This application is for an individual fellowship for an MD-PhD student, with a research training plan designed to aid his long-term goal of becoming an independent physician-scientist in the field of developmental neurobiology. The cerebral cortex is the largest structure in the brain and essential for our higher-order cognitive abilities The basic building blocks of the cortex are neuronal assemblies consisting of excitatory glutamatergic neurons and ?-aminobutyric acid-containing (GABAergic) interneurons. Although most interneurons are inhibitory and make local connections, they represent a highly heterogeneous population of cells in terms of their morphology, electrophysiology, and neurochemical profiles. Abnormal development and function of cortical interneurons has been implicated in the pathobiology of neurological and neuropsychiatric illnesses such as epilepsy, autism, and schizophrenia. Determination of the factors that regulate the type and number of interneurons generated could positively impact clinical approaches to these disorders by allowing for a target gene approach to identifying mutations or allelic variations that contribut to disease. They may also further efforts to generate specific interneuron subtypes from embryonic stem cells for use in cell-based therapies. This proposal seeks to examine the interaction between proliferation and cortical interneuron fate determination through a candidate gene approach. The recently identified gene, Zswim5, encodes a protein of unknown function with a pattern of expression restricted to the subventricular zone (SVZ) of the medial ganglionic eminence (MGE), the birthplace of most cortical interneurons. Importantly, the SVZ contains intermediate progenitor cells (IPCs), which undergo symmetrical neurogenic divisions to give rise to predominantly parvalbumin-expressing interneurons. However, despite the significance of these progenitors to cortical development, the molecular mechanisms governing IPC specification and proliferation remain poorly understood. We hypothesize that Zswim5 is expressed in newly generated IPCs as they migrate into the SVZ and functions to keep them in cycle until they undergo an additional round of division, thereby ensuring a correct ratio of interneuron subgroups in the adult cerebral cortex.
In Aim 1 we will establish Zswim5 as a molecular marker of MGE intermediate progenitor cells and characterize the transcription factor sequence that occurs in the differentiation from radial glia to postmitotic interneuron.
In Aim 2 we will determine the function of Zswim5 in regulating IPC proliferation using gain- and loss-of-function approaches.
In Aim 3 we will determine the role of Zswim5 in interneuron fate determination through analysis of Zswim5 loss-of-function mutant mice. The functional consequences of any interneuron deficits will be measured using EEG recordings from awake- behaving mice in combination with behavioral assays to detect abnormalities in social interaction, learning, and memory. Together, this knowledge will enable a host of future studies on interneuron development and function, with the potential to advance our understanding and treatment of interneuron-related diseases.
Neurological and neuropsychiatric illnesses such as epilepsy, autism, and schizophrenia remain major sources of morbidity and mortality that have seen little advancement in medical treatment. This application proposes to study the developmental signals that regulate fate determination and neuronal output in the ventral forebrain. Only by delineating the basic mechanisms through which cortical circuitry is established can we begin to explain and treat disorders that are rooted in its dysfunction.
| Tischfield, David J; Anderson, Stewart A (2017) Differentiation of Mouse Embryonic Stem Cells into Cortical Interneuron Precursors. J Vis Exp : |
| Tischfield, David J; Saraswat, Dave K; Furash, Andrew et al. (2017) Loss of the neurodevelopmental gene Zswim6 alters striatal morphology and motor regulation. Neurobiol Dis 103:174-183 |
| Tischfield, David J; Kim, Junho; Anderson, Stewart A (2017) Atypical PKC and Notch Inhibition Differentially Modulate Cortical Interneuron Subclass Fate from Embryonic Stem Cells. Stem Cell Reports 8:1135-1143 |
