisted circuit mapping (CRACM) of the entire inhibitory inputs map. For the first time, we revealed that the laserspritzer-induced AAS-IPSCs persisted in the presence of TTX and TEA but not 4-AP. Next, using gramicidin-based perforated patch recordings, we found that the GABA reversal potential (EGABA) was -73.6 ± 1.2 mV when induced at the AIS and -72.8 ± 1.1 mV when induced at the perisomatic site. Our anatomical and physiological results lead to the novel conclusions that: (1) AASs innervate the entire length of the AIS, as opposed to forming a highly concentrated cartridge, (2) AAS inhibition suppresses action potentials and epileptiform activity more robustly than perisomatic inhibitions, and (3) AAS activation alone can be sufficient to inhibit action potential generation and epileptiform activities in vitro.

A key mechanism underlying sensory experience-dependent maturation of neocortical GABAergic circuits in vivo.

Mechanisms underlying experience-dependent refinement of cortical connections, especially GABAergic inhibitory circuits, are unknown. By using a line of mutant mice that lack activity-dependent BDNF expression (bdnf-KIV), we show that experience regulation of cortical GABAergic network is mediated by activity-driven BDNF expression. Levels of endogenous BDNF protein in the barrel cortex are strongly regulated by sensory inputs from whiskers. There is a severe alteration of excitation and inhibition balance in the barrel cortex of bdnf-KIV mice as a result of reduced inhibitory but not excitatory conductance. Within the inhibitory circuits, the mutant barrel cortex exhibits significantly reduced levels of GABA release only from the parvalbumin-expressing fast-spiking (FS) interneurons, but not other interneuron subtypes. Postnatal deprivation of sensory inputs markedly decreased perisomatic inhibition selectively from FS cells in wild-type but not bdnf-KIV mice. These results suggest that postnatal experience, through activity-driven BDNF expression, controls cortical development by regulating FS cell-mediated perisomatic inhibition in vivo.

Modulation of cortical representations of sensory and contextual information underlies aversive associative learning.

Cortical neurons encode both sensory and contextual information, yet it remains unclear how experiences modulate these cortical representations. Here, we demonstrate that trace eyeblink conditioning (TEC), an aversive associative-learning paradigm linking conditioned (CS) with unconditioned stimuli (US), finely tunes cortical coding at both population and single-neuron levels. Initially, we show that the primary somatosensory cortex (S1) is necessary for TEC acquisition, as evidenced by local muscimol administration. At the population level, TEC enhances activity in a small subset (∼20%) of CS- or US-responsive primary neurons (rPNs) while diminishing activity in non-rPNs, including locomotion-tuned or unresponsive PNs. Crucially, TEC learning modulates the encoding of sensory versus contextual information in single rPNs: CS-responsive neurons become less responsive, while US-responsive neurons gain responses to CS. Moreover, we find that the cholinergic pathway, via nicotinic receptors, underlies TEC-induced modulations. These findings suggest that experiences dynamically tune cortical representations through cholinergic pathways.

A prefrontal motor circuit initiates persistent movement.

Persistence reinforces continuous action, which benefits animals in many aspects. Diverse information may trigger animals to start a persistent movement. However, it is unclear how the brain decides to persist with current actions by selecting specific information. Using single-unit extracellular recordings and opto-tagging in awake mice, we demonstrated that a group of dorsal mPFC (dmPFC) motor cortex projecting (MP) neurons initiate a persistent movement selectively encoding contextual information rather than natural valence. Inactivation of dmPFC MP neurons impairs the initiation and reduces neuronal activity in the insular and motor cortex. Finally, a computational model suggests that a successive sensory stimulus acts as an input signal for the dmPFC MP neurons to initiate a persistent movement. These results reveal a neural initiation mechanism on the persistent movement.

A prefrontal motor circuit initiates persistent movement.

Persistence reinforces continuous action, which benefits animals in many aspects. Diverse external or internal signals may trigger animals to start a persistent movement. However, it is unclear how the brain decides to persist with current actions by selecting specific information. Using single-unit extracellular recordings and opto-tagging in awake mice, we demonstrated that a group of dorsal mPFC (dmPFC) motor cortex projecting (MP) neurons initiate a persistent movement by selectively encoding contextual information rather than natural valence. Inactivation of dmPFC MP neurons impairs the initiation and reduces neuronal activity in the insular and motor cortex. After the persistent movement is initiated, the dmPFC MP neurons are not required to maintain it. Finally, a computational model suggests that a successive sensory stimulus acts as an input signal for the dmPFC MP neurons to initiate a persistent movement. These results reveal a neural initiation mechanism on the persistent movement.

