Disorders of cortical development underlie many forms of intractable childhood epilepsy, but the cellular events that regulate corticogenesis are incompletely understood. The earliest maturing neurons of the cortex are the Cajal-Retzius (CR) cells of the embryonic preplate, which have been shown to play a critical role in cortical organization by their recent implication in the pathology of the mouse mutant reeler. This proposal will apply cellular and molecular approaches to study embryonic CR cells. Our proposed experiments are based on preliminary findings that preplate cells are physiologically heterogeneous and that CR-like cells are coupled together by gap junction channels, are spontaneously active at embryonic stages, express a variety of neurotransmitter receptors, and are the first cortical neurons to develop functional NMDA receptors. We plan to determine how glutamatergic neurotransmission in the preplate contributes to early cortical circuitry and organization. We will explore the pattern and function of gap junction coupling in CR cells and characterize the time course of expression and functional properties of the glutamate receptors they express. Patch-clamp recording techniques will be used to study the physiological and pharmacological properties of NMDA, non-NMDA, and metabotropic glutamate receptors in CR cells in situ at E15, E19 and P7. Calcium imaging methods will be applied to measure receptor-specific increases in [Ca2+]i, to test for Ca2+- permeable AMPA/kainate receptors, and to determine the spatiotemporal pattern of spontaneous CR cell activity. Because the early appearing NMDA receptors on CR cells may play a key role in early cortical circuit formation, we will characterize NMDA receptor properties at both whole- cell and single channel levels. In addition, we will explore the molecular basis for the glutamate receptor properties displayed by individual CR cells using single-cell PCR techniques. Because the earliest cortical synapses form on CR cells, we will also study excitatory synaptic currents in CR cells and analyze the contributions of NMDA and non-NMDA glutamate receptors. In a related set of experiments to explicitly address the function of CR cells, we aim to selectively ablate CR cells from developing cortex in utero by kainic acid injection and examine consequences on cortical organization. These experiments represent the first attempt to define the functional properties of CR cells, which may be central to the developmental organization of the cerebral cortex.
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