scholarly journals Parvalbumin interneuron dysfunction in a thalamus - prefrontal cortex circuit in Disc1 deficiency mice

2016 ◽  
Author(s):  
Kristen Delevich ◽  
Hanna Jaaro-Peled ◽  
Mario Penzo ◽  
Akira Sawa ◽  
Bo Li
Keyword(s):  
Prefrontal Cortex ◽  
Mouse Models ◽  
Pyramidal Neurons ◽  
Neural Circuit ◽  
Gaba Release ◽  
Parvalbumin Interneurons ◽  
Parvalbumin Interneuron ◽  
Inhibitory Circuit ◽  
Circuit Function ◽  
Deficient Mice

AbstractTwo of the most consistent findings across disrupted-in-schizophrenia-1 (DISC1) mouse models are impaired working memory and reduced number or function of parvalbumin interneurons within the prefrontal cortex. While these findings suggest parvalbumin interneuron dysfunction in DISC1-related pathophysiology, to date, cortical inhibitory circuit function has not been investigated in depth in DISC1 deficiency mouse models. Here we assessed the function of a feedforward circuit between the mediodorsal thalamus (MD) and the medial prefrontal cortex (mPFC) in mice harboring a deletion in one allele of the Disc1 gene. We found that the inhibitory drive onto layer 3 pyramidal neurons in the mPFC was significantly reduced in the Disc1 deficient mice. This reduced inhibition was accompanied by decreased GABA release from local parvalbumin, but not somatostatin, inhibitory interneurons, and by impaired feedforward inhibition in the MD-mPFC circuit. Our results reveal a cellular mechanism by which deficiency in DISC1 causes neural circuit dysfunction frequently implicated in psychiatric disorders.

scholarly journals Astroglial CD38 regulates social memory and synapse formation through SPARCL1 in the medial prefrontal cortex

2021 ◽  
Author(s):  
TSUYOSHI HATTORI ◽  
Stanislav M Cherepanov ◽  
Ryo Sakaga ◽  
Jureepon Roboon ◽  
Dinh Thi Nguyen ◽  
...  
Keyword(s):  
Prefrontal Cortex ◽  
Social Behavior ◽  
Medial Prefrontal Cortex ◽  
Cortical Neurons ◽  
Pyramidal Neurons ◽  
Synapse Formation ◽  
Neural Circuit ◽  
Social Memory ◽  
Behavioral Abnormalities ◽  
Survival And Reproduction

Social behavior is essential for the health, survival and reproduction of animals, yet the role of astrocytes in social behavior is largely unknown. CD38 is critical for social behaviors by regulating oxytocin release from hypothalamic neurons. On the other hand, CD38 is most abundantly expressed in astrocytes especially in the postnatal cortex, and is important for astroglial development. Here, we demonstrate that astroglial CD38 plays a pivotal role in the social behavior. Selective deletion of CD38 in postnatal astrocytes, but not in adult astrocytes, specifically impaired social memory without any other behavioral abnormalities. Morphological analysis revealed reductions in spine numbers, mature spines and excitatory synapse numbers in the pyramidal neurons of the medial prefrontal cortex (mPFC) due to deletion of astroglial CD38 in the postnatal brain. Astrocyte-conditioned medium (ACM) of CD38 KO astrocytes reduced synaptogenesis of cortical neurons by reducing extracellular SPARCL1, a synaptogenic protein. Finally, the release of SPARCL1 from astrocytes is regulated by CD38/cADPR/calcium signaling. Our data indicate that astroglial CD38 developmentally regulates social memory and neural circuit formation in the developing brain by promoting synaptogenesis through SPARCL1.

