Parvalbumin-positive Neurons Research Articles

NMDA receptors regulate the firing rate set point of hippocampal circuits without altering single-cell dynamics.

Understanding how neuronal circuits stabilize their activity is a fundamental yet poorly understood aspect of neuroscience. Here, we show that hippocampal network properties, such as firing rate distribution and dimensionality, are actively regulated, despite perturbations and single-cell drift. Continuous inhibition of N-methyl-D-aspartate receptors (NMDARs) exvivo lowers the excitation/inhibition ratio and network firing rates while preserving resilience to perturbations. This establishes a new network firing rate set point via NMDAR-eEF2K signaling pathway. NMDARs' capacity to modulate and stabilize network firing is mediated by excitatory synapses and the intrinsic excitability of parvalbumin-positive neurons, respectively. In behaving mice, continuous NMDAR blockade in CA1 reduces network firing without altering single-neuron drift or triggering a compensatory response. These findings expand NMDAR function beyond their canonical role in synaptic plasticity and raise the possibility that some NMDAR-dependent behavioral effects are mediated by their unique regulation of population activity set points.

Dysregulation of parvalbumin expression and neurotransmitter imbalance in the auditory cortex of the BTBR mouse model of autism spectrum disorder.

Individuals diagnosed with autism spectrum disorder (ASD) frequently exhibit abnormalities in auditory perception, a phenomenon potentially attributed to alterations in the excitatory and inhibitory cells constituting cortical circuits. However, the exact genetic factors and cell types affected by ASD remain unclear. The present study investigated the balance of excitatory and inhibitory activity in the auditory cortex using BTBR T+ Itpr3tf/J (BTBR) mice, a well-established model for autism research. Our investigation unveiled a reduction in parvalbumin-positive (PV+) neurons within the AC of BTBR mice. Remarkably, in vivo magnetic resonance spectroscopy studies disclosed an elevation in glutamate (Glu) levels alongside a decrement in γ-aminobutyric acid (GABA) levels in this cortical region. Additionally, transcriptomic analysis of the mouse model facilitated the classification of several ASD-associated genes based on their cellular function and pathways. By comparing autism risk genes with RNA transcriptome sequencing data from the ASD mouse model, we identified the recurrent target gene Scn1a and performed validation. Intriguingly, we uncovered the specific expression of Scn1a in cortical inhibitory neurons. These findings hold significant value for understanding the underlying neural mechanisms of abnormal sensory perception in animal models of ASD.

Spiking networks that efficiently process dynamic sensory features explain receptor information mixing in somatosensory cortex.

How do biological neural systems efficiently encode, transform and propagate information between the sensory periphery and the sensory cortex about sensory features evolving at different time scales? Are these computations efficient in normative information processing terms? While previous work has suggested that biologically plausible models of of such neural information processing may be implemented efficiently within a single processing layer, how such computations extend across several processing layers is less clear. Here, we model propagation of multiple time-varying sensory features across a sensory pathway, by extending the theory of efficient coding with spikes to efficient encoding, transformation and transmission of sensory signals. These computations are optimally realized by a multilayer spiking network with feedforward networks of spiking neurons (receptor layer) and recurrent excitatory-inhibitory networks of generalized leaky integrate-and-fire neurons (recurrent layers). Our model efficiently realizes a broad class of feature transformations, including positive and negative interaction across features, through specific and biologically plausible structures of feedforward connectivity. We find that mixing of sensory features in the activity of single neurons is beneficial because it lowers the metabolic cost at the network level. We apply the model to the somatosensory pathway by constraining it with parameters measured empirically and include in its last node, analogous to the primary somatosensory cortex (S1), two types of inhibitory neurons: parvalbumin-positive neurons realizing lateral inhibition, and somatostatin-positive neurons realizing winner-take-all inhibition. By implementing a negative interaction across stimulus features, this model captures several intriguing empirical observations from the somatosensory system of the mouse, including a decrease of sustained responses from subcortical networks to S1, a non-linear effect of the knock-out of receptor neuron types on the activity in S1, and amplification of weak signals from sensory neurons across the pathway.

