Date of Completion

8-24-2016

Embargo Period

8-8-2017

Keywords

NMDA receptor, Radial glia cells, Human cortical development, Kynurenic acid

Major Advisor

Dr. Nada Zecevic

Associate Advisor

Dr. Srdjan Antic

Associate Advisor

Dr. Eric Levine

Associate Advisor

Dr. Elizabeth Eipper

Associate Advisor

Dr. James Li

Field of Study

Biomedical Science

Degree

Doctor of Philosophy

Open Access

Open Access

Abstract

N-Methyl D-Aspartate receptors (NMDARs), a subtype of glutamate receptors, are important in neural development. The distribution and function of these receptors are well-studied in rodent and adult human brains, but far less is known about NMDARs in the human fetal cerebral cortex. The human cerebral cortex develops from multipotent neural progenitors called the radial glia cells (RGCs) that give rise to intermediate and interneuron progenitors, neurons, and glial cells. In my thesis, I studied the distribution of NMDAR subunits, NR1, NR2A and NR2B, in the human cerebral cortex from 10 to 24 gestational weeks (gw), a period of intense neurogenesis and synaptogenesis. Moreover, I studied the effects of kynurenic acid (KYNA), a neuroactive metabolite of tryptophan degradation that acts as an endogenous NMDAR antagonist. Elevated levels of KYNA have been observed in pregnant women after viral infections and in the cerebrospinal fluid of adult schizophrenic patients. In my thesis work, I used an in vitro system of RGCs enriched from the human cerebral cortex between 16 and 19 gw to study the potential impact of KYNA-induced NMDAR blockade in human corticogenesis. qPCR, in situ hybridization, Western blotting, and double immunolabeling experiments revealed the presence of mRNA and proteins of the NMDAR subunits in cortical progenitors and post-mitotic neurons along the telencephalic wall suggesting possible roles for NMDARs in progenitor proliferation, cell-fate determination, and neuronal differentiation. This was, in fact, observed in the in vitro study where blocking NMDARs either with D-amino phosphovalerate (D-APV) or KYNA significantly decreased survival, proliferation, specification and neuronal differentiation of RGCs, and increased the number of reactive astrocytes, and levels of the pro-inflammatory cytokine IL-6, activating the Jak-STAT signaling pathway. These results suggest a NMDAR-dependent mechanism for impairment of cortical circuitry formation in the human fetal brain.

Available for download on Tuesday, August 08, 2017

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