Postsynaptic density protein-95 (PSD-95) is a highly abundant scaffolding protein located at the dendritic spines of excitatory synapses and is involved in the recruitment, trafficking, and stabilization of N-methyl-D- aspartic acid receptors (NMDAR?s) and ?-amino-3-hydroxy-5-methyl-4-isox-azoleproprionic acid receptors (AMPAR's) to the postsynaptic membrane during synaptic maturation. Previous studies have shown that within the hippocampus, PSD-95 deficiency causes ?silent synapse? formation that may be associated with the pathology observed in the neurological disorders of schizophrenia (SCZ) and autism. However, the effects of PSD-95 deficiency within the prefrontal cortex (PFC), a brain region with delayed maturation, have yet to be investigated. The PFC, located anterior of the frontal lobe, is responsible for cognition, working memory, emotional control, and sociability. It is also highly associated with neurodevelopmental disorders, especially schizophrenia. We hypothesize that PSD-95 deficiency will disrupt synaptic maturation in an age-dependent manner due to an increase in NMDAR/AMPAR-glutamatergic transmission that leads to impairments in PFC development and function. In this study we use a PSD-95-/- mouse to model PSD-95 deficiency and investigate NMDA and AMPA-receptor properties within the medial prefrontal cortex (mPFC). We explore protein expression levels of NMDAR and AMPAR-subunits and other relevant scaffolding proteins. Additionally, we examine NMDAR/AMPAR-transmission to characterize silent synapses, and accordingly, we will examine working memory function and social interaction to measure social novelty and exploration. Furthermore, based on our preliminary finding of increased NMDA/AMPA ratio in corticocortical afferents, we will examine the major inputs of the mPFC ? the mediodorsal thalamus (MD), which is responsible for the development and function of the mPFC via reciprocal connections mediated by glutamatergic transmission. We further hypothesize that PSD-95 deficiency will impair thalamocortical projections via disrupted glutamatergic transmission, resulting in afferent-specific changes in synaptic function and neurodevelopmental deficits of the mPFC that lead to physiological and behavioral dysfunctions. We will inject an adeno-associated virus (AAV) vector expressing channelrhodopsin-2 (ChR2) within the MD and use optogenetics to specifically activate MD inputs to mPFC to record excitatory postsynaptic currents. Together, this data will provide a greater understanding of how PSD-95 affects the glutamate receptor composition and transmission as it relates to mPFC development and function.
Postsynaptic density-95 (PSD-95) is a scaffolding protein involved in synapse maturation, and has been implicated in neurological disorders, such as schizophrenia and autism. However, the effects of PSD-95 deficiency on the synaptic function of prefrontal neurons remain uncharacterized. This project aims to focus on the effects of glutamatergic transmission and cognitive function in the absence of PSD-95.
| Coley, Austin A; Gao, Wen-Jun (2018) PSD95: A synaptic protein implicated in schizophrenia or autism? Prog Neuropsychopharmacol Biol Psychiatry 82:187-194 |