Age-related changes of dopamine D1 and D2 receptors expression in parvalbumin-positive cells of the orbitofrontal and prelimbic cortices of mice.

Dopamine (DA) plays a pivotal role in reward processing, cognitive functions, and emotional regulation. The prefrontal cortex (PFC) is a critical brain region for these processes. Parvalbumin-positive (PV+) neurons are one of the major classes of inhibitory GABAergic neurons in the cortex, they modulate the activity of neighboring neurons, influencing various brain functions. While DA receptor expression exhibits age-related changes, the age-related changes of these receptors in PV+ neurons, especially in the PFC, remain unclear. To address this, we investigated the expression of DA D1 (D1R) and D2 (D2R) receptors in PV+ neurons within the orbitofrontal (OFC) and prelimbic (PrL) cortices at different postnatal ages (P28, P42, P56, and P365). We found that the expression of D1R and D2R in PV+ neurons showed both age- and region-related changes. PV+ neurons in the OFC expressed a higher abundance of D1 than those in the PrL, and those neurons in the OFC also showed higher co-expression of D1R and D2R than those in the PrL. In the OFC and PrL, D1R in PV+ neurons increased from P28 and reached a plateau at P42, then receded to express at P365. Meanwhile, D2R did not show significant age-related changes between the two regions except at P56. These results showed dopamine receptors in the prefrontal cortex exhibit age- and region-specific changes, which may contribute to the difference of these brain regions in reward-related brain functions.

The thalamic reticular nucleus orchestrates social memory

Social memory has been developed in humans and other animals to recognize familiar conspecifics and is essential for their survival and reproduction. Here, we demonstrated that parvalbumin-positive neurons in the sensory thalamic reticular nucleus (sTRNPvalb) are necessary and sufficient for mice to memorize conspecifics. sTRNPvalb neurons receiving glutamatergic projections from the posterior parietal cortex (PPC) transmit individual information by inhibiting the parafascicular thalamic nucleus (PF). Mice in which the PPCCaMKII→sTRNPvalb→PF circuit was inhibited exhibited a disrupted ability to discriminate familiar conspecifics from novel ones. More strikingly, a subset of sTRNPvalb neurons with high electrophysiological excitability and complex dendritic arborizations is involved in the above corticothalamic pathway and stores social memory. Single-cell RNA sequencing revealed the biochemical basis of these subset cells as a robust activation of protein synthesis. These findings elucidate that sTRNPvalb neurons modulate social memory by coordinating a hitherto unknown corticothalamic circuit and inhibitory memory engram.

Srcap haploinsufficiency induced autistic-like behaviors in mice through disruption of Satb2 expression

Mutations in the SRCAP gene are among the genetic alterations identified in autism spectrum disorders (ASD). However, the pathogenic mechanisms remain unclear. In this study, we demonstrate that Srcap+/- mice manifest deficits in social novelty response, as well as increased repetitive behaviors, anxiety, and impairments in learning and memory. Notably, a reduction in parvalbumin-positive neurons is observed in the retrosplenial cortex (RSC) and dentate gyrus (DG) of these mice. Through RNA sequencing, we identify dysregulation in 27 ASD-related genes in Srcap+/- mice. Specifically, we find that Srcap regulates expression of Satb2 via H2A.z in the promoter. Therapeutic intervention via retro-orbital injection of adeno-associated virus (AAV)-Satb2 in neonatal Srcap+/- mice leads to amelioration of the neurodevelopmental and ASD-like abnormalities. Furthermore, the expression of Satb2 only in the RSC of adolescent mice rectifies social novelty impairments. These results underscore the pivotal role of Srcap in neurodevelopment, by regulating Satb2, providing valuable insights for the pathophysiology of ASD.

Spike-induced cytoarchitectonic changes in epileptic human cortex are reduced via MAP2K inhibition.

