Jeffrey D. Macklis, MD
Associate Professor
of Neurology [Neuroscience]
Harvard Medical School/
Massachusetts General Hospital
Department of Neurology [Neuroscience]

MRRC Project(s)

R01 NS41590
Neocortical Precursor Transplants for Circuitry Repair

The central focus of work in our laboratory is on neocortical cellular repair and projection neuron development, i.e., the interactions between neuronal precursors and their molecular environment that guide migration, differentiation, and specificity of connections. The objectives of the research are to apply cellular and molecular control mechanisms to reconstruct complex neocortical projection neuron circuitry by neural transplantation or by manipulation of recently identified, endogenous neural precursors. This work could generate new avenues of treatment for neurodegenerative disease, developmental disorders or neocortical insults that may cause mental retardation. The work also aims toward a better understanding of normal and perturbed cortical projection neuron development that can result in mental retardation. In the neocortex, the effectiveness of potential transplantation or endogenous precursor therapy may depend critically upon whether donor or endogenous precursors can migrate to correct locations, differentiate and integrate appropriately, and reestablish the precise long distance projections and complex interconnective circuitry responsible for cortical function.

We have approached our research goals primarily via study of neuronal migration, differentiation, and connectivity following transplantation of precursors or manipulation of endogenous precursors within neocortex that has undergone a defined and controllable targeted neuronal cell death. This apoptotic neuronal degeneration is biophysically induced by photoactivation of targeting molecules, causing specific degeneration only to desired subpopulations of neurons in vivo. The cell death produces local reexpression of developmental signals responsible for directed neuronal migration, differentiation, and connectivity by transplanted or endogenous precursors.