Learning induced neuronal identity switch in the superficial layers of the primary somatosensory cortex.

During learning, multi-dimensional inputs are integrated within the sensory cortices. However, the strategies by which the sensory cortex employs to achieve learning remains poorly understood. We studied the sensory cortical neuronal coding of trace eyeblink conditioning (TEC) in head-fixed, freely running mice, where whisker deflection was used as a conditioned stimulus (CS) and an air puff to the cornea delivered after an interval was used as unconditioned stimulus (US). After training, mice learned the task with a set of stereotypical behavioral changes, most prominent ones include prolonged closure of eyelids, and increased reverse running between CS and US onset. The local blockade of the primary somatosensory cortex (S1) activities with muscimol abolished the behavior learning suggesting that S1 is required for the TEC. In naive animals, based on the response properties to the CS and US, identities of the small proportion (~20%) of responsive primary neurons (PNs) were divided into two subtypes: CR (i.e. CS-responsive) and UR neurons (i.e. US-responsive). After animals learned the task, identity of CR and UR neurons changed: while the CR neurons are less responsive to CS, UR neurons gain responsiveness to CS, a new phenomenon we defined as 'learning induced neuronal identity switch (LINIS)'. To explore the potential mechanisms underlying LINIS, we found that systemic and local (i.e. in S1) administration of the nicotinic receptor antagonist during TEC training blocked the LINIS, and concomitantly disrupted the behavior learning. Additionally, we monitored responses of two types of cortical interneurons (INs) and observed that the responses of the somatostatin-expressing (SST), but not parvalbumin-expressing (PV) INs are negatively correlated with the learning performance, suggesting that SST-INs contribute to the LINIS. Thus, we conclude that L2/3 PNs in S1 encode perceptual learning by LINIS like mechanisms, and cholinergic pathways and cortical SST interneurons are involved in the formation of LINIS.

Persistence is driven by a prefrontal motor circuit.

Persistence provides a long-lasting effect on actions, including avoiding predators and storing energy, and hence is crucial for the survival (Adolphs and Anderson, 2018). However, how the brain loads persistence on movements is unknown. Here, we demonstrate that being persistent is determined at the initial phase of movement, and this persistency will be sustained until the terminal signaling. The neural coding of persistent movement phases (initial or terminal) is independent from the judgement (i.e. valence) (Li et al., 2022; Wang et al., 2018) upon the external stimuli. Next, we identify a group of dorsal medial prefrontal cortex (dmPFC) motor cortex projecting (MP) neurons (Wang and Sun, 2021), which encodes the initial phase of a persistent movement rather than the valence. Inactivation of dmPFC MP neurons impairs the initiation of persistency and reduce the neural activity in the insular and motor cortex. Finally, a MP network-based computational model suggests that an intact, successive sensory stimulus acts as a triggering signal to direct the initiation of persistent movements. These findings reveal a neural mechanism that transforms the brain state from neutral to persistent during a movement.

Whisker experience modulates long-term depression in neocortical γ-aminobutyric acidergic interneurons in barrel cortex.

Long-term plasticity is believed to be an important mechanism that allows neural circuits to be modulated in an use-dependent manner. However, evidence regarding the role of sensory experience in modulating long-term plasticity of glutamatergic synapses in neocortical GABAergic interneurons is unavailable. Here, we focused on regular-spiking nonpyramidal (RSNP) interneurons and examined spike-pairing-induced plasticity of glutamatergic synapses and its modulation by sensory experiences ex vivo. In our previous studies, RSNP interneurons do not show experience-dependent plasticity of intrinsic properties or alteration of thalamocortical (TC) synapses and exhibit robust modulation by mGluRs. Here we report a spike-pairing-induced long-term depression (spLTD) of glutamatergic synapses in RSNP interneurons of barrels cortex. Using paired recording and thalamic-induced responses, we found that the spLTD was specific for intracortical but not TC synapses. The spLTD was mediated via presynaptic mGluRs. The spLTD was not modulated by chronic or acute administration of NMDAR antagonists but was enhanced by sensory deprivation (via whisker trimming) during a postnatal sensitive period ex vivo. The synapses specific spLTD to intracortical glutamatergic synapses in RSNP cells and their modulation by sensory deprivation may contribute to sensory-dependent remodeling of cortical circuits and redistribution circuit activity along the whisker-related columns.

