The long term interest in our laboratory has been in the synaptic organization, neurochemical anatomy and ontogeny of circuits involved in the control of movement. Recent studies have focused on the developmental expression and adult distribution of several peptides in one of the primary centers of motor control, the cerebellum. Many peptides have defined biological actions outside the central nervous system, yet their physiological significance within neural circuitry remains unclear. The proposed experiments are designed to define the function of two of these peptides, corticotropin releasing factor (CRF) and cholecystokinin (CCK), in the adult and developing cerebellum. Recent in vitro studies have shown that various amino acids (e.g. glutamate, aspartate, GABA) which act as neurotransmitters in adult circuits have a different role during development where they regulate specific aspects of neuronal morphogenesis and survival 56,40. In addition to amino acids, several peptides have also been identified as playing a trophic role during development 37,64,69,70. To date, however, little is known about the type or ontogeny of receptors that mediate the developmental effects of neuropeptides. We propose to use an in vivo model to determine first how peptides modulate synaptic transmission in adult circuits, and second to correlate the timing and distribution of peptide receptor expression with peptide ontogeny and major events in cerebellar development including migration, synaptogenesis and morphogenesis. The general hypothesis is that peptides, as represented by CRF in the present experiments, play a receptor-mediated trophic role in development that is distinct from their physiological action in adult circuits. The climbing fiber-Purkinje cell synapse is well defined anatomically 52 and physiologically and thus provides an excellent model to analyze potential peptide/receptor interactions in both adult and developing circuits. We propose to address these goals by employing receptor binding, immunohistochemical, and physiological techniques. The North American opossum is the animal model of choice as the cerebellum of the newborn opossum has embryonic features and a protracted developmental time course in an external pouch. In addition, we have preliminary data that indicates a physiological action for peptides in adult circuits. The proposed experiments will provide new data on the possible differential role of peptides in adult (CRF, CCK) and developing circuits (CRF).