Prefrontal Cortex

2017 ◽  
pp. 75-84
Author(s):  
Xiao-Jing Wang
Keyword(s):  
Decision Making ◽  
Working Memory ◽  
Prefrontal Cortex ◽  
Pyramidal Neurons ◽  
Synaptic Integration ◽  
Input Output ◽  
Cortical Areas ◽  
Inhibitory Circuit ◽  
Distinct Features ◽  
The Brain

The prefrontal cortex (PFC) circuits are characterized by several distinct features. First, the input–output connections of a PFC circuit with the rest of the brain are extraordinarily extensive. In the primates, pyramidal neurons in PFC are greatly more spinous than in the primary sensory areas, so they have a much larger capacity for synaptic integration. Second, PFC areas are endowed with strong intrinsic recurrent connections that are sufficient to generate reverberatory activity underlying working memory and decision-making. Third, excitation and inhibition are balanced dynamically. Unlike early sensory cortical areas, in the frontal areas of both monkey and mouse, the synaptic inhibitory circuit is predominated by GABAergic cell subclasses that are dedicated to controlling inputs to, rather than outputs from, pyramidal neurons, likely reflecting the functional demand of selectively gating input pathways into the PFC in accordance with the behavioral context and goals.

scholarly journals Reduced hippocampal inhibition and enhanced autism-epilepsy comorbidity in mice lacking neuropilin 2

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Carol Eisenberg ◽  
Deepak Subramanian ◽  
Milad Afrasiabi ◽  
Patryk Ziobro ◽  
Jack DeLucia ◽  
...  
Keyword(s):  
Pyramidal Neurons ◽  
Autism Spectrum ◽  
Resting Membrane Potential ◽  
Behavioral Deficits ◽  
Ca1 Pyramidal Neurons ◽  
Neuronal Processes ◽  
And Migration ◽  
Y Cells ◽  
Circuit Function ◽  
Deficient Mice

AbstractThe neuropilin receptors and their secreted semaphorin ligands play key roles in brain circuit development by regulating numerous crucial neuronal processes, including the maturation of synapses and migration of GABAergic interneurons. Consistent with its developmental roles, the neuropilin 2 (Nrp2) locus contains polymorphisms in patients with autism spectrum disorder (ASD). Nrp2-deficient mice show autism-like behavioral deficits and propensity to develop seizures. In order to determine the pathophysiology in Nrp2 deficiency, we examined the hippocampal numbers of interneuron subtypes and inhibitory regulation of hippocampal CA1 pyramidal neurons in mice lacking one or both copies of Nrp2. Immunostaining for interneuron subtypes revealed that Nrp2−/− mice have a reduced number of parvalbumin, somatostatin, and neuropeptide Y cells, mainly in CA1. Whole-cell recordings identified reduced firing and hyperpolarized shift in resting membrane potential in CA1 pyramidal neurons from Nrp2+/− and Nrp2−/− mice compared to age-matched wild-type controls indicating decrease in intrinsic excitability. Simultaneously, the frequency and amplitude of spontaneous inhibitory postsynaptic currents (sIPSCs) are reduced in Nrp2-deficient mice. A convulsive dose of kainic acid evoked electrographic and behavioral seizures with significantly shorter latency, longer duration, and higher severity in Nrp2−/− compared to Nrp2+/+ animals. Finally, Nrp2+/− and Nrp2−/− but not Nrp2+/+, mice have impaired cognitive flexibility demonstrated by reward-based reversal learning, a task associated with hippocampal circuit function. Together these data demonstrate a broad reduction in interneuron subtypes and compromised inhibition in CA1 of Nrp2−/− mice, which could contribute to the heightened seizure susceptibility and behavioral deficits consistent with an ASD/epilepsy phenotype.

scholarly journals Reduced Hippocampal Inhibition and Enhanced Autism-Epilepsy Comorbidity in Mice Lacking Neuropilin 2

2021 ◽  
Author(s):  
Carol Eisenberg ◽  
Deepak Subramanian ◽  
Milad Afrasiabi ◽  
Patryk Ziobro ◽  
Jack DeLucia ◽  
...  
Keyword(s):  
Pyramidal Neurons ◽  
Autism Spectrum ◽  
Resting Membrane Potential ◽  
Behavioral Deficits ◽  
Ca1 Pyramidal Neurons ◽  
Neuronal Processes ◽  
And Migration ◽  
Y Cells ◽  
Circuit Function ◽  
Deficient Mice