Interictal spikes are electroencephalographic discharges that occur at or near brain regions that produce epileptic seizures. While their role in generating seizures is not well understood, spikes have profound effects on cognition and behaviour, depending on where and when they occur. We previously demonstrated that spiking areas of human neocortex show sustained MAPK activation in superficial cortical Layers I-III and are associated with microlesions in deeper cortical areas characterized by reduced neuronal nuclear protein staining and increased microglial infiltration. Based on these findings, we chose to investigate additional neuronal populations within microlesions, specifically inhibitory interneurons. Additionally, we hypothesized that spiking would be sufficient to induce similar cytoarchitectonic changes within the rat cortex and that inhibition of MAPK signalling, using a MAP2K inhibitor, would not only inhibit spike formation but also reduce these cytoarchitectonic changes and improve behavioural outcomes. To test these hypotheses, we analysed tissue samples from 16 patients with intractable epilepsy who required cortical resections. We also utilized a tetanus toxin-induced animal model of interictal spiking, designed to produce spikes without seizures in male Sprague-Dawley rats. Rats were fitted with epidural electrodes, to permit EEG recording for the duration of the study, and automated algorithms were implemented to quantify spikes. After 6 months, animals were sacrificed to assess the effects of chronic spiking on cortical cytoarchitecture. Here, we show that microlesions may promote excitability due to a significant reduction of inhibitory neurons that could be responsible for promoting interictal spikes in superficial layers. Similarly, we found that the induction of epileptic spikes in the rat model produced analogous changes, including reduced neuronal nuclear protein, calbindin and parvalbumin-positive neurons and increased microglia, suggesting that spikes are sufficient for inducing these cytoarchitectonic changes in humans. Finally, we implicated MAPK signalling as a driving force producing these pathological changes. Using CI-1040 to inhibit MAP2K, both acutely and after spikes developed, resulting in fewer interictal spikes, reduced microglial activation and less inhibitory neuron loss. Treated animals had significantly fewer high-amplitude, short-duration spikes, which correlated with improved spatial memory performance on the Barnes maze. Together, our results provide evidence for a cytoarchitectonic pathogenesis underlying epileptic cortex, which can be ameliorated through both early and delayed MAP2K inhibition. These findings highlight the potential role for CI-1040 as a pharmacological treatment that could prevent the development of epileptic activity and reduce cognitive impairment in both patients with epilepsy and those with non-epileptic spike-associated neurobehavioural disorders.

Delineating mechanisms underlying parvalbumin neuron impairment in different neurological and neurodegenerative disorders: the emerging role of mitochondrial dysfunction.

Given the current paucity of effective treatments in many neurological disorders, delineating pathophysiological mechanisms among the major psychiatric and neurodegenerative diseases may fuel the development of novel, potent treatments that target shared pathways. Recent evidence suggests that various pathological processes, including bioenergetic failure in mitochondria, can perturb the function of fast-spiking, parvalbumin-positive neurons (PV+). These inhibitory neurons critically influence local circuit regulation, the generation of neuronal network oscillations and complex brain functioning. Here, we survey PV+ cell vulnerability in the major neuropsychiatric, and neurodegenerative diseases and review associated cellular and molecular pathophysiological alterations purported to underlie disease aetiology.

DISC1 and reelin interact to alter cognition, inhibition, and neurogenesis in a novel mouse model of schizophrenia.

