Perineuronal Nets in the Prefrontal Cortex of a Schizophrenia Mouse Model: Assessment of Neuroanatomical, Electrophysiological and Behavioral Contributions

Schizophrenia is a neurodevelopmental disorder whose etiopathogenesis includes changes in cellular as well as extracellular structures. Perineuronal nets (PNNs) associated with parvalbumin-positive interneurons (PVs) in the prefrontal cortex (PFC) are dysregulated in schizophrenia. However, the postnatal development of these structures along with their associated neurons in the PFC is unexplored, as is their effects on behavior and neural activity. Therefore, in this study, we employed a DISC1 (Disruption in Schizophrenia) mutation mouse model of schizophrenia to assess these developmental changes and tested whether enzymatic digestion of PNNs in the PFC affected schizophrenia-like behaviors and neural activity. Developmentally, we found that the normal formation of PNNs, PVs, and colocalization of these two in the PFC, peaked around PND 22 (postnatal day 22). However, in DISC1, mutation animals from PND 0 to PND 60, both PNNs and PVs were significantly reduced. After enzymatic digestion of PNNs with chondroitinase in adult animals, the behavioral pattern of control animals mimicked that of DISC1 mutation animals, exhibiting reduced sociability, novelty and increased ultrasonic vocalizations, while there was very little change in other behaviors, such as working memory (Y-maze task involving medial temporal lobe) or depression-like behavior (tail-suspension test involving processing via the hypothalamic pituitary adrenal (HPA) axis). Moreover, following chondroitinase treatment, electrophysiological recordings from the PFC exhibited a reduced proportion of spontaneous, high-frequency firing neurons, and an increased proportion of irregularly firing neurons, with increased spike count and reduced inter-spike intervals in control animals. These results support the proposition that the aberrant development of PNNs and PVs affects normal neural operations in the PFC and contributes to the emergence of some of the behavioral phenotypes observed in the DISC1 mutation model of schizophrenia.

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Subchronic Arsenic Exposure Induces Anxiety-Like Behaviors in Normal Mice and Enhances Depression-Like Behaviors in the Chemically Induced Mouse Model of Depression

BioMed Research International ◽

10.1155/2015/159015 ◽

2015 ◽

Vol 2015 ◽

pp. 1-12 ◽

Cited By ~ 18

Author(s):

Chia-Yu Chang ◽

How-Ran Guo ◽

Wan-Chen Tsai ◽

Kai-Lin Yang ◽

Li-Chuan Lin ◽

...

Keyword(s):

Drinking Water ◽

Prefrontal Cortex ◽

Mouse Model ◽

Arsenic Exposure ◽

Tail Suspension Test ◽

Behavioral Disturbances ◽

Chemically Induced ◽

Contaminated Drinking Water ◽

Swimming Test ◽

Underlying Mechanisms

Accumulating evidence implicates that subchronic arsenic exposure causes cerebral neurodegeneration leading to behavioral disturbances relevant to psychiatric disorders. However, there is still little information regarding the influence of subchronic exposure to arsenic-contaminated drinking water on mood disorders and its underlying mechanisms in the cerebral prefrontal cortex. The aim of this study is to assess the effects of subchronic arsenic exposure (10 mg/LAs2O3 in drinking water) on the anxiety- and depression-like behaviors in normal mice and in the chemically induced mouse model of depression by reserpine pretreatment. Our findings demonstrated that 4 weeks of arsenic exposure enhance anxiety-like behaviors on elevated plus maze (EPM) and open field test (OFT) in normal mice, and 8 weeks of arsenic exposure augment depression-like behaviors on tail suspension test (TST) and forced swimming test (FST) in the reserpine pretreated mice. In summary, in this present study, we demonstrated that subchronic arsenic exposure induces only the anxiety-like behaviors in normal mice and enhances the depression-like behaviors in the reserpine induced mouse model of depression, in which the cerebral prefrontal cortex BDNF-TrkB signaling pathway is involved. We also found that eight weeks of subchronic arsenic exposure are needed to enhance the depression-like behaviors in the mouse model of depression. These findings imply that arsenic could be an enhancer of depressive symptoms for those patients who already had the attribute of depression.