The neuropilin receptors and their secreted semaphorin ligands play key roles in brain circuit development by regulating numerous crucial neuronal processes, including the maturation of synapses and migration of GABAergic interneurons. Consistent with its developmental roles, the neuropilin 2 (Nrp2) locus contains polymorphisms in patients with autism spectrum disorder (ASD). Nrp2 deficient mice show autism-like behavioral deficits and propensity to develop seizures. In order to determine the pathophysiology in Nrp2 deficiency, we examined the hippocampal numbers of interneuron subtypes and inhibitory regulation of hippocampal CA1 pyramidal neurons in mice lacking one or both copies of Nrp2. Immunostaining for interneuron subtypes revealed that Nrp2-/- mice have reduced number of parvalbumin, somatostatin and Neuropeptide Y cells, mainly in CA1. Whole cell recordings identified reduced firing and hyperpolarized shift in resting membrane potential in CA1 pyramidal neurons from Nrp2+/- and Nrp2-/- mice compared to age-matched wild-type controls indicating decrease in intrinsic excitability. Simultaneously, the frequency and amplitude of spontaneous inhibitory postsynaptic currents (sIPSCs) are reduced in Nrp2 deficient mice. A convulsive dose of kainic acid evoked electrographic and behavioral seizures with significantly shorter latency, longer duration and higher severity in Nrp2-/- compared to Nrp2+/+ animals. Finally, Nrp2+/- and Nrp2-/-, but not Nrp2+/+, mice have impaired cognitive flexibility demonstrated by reward-based reversal learning, a task associated with hippocampal circuit function. Together these data demonstrate a broad reduction in interneuron subtypes and compromised inhibition in CA1 of Nrp2-/- mice, which could contribute to the heightened seizure susceptibility and behavioral deficits consistent with an ASD/epilepsy phenotype.

scholarly journals Reliable sensory processing in mouse visual cortex through inhibitory interactions between Somatostatin and Parvalbumin interneurons

2017 ◽  
Author(s):  
Rajeev V. Rikhye ◽  
Ming Hu ◽  
Murat Yildirim ◽  
Mriganka Sur
Keyword(s):  
Visual Cortex ◽  
Cortical Neurons ◽  
Neural Coding ◽  
Computational Models ◽  
Pyramidal Neurons ◽  
Neural Circuit ◽  
Large Variability ◽  
Sensory Stimuli ◽  
Parvalbumin Interneurons ◽  
Mouse Visual Cortex

ABSTRACTCortical neurons often respond to identical sensory stimuli with large variability. However, under certain conditions, the same neurons can also respond highly reliably. The circuit mechanisms that contribute to this modulation, and their influence on behavior remains unknown. Here we used novel double transgenic mice, dual-wavelength calcium imaging and temporally selective optical perturbation to identify an inhibitory neural circuit in visual cortex that can modulate the reliability of pyramidal neurons to naturalistic visual stimuli. Our results, supported by computational models, suggest that somatostatin interneurons (SST-INs) increase pyramidal neuron reliability by suppressing parvalbumin interneurons (PV-INs) via the inhibitory SST→PV circuit. Using a novel movie classification task, we further show that, by reducing variability, activating SST-INs can improve the ability of mice to discriminate between ambiguous stimuli. Together, these findings reveal a novel role of the SST→PV circuit in modulating the fidelity of neural coding critical for visual perception.

scholarly journals Elevated expression of complement C4 in the mouse prefrontal cortex causes schizophrenia-associated phenotypes

2020 ◽  
Author(s):  
Mélanie Druart ◽  
Marika Nosten-Bertrand ◽  
Stefanie Poll ◽  
Sophie Crux ◽  
Felix Nebeling ◽  
...  
Keyword(s):  
Prefrontal Cortex ◽  
Ampa Receptors ◽  
Pyramidal Cells ◽  
Gaba Release ◽  
Time Lapse ◽  
Spine Density ◽  
Cellular Mechanisms ◽  
Parvalbumin Interneurons ◽  
Elevated Expression