The etiology of schizophrenia (SCZ) is multifactorial, and depending on a host of genetic and environmental factors. Two putative SCZ susceptibility genes, Disrupted-in-Schizophrenia-1 (DISC1) and reelin (RELN), interact at a molecular level, suggesting that combined disruption of both may lead to an intensified SCZ phenotype. To examine this gene-gene interaction, we produced a double mutant mouse line. Mice with heterozygous RELN haploinsufficiency were crossed with mice expressing dominant-negative c-terminal truncated human DISC1 to produce offspring with both mutations (HRM/DISC1 mice). We used an array of behavioral tests to generate a behavioral phenotype for these mice, then examined the prefrontal cortex and hippocampus using western blotting and immunohistochemistry to probe for SCZ-relevant molecular and cellular alterations. Compared to wild-type controls, HRM/DISC1 mice demonstrated impaired pre-pulse inhibition, altered cognition, and decreased activity. Diazepam failed to rescue anxiety-like behaviors, paradoxically increasing activity in HRM/DISC1 mice. At a cellular level, we found increased α1-subunit containing GABA receptors in the prefrontal cortex, and a reduction in fast-spiking parvalbumin positive neurons. Maturation of adult-born neurons in the hippocampus was also altered in HRM/DISC1 mice. While there was no difference in the total number proliferating cells, more of these cells were in immature stages of development. Homozygous DISC1 mutation combined with RELN haploinsufficiency produces a complex phenotype with neuropsychiatric characteristics relevant to SCZ and related disorders, expanding our understanding of how multiple genetic susceptibility factors might interact to influence the variable presentation of these disorders.

D-serine reconstitutes synaptic and intrinsic inhibitory control of pyramidal neurons in a neurodevelopmental mouse model for schizophrenia

The hypothesis of N-methyl-D-aspartate receptor (NMDAR) dysfunction for cognitive impairment in schizophrenia constitutes the theoretical basis for the translational application of NMDAR co-agonist D-serine or its analogs. However, the cellular mechanism underlying the therapeutic effect of D-serine remains unclear. In this study, we utilize a mouse neurodevelopmental model for schizophrenia that mimics prenatal pathogenesis and exhibits hypoexcitability of parvalbumin-positive (PV) neurons, as well as PV-preferential NMDAR dysfunction. We find that D-serine restores excitation/inhibition balance by reconstituting both synaptic and intrinsic inhibitory control of cingulate pyramidal neurons through facilitating PV excitability and activating small-conductance Ca2+-activated K+ (SK) channels in pyramidal neurons, respectively. Either amplifying inhibitory drive via directly strengthening PV neuron activity or inhibiting pyramidal excitability via activating SK channels is sufficient to improve cognitive function in this model. These findings unveil a dual mechanism for how D-serine improves cognitive function in this model.

Enhanced anxiety-like behavior induced by chronic neuropathic pain and related parvalbumin-positive neurons in male rats

Anxiety commonly co-occurs with and exacerbates pain, but the interaction between pain progression and anxiety, and its underlying mechanisms remain unclear. Inhibitory interneurons play a crucial role in maintaining normal central nervous system function and are suggested to be involved in pain-induced anxiety. This study aimed to elucidate the time-dependent effects of neuropathic pain on the developmental anxiety-like behaviors and related inhibitory interneurons; parvalbumin (PV)- and cholecystokinin (CCK)-positive neurons in corticolimbic regions. Using an 8-week-old male Wistar rat model with partial sciatic nerve ligation (pSNL), anxiety-like behaviors were biweekly assessed post-surgery through open field (OF) and elevated plus maze (EPM) tests. From 4 weeks post-surgery, pSNL rats exhibited reduced OF center time, rearing, and initial activity, along with diminished EPM open-arm activities (time spent, head dips, movement, and rearing), which correlated with the paw withdrawal threshold. These effects were absent at 2 weeks post-surgery. At 8 weeks post-surgery, specific behaviors (decreased total rearing and increased inactive time in EPM) were observed in the pSNL group. Immunohistochemistry revealed changes in PV- and CCK-positive neurons in specific corticolimbic subregions of pSNL rats at 8 weeks post-surgery. Notably, PV-positive neuron densities in the basolateral amygdaloid complex (BLC) and hippocampal cornu ammonis areas 1 and 2 correlated with anxiety-like behavioral parameters. PV-positive neurons in the BLC of pSNL rats were predominantly changed in large-cell subtypes and were less activated. These findings indicate that anxiety-like behaviors emerge in the late phase of neuropathic pain and relate to PV-positive neurons in corticolimbic regions of pSNL rats.

