Graduation Date

Fall 12-14-2018

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Programs

Pharmaceutical Sciences

First Advisor

Daniel T Monaghan

Abstract

N-methyl-D-aspartate receptors (NMDARs) are ligand-gated ion channels consisting of two GluN1 subunits and two other subunits from among GluN2A-2D and GluN3A-3B subunits. NMDARs play critical roles in synaptic plasticity, learning and memory, and higher brain function such as cognition and perception. Dysfunction of NMDARs (hyper-function and hypo-function of NMDARs) are related to various diseases, including stroke, schizophrenia, Alzheimer’s disease, and others. However, to date, NMDARs antagonists have mostly failed in clinical trials due to adverse effects.

NMDARs antagonists replicate the core symptoms of schizophrenia which may underlie its ability to alter neuronal oscillations in the neural circuitry of different brain regions. Recent evidence has shown that GluN2C subunits of NMDAR are expressed in astrocytes in the cortex, and that GluN2D NMDAR subunits are enriched in the parvalbumin-containing GABAergic inhibitory interneurons in the cortex and midbrain structures. Other studies have shown that both astrocytes and parvalbumin-containing interneurons play an essential role in generating and maintaining neuronal oscillations. These findings imply that GluN2C and GluN2D subunits may be involved in the distinct neural circuitry which regulates neuronal oscillations and thus influence the brain function and contribute to various diseases states. The initial aims of this dissertation are to determine if GluN2C and GluN2D subunits have a role in regulating neuronal oscillations. We also measured the auditory evoked responses in wildtype and GluN2C- and GluN2D-KO mice. Lastly, we use ketamine as the tool drug to determine the role of NMDARs in neuronal oscillations in a CDKL5-KO mouse model.

We found that spontaneous basal neuronal oscillations were elevated in GluN2C- and GluN2D-KO mice compared to WT mice. NMDARs antagonists increased the power of neuronal oscillations in WT mice; we found drug-induced power increase is abolished in GluN2D-KO mice and is augmented in GluN2C-KO mice.

Furthermore, we also found GluN2D-KO mice displayed abnormal auditory evoked responses. Lastly, we test subunit-selective NMDARs drug and NMDARs allosteric modulators with distinct subunits selectivity developed by our lab, including PAMs and NAMs on these KO models.

Available for download on Friday, December 06, 2019

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