The objective of the proposed research is to characterize the anatomy of two synaptic circuits in the forebrain: glutamatergic corticostriatal connections and GABAergic striatonigral connections. The principal actions of the synapses of these connections are excitatory and inhibitory, respectively. Together these connections represent an important route of information processing through the mammalian basal ganglia. They are necessary for the normal development and mature physiological operation of the forebrain. Their pathological destruction is associated with severe human neurological diseases including congenital diplegia, Huntington's disease, and stroke. The mature arrangement, developmental organization and response to brain injury of corticostriatal and striatonigral neurons will be determined in cats, a well-characterized animal model of forebrain anatomy and physiology. The experiments will incorporate combinations of connectivity, transmitter and somatodendritic markers to identify the fine structure and biochemistry of the circuits. The research will be focused on the final events in the formation of the connections: the morphogenesis of pre- and post-synaptic specializations and the presynaptic localization of amino acid transmitters. Three hypotheses will be tested: 1) that the establishment of corticostriatal connections triggers the expression of transmitters and the synaptogenesis of striatonigral connections, 2) that the formation of synaptic inputs directs the final stages of dendritic morphogenesis in neostriatal and nigral neurons and 3) that striatonigral connections respond differently to the loss of synaptic inputs induced by failure-to-form, by removal at an immature stage and by removal at a mature stage. The failure or misdirections of these cell-cell interactions can play a critical role in the pathogenesis of human mental retardation. The remodeling of these connections after early and late damage is also of great importance for the anatomical pathology and possible treatment of developmental disabilities and late- appearing genetic disorders.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
First Independent Research Support & Transition (FIRST) Awards (R29)
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Neurology A Study Section (NEUA)
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University of California Los Angeles
Other Domestic Higher Education
Los Angeles
United States
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Fisher, Robin; Boylan, Marea (2011) Tachykinin-immunoreactive neurons in developing feline neostriatum: somatodendritic morphogenesis demonstrated by combined immunohistochemistry/Golgi impregnation-gold toning. Dev Neurosci 33:75-84
Fisher, R S; Boylan, M K; Xie, Y (2003) Tachykinin expression and localization in developing feline neocortex. Dev Neurosci 25:127-38
Zampighi, G A; Fisher, R S (1997) Polyhedral protein cages encase synaptic vesicles and participate in their attachment to the active zone. J Struct Biol 119:347-59
Duong, T; De Rosa, M J; Poukens, V et al. (1994) Neuronal cytoskeletal abnormalities in human cerebral cortical dysplasia. Acta Neuropathol 87:493-503
Ariano, M A; Fisher, R S; Smyk-Randall, E et al. (1993) D2 dopamine receptor distribution in the rodent CNS using anti-peptide antisera. Brain Res 609:71-80
De Rosa, M J; Secor, D L; Barsom, M et al. (1992) Neuropathologic findings in surgically treated hemimegalencephaly: immunohistochemical, morphometric, and ultrastructural study. Acta Neuropathol 84:250-60
Watson, J B; Sutcliffe, J G; Fisher, R S (1992) Localization of the protein kinase C phosphorylation/calmodulin-binding substrate RC3 in dendritic spines of neostriatal neurons. Proc Natl Acad Sci U S A 89:8581-5
Jensen, K F; Ohmstede, C A; Fisher, R S et al. (1991) Acquisition and loss of a neuronal Ca2+/calmodulin-dependent protein kinase during neuronal differentiation. Proc Natl Acad Sci U S A 88:4050-3
Jensen, K F; Ohmstede, C A; Fisher, R S et al. (1991) Nuclear and axonal localization of Ca2+/calmodulin-dependent protein kinase type Gr in rat cerebellar cortex. Proc Natl Acad Sci U S A 88:2850-3
Boylan, M K; Levine, M S; Buchwald, N A et al. (1990) Patterns of tachykinin expression and localization in developing feline neostriatum. J Comp Neurol 293:151-63

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