Parvalbumin-positive neurons in the medial vestibular nucleus contribute to vestibular compensation through commissural inhibition.

The commissural inhibitory system between the bilateral medial vestibular nucleus (MVN) plays a key role in vestibular compensation. Calcium-binding protein parvalbumin (PV) is expressed in MVN GABAergic neurons. Whether these neurons are involved in vestibular compensation is still unknown. After unilateral labyrinthectomy (UL), we measured the activity of MVN PV neurons by in vivo calcium imaging, and observed the projection of MVN PV neurons by retrograde neural tracing. After regulating PV neurons' activity by chemogenetic technique, the effects on vestibular compensation were evaluated by behavior analysis. We found PV expression and the activity of PV neurons in contralateral but not ipsilateral MVN increased 6 h following UL. ErbB4 is required to maintain GABA release for PV neurons, conditional knockout ErbB4 from PV neurons promoted vestibular compensation. Further investigation showed that vestibular compensation could be promoted by chemogenetic inhibition of contralateral MVN or activation of ipsilateral MVN PV neurons. Additional neural tracing study revealed that considerable MVN PV neurons were projecting to the opposite side of MVN, and that activating the ipsilateral MVN PV neurons projecting to contralateral MVN can promote vestibular compensation. Contralateral MVN PV neuron activation after UL is detrimental to vestibular compensation, and rebalancing bilateral MVN PV neuron activity can promote vestibular compensation, via commissural inhibition from the ipsilateral MVN PV neurons. Our findings provide a new understanding of vestibular compensation at the neural circuitry level and a novel potential therapeutic target for vestibular disorders.

Spatial memory requires hypocretins to elevate medial entorhinal gamma oscillations

The hypocretin (Hcrt) (also known as orexin) neuropeptidic wakefulness-promoting system is implicated in the regulation of spatial memory, but its specific role and mechanisms remain poorly understood. In this study, we revealed the innervation of the medial entorhinal cortex (MEC) by Hcrt neurons in mice. Using the genetically encoded G-protein-coupled receptor activation-based Hcrt sensor, we observed a significant increase in Hcrt levels in the MEC during novel object-place exploration. We identified the function of Hcrt at presynaptic glutamatergic terminals, where it recruits fast-spiking parvalbumin-positive neurons and promotes gamma oscillations. Bidirectional manipulations of Hcrt neurons' projections from the lateral hypothalamus (LHHcrt) to MEC revealed the essential role of this pathway in regulating object-place memory encoding, but not recall, through the modulation of gamma oscillations. Our findings highlight the significance of the LHHcrt-MEC circuitry in supporting spatial memory and reveal a unique neural basis for the hypothalamic regulation of spatial memory.

A frontal transcallosal inhibition loop mediates interhemispheric balance in visuospatial processing

Interhemispheric communication through the corpus callosum is required for both sensory and cognitive processes. Impaired transcallosal inhibition causing interhemispheric imbalance is believed to underlie visuospatial bias after frontoparietal cortical damage, but the synaptic circuits involved remain largely unknown. Here, we show that lesions in the mouse anterior cingulate area (ACA) cause severe visuospatial bias mediated by a transcallosal inhibition loop. In a visual-change-detection task, ACA callosal-projection neurons (CPNs) were more active with contralateral visual field changes than with ipsilateral changes. Unilateral CPN inactivation impaired contralateral change detection but improved ipsilateral detection by altering interhemispheric interaction through callosal projections. CPNs strongly activated contralateral parvalbumin-positive (PV+) neurons, and callosal-input-driven PV+ neurons preferentially inhibited ipsilateral CPNs, thus mediating transcallosal inhibition. Unilateral PV+ neuron activation caused a similar behavioral bias to contralateral CPN activation and ipsilateral CPN inactivation, and bilateral PV+ neuron activation eliminated this bias. Notably, restoring interhemispheric balance by activating contralesional PV+ neurons significantly improved contralesional detection in ACA-lesioned animals. Thus, a frontal transcallosal inhibition loop comprising CPNs and callosal-input-driven PV+ neurons mediates interhemispheric balance in visuospatial processing, and enhancing contralesional transcallosal inhibition restores interhemispheric balance while also reversing lesion-induced bias.

