The pyramidal cell microcircuits of the primate dorsolateral prefrontal cortex (dlPFC) are gravely afflicted in schizophrenia. Research in monkeys has shown that these circuits excite each other through glutamatergic, NMDA receptor (NMDAR) synapses on dendritic spines to generate the persistent neural representations needed for working memory. Immunoelectron microscopy has revealed that both nicotinic-?7 receptors (nic- ?7R), and muscarinic M1 receptors (M1R) are localized in dlPFC glutamate synapses within the post-synaptic density (PSD). During the previous tenure of this grant, we discovered that cholinergic stimulation of nic-?7R enhances neural representations in the primate dlPFC, and is permissive for NMDAR actions, rescuing neuronal firing from NMDAR blockade. As schizophrenia is associated with impaired NMDAR and nic-?7R signaling, these data encourage the development of nic-?7R agonists for the treatment of PFC cognitive deficits. However, this strategy has been hampered by the rapid desensitization of nic-?7R following stimulation, and by drug actions at peripheral nic-?7R. Thus, additional approaches are needed. Stimulation of M1R may have beneficial effects on dlPFC function similar to nic-?7R, and may provide a more tractable target since they are concentrated in brain areas relevant to cognition but are not as prevalent in the peripheral nervous system. As schizophrenia is associated with changes in the M1R gene (CHRM1) and with reduced M1R expression in dlPFC, these data have direct relevance to the etiology and treatment of this disease. In the proposed research, Aim 1 will examine whether stimulation of M1R, like nic-?7R, enhances the firing of dlPFC neurons in monkeys performing a working memory task, and whether M1R stimulation is permissive for NMDAR actions as suggested by their synaptic localization. We will also have the opportunity to test a novel, highly selective M1R positive allosteric modulator (PAM) created by Dr. Jeffrey Conn's Drug Discovery group at Vanderbilt University to see if this compound can enhance dlPFC neuronal firing and improve working memory following systemic administration in monkeys.
Aim 2 will address the mechanism of M1R actions in dlPFC, examining the hypothesis that M1R act by closing KCNQ potassium channels (Kv7; also known as M channels), which are also localized within the PSD of layer III glutamate synapses, positioned to depolarize the synaptic membrane and facilitate NMDAR signaling when closed by M1R actions. Finally, Aim 3 will test whether the same neurons that respond to nic-?7R stimulation also respond to M1R, and if so, whether they have additive or synergistic interactions. Additive or synergistic actions of nic-?7R and M1R stimulation could lead to combined treatments that allow lower doses with fewer side effects, circumventing a major hurdle in the development of cholinergic therapeutics for cognitive disorders.
Disorders such as schizophrenia have devastating effects on patients and their families, and there are currently no treatments for cognitive impairment in this illness. The proposed research will examine how acetylcholine stimulation of the muscarinic M1 and alpha-7 receptors influence higher cognitive functioning. As expression of these receptors is diminished in many patients with schiozphrenia, this research may help to identify new treatment strategies for patients with cognitive disorders.