A long-range, recurrent neuronal network linking the emotion regions with the somatic motor cortex.

Recurrent neural networks (RNNs) are designed to learn sequential patterns in silico, but it is unclear whether and how an RNN forms in the native networks of the mammalian brain. Here, we report an innate RNN, which is formed by the unidirectional connections from three basic units: input units arriving from emotion regions, a hidden unit in the medial prefrontal cortex (mPFC), and output units located at the somatic motor cortex (sMO). Specifically, the neurons from basal lateral amygdala (BLA) and the insular cortex (IC) project to the mPFC motor-cortex-projecting (MP) neurons. These MP neurons form a local self-feedback loop and target major projecting neurons of the sMO. Within the sMO, the neurons in the infragranular layers receive stronger input than the neurons in supragranular layers. Finally, we show in vivo evidence that the communications from the emotion regions to the sMO are abolished when MP neurons are chemogenetically silenced.

Circuit Mechanisms Underlying Epileptogenesis in a Mouse Model of Focal Cortical Malformation.

The way in which aberrant neural circuits contribute to epilepsy remains unclear. To elucidate this question, we dissected the circuit mechanisms underlying epileptogenesis using a mouse model of focal cortical malformation with spontaneous epileptiform discharges. We found that spontaneous spike-wave discharges and optogenetically induced hyperexcitable bursts in vivo were present in a cortical region distal to (>0.7 mm) freeze-lesion-induced microgyrus, instead of near the microgyrus. ChR2-assisted circuit mapping revealed ectopic inter-laminar excitatory input from infragranular layers to layers 2/3 pyramidal neurons as the key component of hyperexcitable circuitry. This hyperactivity disrupted the balance between excitation and inhibition and was more prominent in the cortical region distal to the microgyrus. Consistently, the inhibition from both parvalbumin-positive interneurons (PV) and somatostatin-positive interneurons (SOM) to pyramidal neurons were altered in a layer- and site-specific fashion. Finally, closed-loop optogenetic stimulation of SOM, but not PV, terminated spontaneous spike-wave discharges. Together, these results demonstrate the occurrence of highly site- and cell-type-specific synaptic reorganization underlying epileptic cortical circuits and provide new insights into potential treatment strategies.

GABAergic inhibitory interneurons in the posterior piriform cortex of the GAD67-GFP mouse.

Gamma-aminobutyric acid (GABA)-releasing inhibitory interneurons, a critical component of cortical circuitry, are involved in myriad known functional roles. However, information regarding the cytoarchitectural, physiological, and molecular properties of interneurons in posterior piriform cortex (PPC) is sparse. Taking advantage of the glutamic acid decarboxylase (GAD)67-enhanced green fluorescent protein (EGFP) mouse, we used in vitro whole-cell patch-clamp techniques to record from GABAergic interneurons across all 3 layers of PPC and, subsequently, to reconstruct their morphology. For the first time, 5 groups of interneurons are identified, whose firing types are defined based on those described within neocortex. Interestingly, each interneuron group with a distinct firing type also exhibits unique morphological properties, laminar distributions, and excitatory synaptic properties. The dendritic and axonal processes demonstrate subtype-specific orientations and a differential expression of spines and boutons, respectively. In addition, the active and passive electrophysiological properties of these cells show marked intergroup differences. Immunohistochemical techniques revealed a laminar-specific distribution of calcium-binding proteins and vasoactive intestinal peptide (VIP) expression. Surprisingly, excitatory synaptic properties in several groups lack target-specific differences seen in neocortical circuits, reflecting a circuit arranged with less complexity. These data aid in the identification of PPC interneurons and allow us to make well-supported postulations about their functional properties.

Experience-dependent intrinsic plasticity in interneurons of barrel cortex layer IV.

