Regulation of glutamatergic neurotransmission, synaptic plasticity, sleep and behavior by D2-GSK3B-FXR1

Authors: Khlghatyan, Jivan
Advisor: Beaulieu, Jean MartinToth, Katalin
Abstract: Variants in Fxr1 gene are GWAS-associated to schizophrenia, bipolar disorders, insomnia, and sleep duration. Gsk3β can directly phosphorylate and negatively regulate Fxr1. Moreover, functional interaction between Gsk3β and Fxr1 is associated with emotional stability in humans. How Gsk3β-Fxr1 regulates neuronal activity, plasticity and behaviors remains unclear. Gsk3β can be activated downstream of dopamine D2 receptors. Gsk3β activity can be modulated by mood stabilizers, antipsychotics and antidepressants to regulate behaviors. Nevertheless, neuroanatomical correlates of Gsk3β functions downstream of D2 receptors remain elusive. First, we investigated the relationship of Gsk3β-Fxr1 to neuronal activity and behaviors. We discovered that Fxr1 and its negative regulator Gsk3β affect anxiety-related behaviors and glutamatergic neurotransmission via regulation of synaptic AMPA receptors. Second, we addressed the involvement of Gsk3β-Fxr1 in synaptic plasticity and sleep. We discovered that Fxr1 is a master regulator of homeostatic synaptic scaling. Moreover, it is engaged during sleep homeostasis to modulate synaptic strength via regulation of transcripts involved in local protein synthesis and synaptic structure. Third, to understand neuroanatomical correlates of D2 receptor signaling we generated a cortex-wide map of D2 expressing neurons and their projection targets. Fourth, we aimed to understand anatomically defined functions of Gsk3β downstream of D2 receptors. CRISPR/Cas9 mediated intersectional knockout of Gsk3β in D2 neurons of mPFC elucidated its contribution to the regulation of cognitive, social and mood-related behaviors. Overall, this thesis sheds light on brain functions of a GWAS-identified risk gene Fxr1 and shows the utility of intersectional CRISPR/Cas9 mediated genetic targeting for the interrogation of circuitspecific functions of genes.
Document Type: Thèse de doctorat
Issue Date: 2020
Open Access Date: 13 February 2020
Grantor: Université Laval
Collection:Thèses et mémoires

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