Shank3 deletion in PV neurons is associated with abnormal behaviors and neuronal functions that are rescued by increasing GABAergic signaling

BackgroundPhelan–McDermid syndrome (PMS) is a neurodevelopmental disorder characterized by developmental delay, intellectual disability, and autistic-like behaviors and is primarily caused by haploinsufficiency of SHANK3 gene. Currently, there is no specific treatment for PMS, highlighting the need for a better understanding of SHANK3 functions and the underlying pathophysiological mechanisms in the brain. We hypothesize that SHANK3 haploinsufficiency may lead to alterations in the inhibitory system, which could be linked to the excitatory/inhibitory imbalance observed in models of autism spectrum disorder (ASD). Investigation of these neuropathological features may shed light on the pathogenesis of PMS and potential therapeutic interventions.MethodsWe recorded local field potentials and visual evoked responses in the visual cortex of Shank3∆11−/− mice. Then, to understand the impact of Shank3 in inhibitory neurons, we generated Pv-cre+/−Shank3Fl/Wt conditional mice, in which Shank3 was deleted in parvalbumin-positive neurons. We characterized the phenotype of this murine model and we compared this phenotype before and after ganaxolone administration.ResultsWe found, in the primary visual cortex, an alteration of the gain control of Shank3 KO compared with Wt mice, indicating a deficit of inhibition on pyramidal neurons. This alteration was rescued after the potentiation of GABAA receptor activity by Midazolam. Behavioral analysis showed an impairment in grooming, memory, and motor coordination of Pv-cre+/−Shank3Fl/Wt compared with Pv-cre+/−Shank3Wt/Wt mice. These deficits were rescued with ganaxolone, a positive modulator of GABAA receptors. Furthermore, we demonstrated that treatment with ganaxolone also ameliorated evocative memory deficits and repetitive behavior of Shank3 KO mice.LimitationsDespite the significant findings of our study, some limitations remain. Firstly, the neurobiological mechanisms underlying the link between Shank3 deletion in PV neurons and behavioral alterations need further investigation. Additionally, the impact of Shank3 on other classes of inhibitory neurons requires further exploration. Finally, the pharmacological activity of ganaxolone needs further characterization to improve our understanding of its potential therapeutic effects.ConclusionsOur study provides evidence that Shank3 deletion leads to an alteration in inhibitory feedback on cortical pyramidal neurons, resulting in cortical hyperexcitability and ASD-like behavioral problems. Specifically, cell type-specific deletion of Shank3 in PV neurons was associated with these behavioral deficits. Our findings suggest that ganaxolone may be a potential pharmacological approach for treating PMS, as it was able to rescue the behavioral deficits in Shank3 KO mice. Overall, our study highlights the importance of investigating the role of inhibitory neurons and potential therapeutic interventions in neurodevelopmental disorders such as PMS.

Disease-modifying effects of a glial-targeted inducible nitric oxide synthase inhibitor (1400W) in mixed-sex cohorts of a rat soman (GD) model of epilepsy

