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PMID: 31263190 Published · epublish English Journal Article Research Support, N.I.H., Extramural

PSD-95 deficiency disrupts PFC-associated function and behavior during neurodevelopment.

Scientific reports ·Vol. 9 ·No. 1 ·2019-00-01 ·Pages 9486

Coley AA, Gao WJ

Abstract

Postsynaptic density protein-95 (PSD-95) is a major regulator in the maturation of excitatory synapses by interacting and trafficking N-methyl-D-aspartic acid receptors (NMDAR) and α-amino-3-hydroxy-5-methyl-4-isox-azoleproprionic acid receptors (AMPAR) to the postsynaptic membrane. PSD-95 disruption has recently been associated with neuropsychiatric disorders such as schizophrenia and autism. However, the effects of PSD-95 deficiency on the prefrontal cortex (PFC)-associated functions, including cognition, working memory, and sociability, has yet to be investigated. Using a PSD-95 knockout mouse model (PSD-95-/-), we examined how PSD-95 deficiency affects NMDAR and AMPAR expression and function in the medial prefrontal cortex (mPFC) during juvenile and adolescent periods of development. We found significant increases in total protein levels of NMDAR subunits GluN1, and GluN2B, accompanied by decreases in AMPAR subunit GluA1 during adolescence. Correspondingly, there is a significant increase in NMDAR/AMPAR-mediated current amplitude ratio that progresses from juvenile-to-adolescence. Behaviorally, PSD-95-/- mice exhibit a lack of sociability, as well as learning and working memory deficits. Together, our data indicate that PSD-95 deficiency disrupts mPFC synaptic function and related behavior at a critical age of development. This study highlights the importance of PSD-95 during neurodevelopment in the mPFC and its potential link in the pathogenesis associated with schizophrenia and/or autism.

MeSH Terms
Animals Autistic Disorder/genetics,metabolism,pathology Behavior, Animal Disks Large Homolog 4 Protein/deficiency,metabolism Mice Mice, Knockout Nerve Tissue Proteins/genetics,metabolism Prefrontal Cortex/growth & development,pathology Receptors, AMPA/genetics,metabolism Receptors, N-Methyl-D-Aspartate/genetics,metabolism Schizophrenia/genetics,metabolism,pathology Synapses/genetics,metabolism
Chemicals
Disks Large Homolog 4 Protein Dlg4 protein, mouse Gprin1 protein, mouse NR2B NMDA receptor Nerve Tissue Proteins Receptors, AMPA Receptors, N-Methyl-D-Aspartate
Authors & Affiliations
2 authors, click to expand affiliations / ORCID
Coley Austin A
Department of Neurobiology and Anatomy, Drexel University College of Medicine, Philadelphia, PA, 19129, USA.
Gao Wen-Jun ORCID
Department of Neurobiology and Anatomy, Drexel University College of Medicine, Philadelphia, PA, 19129, USA. [email protected].
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Article Info
Journal
Scientific reports
Abbr.
Sci Rep
ISSN
2045-2322
DOI
10.1038/s41598-019-45971-w
Email
[email protected]
Published
2019-00-01
Epub
2019-00-01
Pages
9486
Language
English
Region
England
NLM ID
101563288
PMCID
PMC6602948
Subset
IM
Grants
NINDS NIH HHS · F99 NS105185 · United States
NIMH NIH HHS · R01 MH085666 · United States
External Links
PubMed source DOI: 10.1038/s41598-019-45971-w PMC Full Text View journal details
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