AbstractAccumulating evidence supports immune involvement in the pathogenesis of schizophrenia, a severe psychiatric disorder. In particular, high expression variants of C4, a gene of the innate immune complement system, were shown to confer susceptibility to schizophrenia. However, how elevated C4 expression may impact brain circuits remains largely unknown. We used in utero electroporation to overexpress C4 in the mouse prefrontal cortex (PFC). We found reduced glutamatergic input to pyramidal cells of juvenile and adult, but not of newborn C4-overexpressing (C4-OE) mice, together with decreased spine density, which mirrors spine loss observed in the schizophrenic cortex. Using time-lapse two-photon imaging in vivo, we observed that these deficits were associated with decreased dendritic spine gain and elimination in juvenile C4-OE mice, which may reflect poor formation and/or stabilization of immature spines. In juvenile and adult C4-OE mice we found evidence for NMDA receptor hypofunction, another schizophrenia-associated phenotype, and synaptic accumulation of calcium-permeable AMPA receptors. Alterations in cortical GABAergic networks have been repeatedly associated with schizophrenia. We found that functional GABAergic transmission was reduced in C4-OE mice, in line with diminished GABA release probability from parvalbumin interneurons, lower GAD67 expression and decreased intrinsic excitability in parvalbumin interneurons. These cellular abnormalities were associated with working memory impairment. Our results substantiate the causal relationship between an immunogenetic risk factor and several distinct cortical endophenotypes of schizophrenia, and shed light on the underlying cellular mechanisms.

scholarly journals δ-Catenin engages the autophagy pathway to sculpt the developing dendritic arbor

2020 ◽  
Vol 295 (32) ◽  
pp. 10988-11001
Author(s):  
Cheryl Ligon ◽  
Eunju Seong ◽  
Ethan J. Schroeder ◽  
Nicholas W. DeKorver ◽  
Li Yuan ◽  
...  
Keyword(s):  
Pyramidal Neurons ◽  
Neural Circuit ◽  
Time Lapse ◽  
Apical Dendrite ◽  
Dendritic Arbor ◽  
Autophagy Pathway ◽  
Circuit Function ◽  
Time Lapse Imaging ◽  
Cellular Components ◽  
Adhesion Complex

The development of the dendritic arbor in pyramidal neurons is critical for neural circuit function. Here, we uncovered a pathway in which δ-catenin, a component of the cadherin–catenin cell adhesion complex, promotes coordination of growth among individual dendrites and engages the autophagy mechanism to sculpt the developing dendritic arbor. Using a rat primary neuron model, time-lapse imaging, immunohistochemistry, and confocal microscopy, we found that apical and basolateral dendrites are coordinately sculpted during development. Loss or knockdown of δ-catenin uncoupled this coordination, leading to retraction of the apical dendrite without altering basolateral dendrite dynamics. Autophagy is a key cellular pathway that allows degradation of cellular components. We observed that the impairment of the dendritic arbor resulting from δ-catenin knockdown could be reversed by knockdown of autophagy-related 7 (ATG7), a component of the autophagy machinery. We propose that δ-catenin regulates the dendritic arbor by coordinating the dynamics of individual dendrites and that the autophagy mechanism may be leveraged by δ-catenin and other effectors to sculpt the developing dendritic arbor. Our findings have implications for the management of neurological disorders, such as autism and intellectual disability, that are characterized by dendritic aberrations.

scholarly journals Mature parvalbumin interneuron function in prefrontal cortex requires activity during a postnatal sensitive period

2021 ◽  
Author(s):  
Sarah E Canetta ◽  
Emma S Holt ◽  
Laura J Benoit ◽  
Eric Teboul ◽  
R. Todd Ogden ◽  
...  
Keyword(s):  
Prefrontal Cortex ◽  
Sensitive Period ◽  
Network Function ◽  
Parvalbumin Interneuron ◽  
Circuit Integration ◽  
Circuit Function ◽  
And Behavior ◽  
Activity Dependent

Sensitive periods in which experience-driven changes in activity persistently shape circuit function are well-described in sensory cortex. Whether comparable periods govern the development of associative cortical areas, like the prefrontal cortex, remains unclear. Here, we focus on the role of activity in the maturation and circuit integration of prefrontal parvalbumin-expressing interneurons, as these cells play an essential role in sensory cortical maturation and develop in lockstep with overall prefrontal circuit function. We found that transiently decreasing prefrontal parvalbumin activity during peripubertal and adolescent development results in persistent impairments in adult functional connectivity, in vivo network function and set-shifting behavior that can be rescued by targeted activation of these interneurons in the adult animal. In contrast, comparable adult inhibition had no lasting effects. These findings identify an activity-dependent sensitive period for prefrontal parvalbumin maturation and highlight how abnormal parvalbumin activity early in life can persistently alter adult circuit function and behavior.

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