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M181. DEVELOPMENTAL PROGRESSION OF INTERNEURON NETWORK DEFICITS IN A 15Q13.3 MICRODELETION MOUSE MODEL – A GLIMPSE ON ADOLESCENT PRIMING FOR SCHIZOPHRENIA?

Schizophrenia Bulletin ◽

10.1093/schbul/sbaa030.493 ◽

2020 ◽

Vol 46 (Supplement_1) ◽

pp. S205-S205

Author(s):

Marzieh Funk ◽

Stefan Jaeger ◽

Niklas Schülert ◽

Cornelia Dorner-Ciossek ◽

Holger Rosenbrock ◽

...

Keyword(s):

Prefrontal Cortex ◽

Mouse Model ◽

Critical Period ◽

Neurodevelopmental Disorder ◽

Brain Slices ◽

Cortical Network ◽

Wild Type ◽

Perineuronal Net ◽

Network Function ◽

Adult Mice

Abstract Background Schizophrenia is a complex neurodevelopmental disorder. Patients typically start exhibiting symptoms during adolescence, coinciding with a critical period for the maturation of the prefrontal cortex. While previous studies have identified deficits in cortical interneuron integrity and network function in chronic patients, little is known about the maladaptive circuitry in the early prodromal phase of the disease. To assess pathophysiological changes during adolescence that might contribute to the disruption of cortical network function we have studied a 15q13.3 microdeletion mouse model Df[h15q13]−/+ resembling a human copy number variant (CNV) known to confer high risk for psychiatric disorders such as schizophrenia. Using a combination of histology, in vitro electrophysiology and electroencephalography (EEG) we explored the interneuronal connectivity and cortical network functionality in the Df[h15q13]−/+ mouse model from adolescence to early adulthood Methods Immunohistological analysis was performed on brain slices within the prefrontal cortex, dorsal hippocampus and amygdala region from Df[h15q13]−/+ and wild-type mice (N=8) at PND35 and PND70 (4 sections/brain). Sections were immunostained for markers of interneuron subtypes and respective synapses. Fluorescence images were recorded and processed with an Opera Phenix (PerkinElmer) using the 63x objective in confocal mode. EEG studies were performed on Df[h15q13]−/+ and wild-type mice within the age range of PND41 to PND70 (6). Mice were obtained from Taconic and housed within the experimental facility for at least one week prior to experimental procedures. Results We initially confirmed that the adult Df[h15q13]−/+ microdeletion mouse model exhibits robust markers reminiscent of schizophrenia-linked pathology, such as the reduction of parvalbumin positive (PV+) interneurons, lower abundance of perineuronal net proteins (PNNs) and an impaired cortical processing of sensory information. We identified abnormalities in the number and distribution of interneuron synapses in the prefrontal cortex, hippocampus and amygdala, the phenotype in the adolescent brain, which were opposed to pathophysiological changes identified in adult Df[h15q13]−/+ microdeletion mice. We discovered an enhanced inhibitory drive from specific subpopulations of interneurons during adolescence that might contribute to deficits in the adult hippocampal and PFC network. Likewise, we found Df[h15q13]−/+ specific differences in cortical network processing between adolescent and adult mice revealed by EEG. To align the development of cortical network function to the progressive changes in network structure we performed longitudinal EEG recordings and uncovered particular abnormalities in basal and evoked oscillatory rhythms in adolescent and adult mice. Discussion In this study, we discovered abnormalities in the interneuron integration during a critical period for the maturation of the prefrontal cortex in a 15q13.3 microdeletion mouse model. Our findings provide novel insights into early deficits in the limbic and cortical neuronal networks that may drive circuit dysfunction in schizophrenia patients. Identification of adolescent pathophysiology in models for schizophrenia risk will provide the opportunity to explore new mechanisms for early intervention.

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The development of perineuronal nets around parvalbumin gabaergic neurons in the medial prefrontal cortex and basolateral amygdala of rats.

