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The Hillock Newsletter - Department of Neurobiology and Anatomy Revealing the Effects of PSD-95 Deficiency in the Prefrontal Cortex

Austin A. Coley, PhD

By Austin A. Coley, PhD

I joined the PhD program in the Neurobiology and Anatomy Department at Drexel University College of Medicine in Dr. Wen-Jun Gao's Laboratory in 2014. Dr. Gao's laboratory focuses on understanding the cellular and molecular underpinnings of neuropsychiatric disorders such as schizophrenia and autism. His laboratory combines electrophysiology techniques with biochemical and behavioral assays to address these questions.

My thesis project focused on the development and synaptic function of the prefrontal cortex (PFC), which is responsible for cognition, working memory, emotional control and sociability. The goal of my project was to determine the effects of postsynaptic density protein-95 (PSD-95) — a highly abundant scaffolding protein involved in trafficking NMDARs and AMPARs to the postsynaptic membrane — in the PFC (Figure 1). PSD-95 is responsible for synaptic maturation and has recently been implicated in schizophrenia and autism. However, the effects of PSD-95 deficiency within the mPFC remained unknown.

To test this, I utilized a combination of techniques to identify the effects of NMDAR and AMPAR presence and function due to PSD-95 deficiency within the medial prefrontal cortex (mPFC). For instance, using Western Blot techniques, I showed PSD-95 deficiency causes a significant increase in NMDA receptor subunits and a decrease in AMPA receptor subunits at the adolescent age range in a PSD-95 knock-out mouse model. Using whole-cell patch clamp techniques, I showed a significant increase in NMDAR/AMPAR-transmission in layer V pyramidal neurons in the mPFC of PSD-95 knock-out mice. These results revealed PSD-95 deficiency alters PFC glutamatergic transmission during a critical period of PFC development. We also showed PSD-95 deficient mice exhibit behavioral deficits that include learning and working memory impairments, and reduced sociability. These findings were recently published in the Scientific Reports journal entitled “PSD-95 deficiency disrupts PFCassociated function and behavior during neurodevelopment” (Coley and Gao, 2019).

In an additional project, I examined mPFC neural circuit function in response to PSD-95 deficiency. The mPFC contains major reciprocal connections with the MD (mediodorsal thalamus), which is responsible for the development and function of the mPFC via glutamatergic transmission. The MD also contributes to mPFC-associated behavior such as cognition and working memory.

Our goals were to explore how PSD-95 deficiency impairs mPFC connectivity by utilizing a PSD-95 deficient mouse model to better understand mPFC neural circuitry and associated behavior and further determine the effects of PSD-95 deficiency at a pathway or input-specific manner. We utilized optogenetics and ex vivo whole-cell electrophysiology techniques to examine NMDAR- and AMPARmediated synaptic functional properties at intra-cortical (IC), corticocortical (CC), and thalamo-cortical (TC) inputs to the mPFC. Our results showed there are profound differential effects of NMDAR function at CC and TC synapses in PSD-95 deficient mice compared to control mice, indicating input-specific changes that occur in response to PSD95 deficiency. This study provided greater insight into understanding mPFC connectivity and the effects of PSD-95 deficiency at specific inputs that may relate to mPFC-associated behavioral abnormalities.

Outside of the laboratory, I aimed to assist in community outreach programs to enable minority students into STEM at St. James School and Trenton's Upward Bound program in Philadelphia and New Jersey, respectively. I also facilitated a visit for Virginia Union University (VUU) students to tour the Gao Lab. Additionally, I was an invited seminar speaker in the Natural Sciences Department at VUU in 2018. During these talks, I discussed my research as well as the journey to obtaining my PhD. I have now begun my postdoctoral fellowship at the Salk Institute for Biological Studies under the mentorship of Dr. Kay Tye. My work will investigate the neural circuits and behavior, as well as state-dependent and region-specific cellular aberrations implicated in schizophrenia and major depression disorders using ex-vivo electrophysiology and Ca2+ imaging techniques.

I will continue my goal of becoming an academic professor in the neuroscience field where I can mentor and train others in a laboratory and classroom environment.

PSD-95 interactions in the PSD

(Left) PSD-95 interactions in the PSD. An illustration describing the molecular organization of the postsynaptic density (PSD) located in the dendritic spine of glutamatergic synapses. Postsynaptic density-95 (PSD-95) contains direct and indirect interactions with many macromolecules at the PSD. PDZ1 domains of PSD-95 bind directly to N-methylD-aspartic acid receptors (NMDARs), more specifically, GluN2-containing NMDA-receptors. PSD-95 also interacts with ErbB4, neuroligin, and nNos. PSD-95 has indirect interactions with α-amino-3-hydroxy-5-methyl-4-isox-azoleproprionic acid receptors (AMPARs) via stargazin. Other indirect interactions include group 1/5 mGluRs via GKAP, shank, and homer; and actin polymers via GKAP and cortactin. nNos, Neuronal nitric oxide synthase; GKAP, guanylate kinase-associated protein; mGluR, metabotropic glutamate receptors.

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