The Role of GSK3[beta] in the Parvalbumin-Pyramidal Prefrontal Cortex Microcircuit

Abstract

Glycogen synthase kinase 3[beta] (GSK3[beta]), an enzyme classically focused on in the context of metabolism, has gained interest regarding its involvement in psychiatric and neurodegenerative disorders largely due to the beneficial effects of lithium, a direct inhibitor of GSK3[beta], administration in both animal research and clinically. Recently GSK3 inhibitors were highlighted as promising rescuers of cognitive impairments for a gamut of CNS disorders. Complex cognitive behaviors regulated by the prefrontal cortex (PFC) depend on an optimal balance of excitation and inhibition (E/I), which is essential for driving computational activity of cortical circuits. Glutamatergic pyramidal neurons mediate the excitatory component, while GABAergic interneurons facilitate inhibition. Growing evidence supports that fast-spiking parvalbumin (PV) interneurons are critical regulators of the E/I balance, shaping and synchronizing excitatory activity that improves clarity through contrast. Furthermore, disruption of either NMDARs or PV-GABAergic neurotransmission is strongly implicated in disorders with cognitive impairments. Albeit, how excitatory receptors on PV interneurons are regulated and how this affects cognitive function remains unknown. Our previous findings support that GSK3[beta] is a promising therapeutic target, leading us to elucidate its role in PV interneurons. To address these questions, we have generated a novel triple-transgenic conditional mouse with GSK3[beta] genetically deleted from PV interneurons. PV-GSK3[beta]-/- resulted in increased excitability and sensitivity to synaptic inputs, as well as augmented excitatory synaptic strength in PV interneurons. PV-GSK3[beta]-/- also demonstrated augmented NMDA functionality in mPFC pyramidal neurons. More importantly, these synaptic changes are correlated with accelerated learning with no changes in locomotion and sociability. Our study, for the first time, examined how GSK3[beta] activity affects learning capability via regulation of PV interneurons. This study provides novel insight into how GSK3[beta] may contribute to the disorders afflicted by cognitive deficits.Ph.D., Neuroscience -- Drexel University, 201