Behavioral Neuroscience ◽

10.1037/bne0000203 ◽

2017 ◽

Vol 131 (4) ◽

pp. 289-303 ◽

Cited By ~ 25

Author(s):

Kathryn D. Baker ◽

Arielle R. Gray ◽

Rick Richardson

Keyword(s):

Prefrontal Cortex ◽

Medial Prefrontal Cortex ◽

Basolateral Amygdala ◽

Gabaergic Neurons ◽

Perineuronal Nets

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Intranasal oxytocin administration ameliorates social behavioral deficits in a POGZWT/Q1038R mouse model of autism spectrum disorder

Molecular Brain ◽

10.1186/s13041-021-00769-8 ◽

2021 ◽

Vol 14 (1) ◽

Author(s):

Kohei Kitagawa ◽

Kensuke Matsumura ◽

Masayuki Baba ◽

Momoka Kondo ◽

Tomoya Takemoto ◽

...

Keyword(s):

Autism Spectrum Disorder ◽

Social Behavior ◽

Mouse Model ◽

Mouse Models ◽

De Novo ◽

Neurodevelopmental Disorder ◽

Autism Spectrum ◽

Spectrum Disorder ◽

De Novo Mutation ◽

Behavioral Deficits

AbstractAutism spectrum disorder (ASD) is a highly prevalent neurodevelopmental disorder characterized by core symptoms of impaired social behavior and communication. Recent studies have suggested that the oxytocin system, which regulates social behavior in mammals, is potentially involved in ASD. Mouse models of ASD provide a useful system for understanding the associations between an impaired oxytocin system and social behavior deficits. However, limited studies have shown the involvement of the oxytocin system in the behavioral phenotypes in mouse models of ASD. We have previously demonstrated that a mouse model that carries the ASD patient-derived de novo mutation in the pogo transposable element derived with zinc finger domain (POGZWT/Q1038R mice), showed ASD-like social behavioral deficits. Here, we have explored whether oxytocin (OXT) administration improves impaired social behavior in POGZWT/Q1038R mice and found that intranasal oxytocin administration effectively restored the impaired social behavior in POGZWT/Q1038R mice. We also found that the expression level of the oxytocin receptor gene (OXTR) was low in POGZWT/Q1038R mice. However, we did not detect significant changes in the number of OXT-expressing neurons between the paraventricular nucleus of POGZWT/Q1038R mice and that of WT mice. A chromatin immunoprecipitation assay revealed that POGZ binds to the promoter region of OXTR and is involved in the transcriptional regulation of OXTR. In summary, our study demonstrate that the pathogenic mutation in the POGZ, a high-confidence ASD gene, impairs the oxytocin system and social behavior in mice, providing insights into the development of oxytocin-based therapeutics for ASD.

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Diurnal changes in perineuronal nets and parvalbumin neurons in the rat medial prefrontal cortex

Brain Structure and Function ◽

10.1007/s00429-021-02229-4 ◽

2021 ◽

Author(s):

John H. Harkness ◽

Angela E. Gonzalez ◽

Priyanka N. Bushana ◽

Emily T. Jorgensen ◽

Deborah M. Hegarty ◽

...

Keyword(s):

Prefrontal Cortex ◽

Medial Prefrontal Cortex ◽

Perineuronal Nets ◽

Diurnal Changes ◽

Parvalbumin Neurons

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Aberrant aggressive behavior in a mouse model of Angelman syndrome

Scientific Reports ◽

10.1038/s41598-020-79984-7 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Lilach Simchi ◽

Hanoch Kaphzan

Keyword(s):

