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 th... More
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.
