Research Overview
SPECIFICATION OF INTERNEURONS IN THE DEVELOPING CEREBRAL CORTEX
For more information please contact Dr. Anderson at saa2007@med.cornell.edu The cerebral cortex contains two types of neurons, excitatory projection neurons and inhibitory interneurons. Based on chemical, physiological and morphological criterion, the inhibitory interneurons occur in distinct subtypes that subserve distinct functions. Several common Illnesses, including epilepsy and schizophrenia, involve the abnormal development and/or dysfunction of particular interneuron subtypes. The long-term objective of my research is to understand the molecular basis for interneuron subtype fate determination. Unlike cortical projection neurons, most cortical interneurons originate in the ventral forebrain, in the anlage of the basal ganglia. This finding raises the following questions: Are cortical interneurons fated to become specific subtypes within the ventral forebrain where they are born? Alternatively, (or in addition) do they migrate into the cortex as GABAergic "protointerneurons" that utilize local factors to determine their ultimate subtype? Focus #1: Regional and temporal influences on interneuron subtype specification Two methods are being employed to examine whether distinct interneuron subtypes have distinct sources. First, cells from various cortical and subcortical regions of mouse forebrains, at various times over the age-range of cortical neurogenesis, are transplanted into neonatal cortical environments in vivo and in vitro. The effect of the donor cell's place and time of birth on their differentiated fate is assessed. Second, a transgenic mouse expressing the Cre-recombinase under control of the transcription factor Nkx2.1 has been generated. This mouse will permit fate-mapping of neurons that originated within a particular subregion of the ventral forebrain. Focus #2: Specification of cortical interneurons: A candidate molecule approach. Since some aspects of interneuron subtype specification do appear to occur within the ventral forebrain, a candidate molecule approach is being taken to study factors which may influence this process. Two of the factors currently under investigation, by analysis of transgenic animals and by manipulating gene expression in explant cultures followed by transplantation, are the secreted signalling molecule Sonic Hedgehog, and the transcription factor Lhx6. Focus # 3. Derivation of functional cerebral cortical interneurons from embryonic stem cells. This project involves collaboration with Dr. Lorenz Studer at the Sloan Kettering Institute, and focuses on the derivation of Nkx2.1-expressing cortical interneuron progenitors from embryonic stem cells. We are transplanting these cells to determine whether functional interneurons can be derived from embryonic stem cells, and may extend this work to the study of cell-based therapies for chronic focal seizures. In a related project, we are studying the ability of transplanted interneuron progenitors from transgenic mice to reduce seizures in a mouse model of chronic epilepsy, in collaboration with Drs. Minah Suh and Theodore Schwartz in the department of Neurological Surgery at WCMC.