Social Behavior ◽

Mouse Model ◽

Aggressive Behavior ◽

Social Interactions ◽

Angelman Syndrome ◽

Case Reports ◽

Neurodevelopmental Disorder ◽

Therapeutic Interventions ◽

Affiliative Behavior ◽

Severe Difficulty

AbstractAngelman syndrome (AS) is a genetic neurodevelopmental disorder due to the absence of the E3-ligase protein, UBE3A. Inappropriate social interactions, usually hyper-sociability, is a part of that syndrome. In addition, clinical surveys and case reports describe aggressive behavior in AS individuals as a severe difficulty for caretakers. A mouse model for AS recapitulates most of the human AS phenotypes. However, very few studies utilized this mouse model for investigating affiliative social behavior, and not even a single study examined aggressive behavior. Hence, the aim of the herein study was to examine affiliative and aggressive social behavior. For that, we utilized a battery of behavioral paradigms, and performed detailed analyses of these behaviors. AS mice exhibited a unique characteristic of reduced habituation towards a social stimulus in comparison to their wild-type (WT) littermates. However, overall there were no additional marked differences in affiliative social behavior. In contrast to the mild changes in affiliative behavior, there was a striking enhanced aggression in the AS mice compared to their WT littermates. The herein findings emphasize the use of AS mouse model in characterizing and measuring inappropriate aggressive behavior, and suggests these as tools for investigating therapeutic interventions aimed at attenuating aggressive behavior.

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Thalamic pathways underlying prefrontal cortex–medial temporal lobe oscillatory interactions

Trends in Neurosciences ◽

10.1016/j.tins.2014.09.007 ◽

2015 ◽

Vol 38 (1) ◽

pp. 3-12 ◽

Cited By ~ 48

Author(s):

Nicholas A. Ketz ◽

Ole Jensen ◽

Randall C. O’Reilly

Keyword(s):

Prefrontal Cortex ◽

Temporal Lobe ◽

Medial Temporal Lobe

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Neural activity in macaque prefrontal cortex in flexible switching of search strategies

Neuroscience Research ◽

10.1016/j.neures.2011.07.1208 ◽

2011 ◽

Vol 71 ◽

pp. e276-e277

Author(s):

Atsushi Fujimoto ◽

Satoshi Nishida ◽

Tadashi Ogawa

Keyword(s):

Prefrontal Cortex ◽

Neural Activity ◽

Search Strategies

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Hippocampal–diencephalic–cingulate networks for memory and emotion: An anatomical guide

Brain and Neuroscience Advances ◽

10.1177/2398212817723443 ◽

2017 ◽

Vol 1 ◽

pp. 239821281772344 ◽

Cited By ~ 64

Author(s):

Emma J. Bubb ◽

Lisa Kinnavane ◽

John P. Aggleton

Keyword(s):

Prefrontal Cortex ◽

Medial Temporal Lobe ◽

Current Knowledge ◽

Hippocampal Formation ◽

Retrosplenial Cortex ◽

Thalamic Nuclei ◽

Mammillary Bodies ◽

Individual Site ◽

Multi Stage ◽

Anterior Thalamic Nuclei

This review brings together current knowledge from tract tracing studies to update and reconsider those limbic connections initially highlighted by Papez for their presumed role in emotion. These connections link hippocampal and parahippocampal regions with the mammillary bodies, the anterior thalamic nuclei, and the cingulate gyrus, all structures now strongly implicated in memory functions. An additional goal of this review is to describe the routes taken by the various connections within this network. The original descriptions of these limbic connections saw their interconnecting pathways forming a serial circuit that began and finished in the hippocampal formation. It is now clear that with the exception of the mammillary bodies, these various sites are multiply interconnected with each other, including many reciprocal connections. In addition, these same connections are topographically organised, creating further subsystems. This complex pattern of connectivity helps explain the difficulty of interpreting the functional outcome of damage to any individual site within the network. For these same reasons, Papez’s initial concept of a loop beginning and ending in the hippocampal formation needs to be seen as a much more complex system of hippocampal–diencephalic–cingulate connections. The functions of these multiple interactions might be better viewed as principally providing efferent information from the posterior medial temporal lobe. Both a subcortical diencephalic route (via the fornix) and a cortical cingulate route (via retrosplenial cortex) can be distinguished. These routes provide indirect pathways for hippocampal interactions with prefrontal cortex, with the preponderance of both sets of connections arising from the more posterior hippocampal regions. These multi-stage connections complement the direct hippocampal projections to prefrontal cortex, which principally arise from the anterior hippocampus, thereby creating longitudinal functional differences along the anterior–posterior plane of the hippocampus.

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