VCOM Research Day Program Book 2023

Medical Student Research Biomedical

04 Novel Glutamate Concentration Dependent NMDAR Modulators Remedially Alter the Expression of Post-Synaptic Signaling Cascade

Leah Dunn BS, VCOM, Seth Boehringer, VT; Patrick Rafael BS, VT; Alyssa Ingram BS, VCOM; Blaise Costa PhD, VCOM Corresponding author:

Edward Via College of Osteopathic Medicine-Virginia Campus

Glutamate is a major excitatory neurotransmitter in the human brain. Glutamate activates the N-methyl D-aspartate (NMDA) sensitive ion channel known as NMDA receptor. Recently discovered novel compounds (CNS4 and CNS42) potentiate NMDA receptor based on glutamate concentration. NMDA receptor is made up of two glycine-binding GluN1 subunits and two glutamate binding GluN2 subunits and PSD95 is a scaffolding protein that stabilizes the NMDA receptor on the post-synaptic neuronal membrane. In this work, we have studied the effect of CNS4&42 GluN1 and PSD95 expression in cultured rat brain cortical and striatal neurons. The result from western blots shows that low concentrations of CNS4 numerically increases the expression of GluN1 and statistically increases PSD95 expression.

Effects of CNS4 & 42 on PSD95, CREB, and pCREB expression during NMDA induced excitotoxicity was also studied through western blots. CREB and pCREB are involved in the cAMP secondary messenger system with the NMDA receptor. NMDA receptor excitotoxicity is associated with neurodegeneration and thus protective mechanisms such as receptor downregulation must be in place to avoid receptor destruction and cell death. Results from this set of experiments reveal that when excess NMDA is present, the expression of GluN1 is significantly reduced. This reduction is completely reversed by a clinically used NMDA receptor blocker, memantine. CREB and pCREB proteins also show a corresponding decrease in expression in CNS4 & 42 treated NMDA excitotoxicity.

In summary, CNS4 & 42 improve the synaptic strength by upregulating the expression of GluN1 and PSD-95 during hypoglutamatergic conditions. In contrast to this, during hyperglutamatergic conditions, CNS4 & 42 do not interfere with the endogenous neuroprotective mechanisms that downregulate NMDA activation-induced CREB signaling. Therefore, these compounds might serve as potential lead candidates to develop drugs for the treatment of neuropsychiatric disorders.


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