The humanbrain consists ofoveronehundred billionneuronsassembled into functionalneural circuits, which underlie all sophisticated brain functions. A precise balance between neuronal excitation and inhibition is required for proper brain function, and the imbalance between them leads to various types of behavioral and neurological problems including many complex brain disorders, such as schizophrenia, depression, and autism. Regulatory mechanisms for excitatory and inhibitory neuron formation have been studied in great detail,butthosemechanismsregulatinginhibitoryinterneuronsarestillbeingelucidated.Theoverarchinggoal of this project is to better understand the regulatory pathways underlying inhibitory interneuron formation with thehopethatsuchinsightwillleadtothebetterunderstandingofcomplexbraindisordersandthedevelopment ofeffectivetherapeutics.Inordertoreachthisgoal,webeganbyidentifyingfactorsthatcouldpotentiallyaffect the development of the embryonic ganglionic eminences (GE), a ventral forebrain region where inhibitory interneuronsareborn.WerationalizedthatsuchfactorsshouldbeexpressedintheGEandregulatesignaling pathways essential for controlling neurogenesis. Our initial studies reveal that Nemo-like kinase (NLK), an evolutionarily conserved serine/threonine kinase, satisfies these criteria. We have found that Nlk (mouse homologue of NLK) is specifically expressed in different regions of the GE, and loss of Nlk in mice causes adramatic increase in the proliferation of neural progenitor cells and impairment of their differentiation into mature inhibitory interneurons. Based on these preliminary studies, we hypothesize that Nlk plays a fundamental role in the development of inhibitory interneurons. To investigate this idea, we propose the following two major aims.
In Aim 1, we will determine the role of Nlk in the control of neural progenitor cell proliferation in the mouse GE. We will investigate specifically when, and how, Nlk influences progenitor cell number in specific regions of the GE.
In Aim 2, we will examine if Nlk is required for the proper differentiationand maintenance of specific subtypes of inhibitory interneurons in the cortex and striatum during embryonicand adult stages. We believe that the knowledge gained from the studies proposed in this application will fundamentally advance our understanding of the regulatory mechanisms of normal inhibitory interneuronformation, and thus provide insights into the relevance of this important process to understanding thepathogenesisofcomplexbraindisorders.
The burden of complex mental health disorders such as autism spectrum disorders is large, yet no effectivetherapeuticsexistforamajorityofthesedevastatingmentalillnesses.Thestudiesoutlinedinthisproposalwillallow us to determine key regulatory mechanisms underlying inhibitory interneuron formation and provide insights into the relevance of these findings to the pathophysiology of many mental health disorders,with theaimthatthisstudymayleadtothedevelopmentofeffectivetherapeuticsinthefuture.