Date of Award

January 2017

Document Type

Thesis

Degree Name

Medical Doctor (MD)

Department

Medicine

First Advisor

Amy F. Arnsten

Abstract

Schizophrenia is associated with profound cognitive deficits, including profound impairments in working memory that drive occupational, social and economic disabilities [1, 2]. Patients with Schizophrenia have profound deficits in the working memory functions of the dlPFC that correlate with symptoms of thought disorder [3].

Persistent activity across a delay period is considered the neuronal basis of working memory, which is generated by recurrent activity among a group of layer III PFC pyramidal cells, that excite each other via NMDA receptor synapses on dendritic spines. NMDAR requires a depolarized membrane to open; in some areas of the brain (e.g. visual cortex) this is done by AMPAR, but acetylcholine performs this function in layer III PFC, through actions at nicotinic a7 receptors [4], and possibly, through muscarinic M1 receptor (M1R) closing of M-type KCNQ potassium channels in the synaptic membrane.

Immunoelectron microscopy data has demonstrated the presence of both M1R and KCNQ in glutamate-like synapses in layer III of primate dlPFC. This study aimed to test the hypothesis that stimulation of the M1R would enhance working memory though closure of hyperpolarizing KCNQ channels. To examine the role of the M1-KCNQ signaling pathway in working memory, we tested the effect of agents that modulated M1R and the KCNQ channel on neuronal activity in dlPFC.

Single unit neuronal recordings were performed in non-human primates performing a working memory task. Drugs manipulating M1R and KCNQ were iontophoresed onto the recording site and the effect on firing was captured by a carbon fiber electrode.

We found that both M1R activation and KCNQ blockade enhanced working memory related activity in the monkey dlPFC (p<0.01) while M1R blockade (p<0.0001) and KCNQ channel opening (p<0.01) reduced neuronal activity in the dlPFC. Finally, the effect of the M1R was found to be influenced by the open state of the KCNQ channel. Reduced firing from M1R blockade in the dlPFC was reversed by closure of KCNQ channel (p<0.01).

The current study shows that both M1R and KCNQ channels regulate working memory circuitry at the neuronal level. The effects of M1R on neural activity in the working memory circuitry, is mediated by the open state of KCNQ channel. These findings suggest that M1R activation is a viable strategy to enhance working memory circuits and maybe be a potential target for agents developed to improve cognition. This strategy would have special relevance to cognitive dysfunction in schizophrenia, as patients have been found to have working memory deficits and downregulation of the M1R in working memory circuitry of the dlPFC [5].

Comments

This thesis is restricted to Yale network users only. This thesis is permanently embargoed from public release.

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