It is unclear whether intrinsic excitabilities of specific interneurons are modulated by sensory experiences. Here, I examined the intrinsic excitabilities of interneurons in "sensory-spared" and "sensory-deprived" cortices of GAD67-GFP mice. The results showed that whisker trimming, begun at postnatal day 7 for 3 wk, induced significant changes in intrinsic and firing properties of fast-spiking (FS) but not regular spiking nonpyramidal (RSNP) cells. Firing threshold, spike frequency, spike adaptation index, and input resistance of FS cells were significantly altered by sensory deprivation such that FS cells became less excitable. An up-regulation of IA currents in FS cells appeared to be responsible. Along with changes in the intrinsic properties of FS cells, whisker trimming also induced a robust reduction in the number of vesicular glutamate transporter 2 positive varicosities and parvalbumin expression and the strength of thalamocortical (TC) excitatory postsynaptic currents in FS cells in the "sensory-deprived barrels." The probability of spike induction by TC stimulus was reduced by 30% and the spike jitter was increased in sensory-deprived FS cells. These results suggest that the FS networks are selectively inhibited by sensory deprivation. The concurrent changes of intrinsic properties and expression of parvalbumin in FS but not RSNP cells with TC synapses support a contribution from the TC pathway and glutamate to sensory-induced activity-dependent intrinsic plasticity of inhibitory networks in barrel cortex.

A novel role of dendritic gap junction and mechanisms underlying its interaction with thalamocortical conductance in fast spiking inhibitory neurons.

BACKGROUND: Little is known about the roles of dendritic gap junctions (GJs) of inhibitory interneurons in modulating temporal properties of sensory induced responses in sensory cortices. Electrophysiological dual patch-clamp recording and computational simulation methods were used in combination to examine a novel role of GJs in sensory mediated feed-forward inhibitory responses in barrel cortex layer IV and its underlying mechanisms. RESULTS: Under physiological conditions, excitatory post-junctional potentials (EPJPs) interact with thalamocortical (TC) inputs within an unprecedented few milliseconds (i.e. over 200 Hz) to enhance the firing probability and synchrony of coupled fast-spiking (FS) cells. Dendritic GJ coupling allows fourfold increase in synchrony and a significant enhancement in spike transmission efficacy in excitatory spiny stellate cells. The model revealed the following novel mechanisms: 1) rapid capacitive current (Icap) underlies the activation of voltage-gated sodium channels; 2) there was less than 2 milliseconds in which the Icap underlying TC input and EPJP was coupled effectively; 3) cells with dendritic GJs had larger input conductance and smaller membrane response to weaker inputs; 4) synchrony in inhibitory networks by GJ coupling leads to reduced sporadic lateral inhibition and increased TC transmission efficacy. CONCLUSION: Dendritic GJs of neocortical inhibitory networks can have very powerful effects in modulating the strength and the temporal properties of sensory induced feed-forward inhibitory and excitatory responses at a very high frequency band (>200 Hz). Rapid capacitive currents are identified as main mechanisms underlying interaction between two transient synaptic conductances.

Cortical Layer and Spectrotemporal Architecture of Epileptiform Activity in vivo in a Mouse Model of Focal Cortical Malformation.

Our objective is to examine the layer and spectrotemporal architecture and laminar distribution of high-frequency oscillations (HFOs) in a neonatal freeze lesion model of focal cortical dysplasia (FCD) associated with a high prevalence of spontaneous spike-wave discharges (SWDs). Electrophysiological recording of local field potentials (LFPs) in control and freeze lesion animals were obtained with linear micro-electrode arrays to detect presence of HFOs as compared to changes in spectral power, signal coherence, and single-unit distributions during "hyper-excitable" epochs of anesthesia-induced burst-suppression (B-S). Result were compared to HFOs observed during spontaneous SWDs in animals during sleep. Micro-electrode array recordings from the malformed cortex indicated significant increases in the presence of HFOs above 100 Hz and associated increases in spectral power and altered LFP coherence of recorded signals across cortical lamina of freeze-lesioned animals with spontaneous bursts of high-frequency activity, confined predominately to granular and supragranular layers. Spike sorting of well-isolated single-units recorded from freeze-lesioned cortex indicated an increase in putative excitatory cell activity in the outer cortical layers that showed only a weak association with HFOs while deeper inhibitory units were strongly phase-locked to high-frequency ripple (HFR) oscillations (300-800 Hz). Both SWDs and B-S show increases in HFR activity that were phase-locked to the high-frequency spike pattern occurring at the trough of low frequency oscillations. The spontaneous cyclic spiking of cortical inhibitory cells appears to be the driving substrate behind the HFO patterns associated with SWDs and a hyperexcitable supragranular layer near the malformed cortex may play a key role in epileptogenesis in our model. These data, derived from a mouse model with a distinct focal cortical malformation, support recent clinical data that HFOs, particularly fast ripples, is a biomarker to help define the cortical seizure zone, and provide limited insights toward understanding cellular level changes underlying the HFOs.

