Project Summary/Abstract
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 a-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.