BackgroundAcute exposure to seizurogenic organophosphate (OP) nerve agents (OPNA) such as diisopropylfluorophosphate (DFP) or soman (GD), at high concentrations, induce immediate status epilepticus (SE), reactive gliosis, neurodegeneration, and epileptogenesis as a consequence. Medical countermeasures (MCMs—atropine, oximes, benzodiazepines), if administered in < 20 min of OPNA exposure, can control acute symptoms and mortality. However, MCMs alone are inadequate to prevent OPNA-induced brain injury and behavioral dysfunction in survivors. We have previously shown that OPNA exposure-induced SE increases the production of inducible nitric oxide synthase (iNOS) in glial cells in both short- and long- terms. Treating with a water soluble and highly selective iNOS inhibitor, 1400W, for 3 days significantly reduced OPNA-induced brain changes in those animals that had mild–moderate SE in the rat DFP model. However, such mitigating effects and the mechanisms of 1400W are unknown in a highly volatile nerve agent GD exposure.MethodsMixed-sex cohort of adult Sprague Dawley rats were exposed to GD (132 μg/kg, s.c.) and immediately treated with atropine (2 mg/kg, i.m) and HI-6 (125 mg/kg, i.m.). Severity of seizures were quantified for an hour and treated with midazolam (3 mg/kg, i.m.). An hour post-midazolam, 1400W (20 mg/kg, i.m.) or vehicle was administered daily for 2 weeks. After behavioral testing and EEG acquisition, animals were euthanized at 3.5 months post-GD. Brains were processed for neuroinflammatory and neurodegeneration markers. Serum and CSF were used for nitrooxidative and proinflammatory cytokines assays.ResultsWe demonstrate a significant long-term (3.5 months post-soman) disease-modifying effect of 1400W in animals that had severe SE for > 20 min of continuous convulsive seizures. 1400W significantly reduced GD-induced motor and cognitive dysfunction; nitrooxidative stress (nitrite, ROS; increased GSH: GSSG); proinflammatory cytokines in the serum and some in the cerebrospinal fluid (CSF); epileptiform spikes and spontaneously recurring seizures (SRS) in males; reactive gliosis (GFAP + C3 and IBA1 + CD68-positive glia) as a measure of neuroinflammation, and neurodegeneration (especially parvalbumin-positive neurons) in some brain regions.ConclusionThese findings demonstrate the long-term disease-modifying effects of a glial-targeted iNOS inhibitor, 1400W, in a rat GD model by modulating reactive gliosis, neurodegeneration (parvalbumin-positive neurons), and neuronal hyperexcitability.

Enriched environmental exposure reduces the onset of action of the serotonin norepinephrin reuptake inhibitor venlafaxine through its effect on parvalbumin interneurons plasticity in mice

Mood disorders are associated with hypothalamic-pituitary-adrenal axis overactivity resulting from a decreased inhibitory feedback exerted by the hippocampus on this brain structure. Growing evidence suggests that antidepressants would regulate hippocampal excitatory/inhibitory balance to restore an effective inhibition on this stress axis. While these pharmacological compounds produce beneficial clinical effects, they also have limitations including their long delay of action. Interestingly, non-pharmacological strategies such as environmental enrichment improve therapeutic outcome in depressed patients as in animal models of depression. However, whether exposure to enriched environment also reduces the delay of action of antidepressants remains unknown. We investigated this issue using the corticosterone-induced mouse model of depression, submitted to antidepressant treatment by venlafaxine, alone or in combination with enriched housing. We found that the anxio-depressive phenotype of male mice was improved after only two weeks of venlafaxine treatment when combined with enriched housing, which is six weeks earlier than mice treated with venlafaxine but housed in standard conditions. Furthermore, venlafaxine combined with exposure to enriched environment is associated with a reduction in the number of parvalbumin-positive neurons surrounded by perineuronal nets (PNN) in the mouse hippocampus. We then showed that the presence of PNN in depressed mice prevented their behavioral recovery, while pharmacological degradation of hippocampal PNN accelerated the antidepressant action of venlafaxine. Altogether, our data support the idea that non-pharmacological strategies can shorten the onset of action of antidepressants and further identifies PV interneurons as relevant actors of this effect.

Neuroanatomical Alterations in the CNTNAP2 Mouse Model of Autism Spectrum Disorder.