Engineering Adenylate Cyclase Activated by Near-Infrared Window Light for Mammalian Optogenetic Applications.

Light in the near-infrared optical window (NIRW) penetrates deep through mammalian tissues, including the skull and brain tissue. Here we engineered an adenylate cyclase (AC) activated by NIRW light (NIRW-AC) and suitable for mammalian applications. To accomplish this goal, we constructed fusions of several bacteriophytochrome photosensory and bacterial AC modules using guidelines for designing chimeric homodimeric bacteriophytochromes. One engineered NIRW-AC, designated IlaM5, has significantly higher activity at 37 °C, is better expressed in mammalian cells, and can mediate cAMP-dependent photoactivation of gene expression in mammalian cells, in favorable contrast to the NIRW-ACs engineered earlier. The ilaM5 gene expressed from an AAV vector was delivered into the ventral basal thalamus region of the mouse brain, resulting in the light-controlled suppression of the cAMP-dependent wave pattern of the sleeping brain known as spindle oscillations. Reversible spindle oscillation suppression was observed in sleeping mice exposed to light from an external light source. This study confirms the robustness of principles of homodimeric bacteriophytochrome engineering, describes a NIRW-AC suitable for mammalian optogenetic applications, and demonstrates the feasibility of controlling brain activity via NIRW-ACs using transcranial irradiation.

Circuit-specific and neuronal subcellular-wide E-I balance in cortical pyramidal cells.

We used ChR2-assisted circuit mapping (CRACM) to examine neuronal/compartmental excitatory and inhibitory synaptic balance (E-I balance) in pyramidal cells (PCs) located in several brain regions (including both neocortices and paleocortices). Within the vS1, different inputs on the same neurons, or the same inputs formed on different targets, induced different E/I ratios. E/I ratios in PCs from different regions were largely different. Chemogenetic silencing of somatostatin (SOM)- or parvalbumin (PV)-containing interneurons (INs) while optogenetically activating long-range M1 inputs demonstrated differential contribution of PV and SOM INs to the E/I ratios in a layer-specific manner in S1. Our results thus demonstrate that there are both universal subcellular-wide E-I balance within single PC and high specificity in the value of E/I ratios across different circuits (i.e. visual, somatosensory, piriform and hippocampal). Specificity of E/I balance are likely caused by unique glutamatergic innervation of interneurons. The dichotomy of high specificity and generalization of subcellular E-I balance in different circuits forms the basis for further understanding of neuronal computation under physiological conditions and various neuro-psychiatric disease-states.

Major effects of sensory experiences on the neocortical inhibitory circuits.

During postnatal development, sensory experiences play critical roles in the refinement of cortical connections. However, both the process of postnatal experience-dependent maturation of neocortical inhibitory networks and its underlying mechanisms remain elusive. Here, we examined the differential properties of intracortical inhibitory networks of layer IV in "sensory-spared" and "sensory-deprived" cortices of glutamate acid decarboxylase 67 (GAD67)-green fluorescent protein (GFP) (delta neo) and wild-type mouse. Our results showed that row D whisker trimming (WT) begun at postnatal day 7 (P7), but not after P15, induced a robust reduction of parvalbumin (PV) expression, measured by the PV/GFP ratio and PV cell densities, in the deprived barrels. WT also induced a robust reduction in the number of inhibitory perisomatic varicosities and synaptic GAD65/67 immunoreactivities in spiny neurons of the deprived barrels. Although the GAD65/67 expressions in interneurons were also downregulated in the deprived barrels, the GFP expression remained unchanged. Patch-clamp recording from spiny cells showed a 1.5-fold reduction of intracortical evoked IPSCs (eIPSCs) in deprived versus spared cortices. The reduction in eIPSCs occurred via changes in presynaptic properties and unitary IPSC amplitudes. Miniature IPSCs showed subtle but significant differences between the two experimental conditions. In addition, properties of the IPSCs in deprived barrels resemble those of IPSCs recorded in immature brains (P7). Together, these results suggest that the properties of local intracortical inhibitory networks are modified by sensory experiences. Perisomatic inhibition mediated by PV-positive basket cells is pruned by sensory deprivation.