MECHANISMS OF MAMMALIAN NEURONAL INTEGRATION

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The long term objective is to improve understanding of the synaptic and integrative mechanisms involved in motor control circuits in the mammalian spinal cord. These mechanisms play vital roles in all parts of the central nervous system and may, when unregulated or damaged, be involved in certain pathophysiological states such as spasticity, epilepsy, and neurodegenerative disorders. Synaptic location is a major factor in determining synaptic efficacy because, as a result of the passive cable (electrotonic) properties of dendrites, synaptic potentials generated by synapses at distal dendritic locations are severely attenuated and distorted as they propagate towards the cell body. But there may also exist mechanisms to compensate for this attenuation, including the possibility that there are more receptors present at distal synapses compared to synapses close to the soma. Understanding the structural and molecular basis of synaptic integration thus requires a precise knowledge of the distribution of different classes of synapses and their corresponding neurotransmitter receptors on individual identified neurons in vivo. Our working hypothesis is that the integrative properties of neurons and the efficacy of synaptic connections are intimately linked to neuron-specific patterns of receptor expression and synaptic input. To test this hypothesis the specific aims of this proposal are to answer the following questions: l) what are the precise patterns of receptor distribution in different cell types and are there differences in receptor cluster size and/or density in different compartments (e.g. proximal vs distal dendrites)? and 2) how are different classes of synaptic inputs organized over the surface of single neurons? These questions will be answered in two ways: l) by using immunocytochemistry combined with intracellular staining to determine receptor expression patterns in individual, physiologically identified, neurons in vivo and 2) by determining the precise distribution of immunohistochemically defined presynaptic terminals in contact with single intracellularly stained neurons in vivo. Each study will also use electronmicroscopy to examine the ultrastructural features of identified synapses. This study will focus on identified alpha- and gamma-motoneurons, Renshaw cells and Ia inhibitory interneurons. Among the transmitter/receptor families to be studied are those involved in glycinergic, GABA-ergic, glutamatergic, monoaminergic and cholinergic neurotransmission, all of which play important roles in segmental motor control. This highly integrative approach will produce results of general significance for advancing understanding of synaptic and integrative mechanisms as well as novel details on the segmental motor system.