Autism spectrum disorder (ASD) is associated with neurodevelopmental alterations, including atypical forebrain cellular organization. Mutations in several ASD-related genes often result in cerebral cortical anomalies, such as the abnormal developmental migration of excitatory pyramidal cells and the malformation of inhibitory neuronal circuitry. Notably here, mutations in the CNTNAP2 gene result in ectopic superficial cortical neurons stalled in lower cortical layers and alterations to the balance of cortical excitation and inhibition. However, the broader circuit-level implications of these findings have not been previously investigated. Therefore, we assessed whether ectopic cortical neurons in CNTNAP2 mutant mice form aberrant connections with higher-order thalamic nuclei, potentially accounting for some autistic behaviors, such as repetitive and hyperactive behaviors. Furthermore, we assessed whether the development of parvalbumin-positive (PV) cortical interneurons and their specialized matrix support structures, called perineuronal nets (PNNs), were altered in these mutant mice. We found alterations in both ectopic neuronal connectivity and in the development of PNNs, PV neurons and PNNs enwrapping PV neurons in various sensory cortical regions and at different postnatal ages in the CNTNAP2 mutant mice, which likely lead to some of the cortical excitation/inhibition (E/I) imbalance associated with ASD. These findings suggest neuroanatomical alterations in cortical regions that underlie the emergence of ASD-related behaviors in this mouse model of the disorder.

Responses in fast-spiking interneuron firing rates to parameter variations associated with degradation of perineuronal nets

The perineuronal nets (PNNs) are sugar coated protein structures that encapsulate certain neurons in the brain, such as parvalbumin positive (PV) inhibitory neurons. As PNNs are theorized to act as a barrier to ion transport, they may effectively increase the membrane charge-separation distance, thereby affecting the membrane capacitance. Tewari et al. (2018) found that degradation of PNNs induced a 25%-50% increase in membrane capacitance c_text {m} and a reduction in the firing rates of PV-cells. In the current work, we explore how changes in c_text {m} affects the firing rate in a selection of computational neuron models, ranging in complexity from a single compartment Hodgkin-Huxley model to morphologically detailed PV-neuron models. In all models, an increased c_text {m} lead to reduced firing, but the experimentally reported increase in c_text {m} was not alone sufficient to explain the experimentally reported reduction in firing rate. We therefore hypothesized that PNN degradation in the experiments affected not only c_text {m}, but also ionic reversal potentials and ion channel conductances. In simulations, we explored how various model parameters affected the firing rate of the model neurons, and identified which parameter variations in addition to c_text {m} that are most likely candidates for explaining the experimentally reported reduction in firing rate.

Dose and time-dependence of acute intermittent theta-burst stimulation on hippocampus-dependent memory in parkinsonian rats.

The treatment options for cognitive impairments in Parkinson's disease (PD) are limited. Repetitive transcranial magnetic stimulation has been applied in various neurological diseases. However, the effect of intermittent theta-burst stimulation (iTBS) as a more developed repetitive transcranial magnetic stimulation paradigm on cognitive dysfunction in PD remains largely unclear. Our aim was to explore the effect of acute iTBS on hippocampus-dependent memory in PD and the mechanism underlying it. Different blocks of iTBS protocols were applied to unilateral 6-hydroxidopamine-induced parkinsonian rats followed by the behavioral, electrophysiological and immunohistochemical analyses. The object-place recognition and hole-board test were used to assess hippocampus-dependent memory. Sham-iTBS and 1 block-iTBS (300 stimuli) didn't alter hippocampus-dependent memory, hippocampal theta rhythm and the density of c-Fos- and parvalbumin-positive neurons in the hippocampus and medial septum. 3 block-iTBS (900 stimuli) alleviated 6-hydroxidopamine-induced memory impairments, and increased the density of hippocampal c-Fos-positive neurons at 80 min post-stimulation but not 30 min compared to sham-iTBS. Interestingly, 3 block-iTBS first decreased and then increased normalized theta power during a period of 2 h following stimulation. Moreover, 3 block-iTBS decreased the density of parvalbumin-positive neurons in the medial septum at 30 min post-stimulation compared to sham-iTBS. The results indicate that multiple blocks of iTBS elicit dose and time-dependent effects on hippocampus-dependent memory in PD, which may be attributed to changes in c-Fos expression and the power of theta rhythm in the hippocampus.