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.
Highlights
Postsynaptic density-95 (PSD-95), a member of the membrane-associated guanylate kinase family (MAGUK)[1], is a major scaffolding protein located within the postsynaptic density (PSD) of excitatory synapses
AMPAR and N-methyl-D-aspartic acid receptors (NMDAR) protein levels are altered during a critical period of development in the medial prefrontal cortex (mPFC) of PSD-95−/− mice
To determine if AMPAR and NMDAR protein levels are altered during development in the mPFC of PSD-95 deficient mice, we used western blot analysis to examine specific AMPAR subunits GluA1 and GluA2; and NMDAR subunits GluN1, GluN2A, GluN2B and GluN3A protein expression levels at juvenile (P21) and adolescent (P35) age ranges
Summary
Postsynaptic density-95 (PSD-95), a member of the membrane-associated guanylate kinase family (MAGUK)[1], is a major scaffolding protein located within the postsynaptic density (PSD) of excitatory synapses. PSD-95 knockdown studies show an increase in GluN2B clustering at dendritic spines[13], and a triple knockdown of PSD-95/SAP-102/PSD-93 attenuates NMDAR current[12] These studies infer PSD-95 deficiency causes an imbalance of NMDAR and AMPAR presence and function, thereby altering glutamatergic transmission. We hypothesized that PSD-95 deficiency (Supplemental Figs 1 and 2) will disrupt synaptic maturation during critical periods of neurodevelopment due to an alteration in NMDAR/AMPAR-glutamatergic transmission that leads to impairments in mPFC development and function. By utilizing a PSD-95 knockout mouse model, this study characterizes changes in specific NMDAR-and AMPAR-subunit expression levels at the synapse, accompanied with fluctuations in SAP102 and PSD-93 protein levels in response to PSD-95 deficiency in the mPFC. This study provides great insight into the effects of PSD-95 deficiency on synaptic function and development of the mPFC and its potential implications in aberrant behavior associated with neuropsychiatric disorders
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