The objective of this study is to understand the mechanisms by which extrathalamic transmitters (norepinephrine: NE;acetylcholine: ACH; and serotonin: 5HT) modulate the firing behavior of cat neocortical neurons during ontogeny. The focus of the proposed study is at the level of the neuron as an integrative unit rather than on the kinetics of individuals ion channels. The specific neurons studied are those which give rise to the primary motor output of cerebral cortex (layer V pyramidal neurons). The proposed experiments will use isolated neocortical brain slices and acutely dissociated neurons. Neuronal firing behavior and electrical properties will be studied using standard intracellular recording techniques. Singles electrode voltage clamp (SEVC), ionic substitution and pharmacological manipulations will provide qualitative information concerning the ionic basis for the observed cell behavior. The use of pharmacological blockers and current-clamp recording will then be used to test hypothesis derived from SEVC experiments. Whole cell patch-clamp of acutely dissociated cells will characterized Ca2+ and Ca-dependent K+ currents, their modulation by NE and 5HT, and the second messengers involved. Prerequisite to the study of modulation of firing behavior during development, one must know: (i) the effects extrathalamic transmitters exert on adult neurons, and (ii) the substrate for modulation: the development of firing behavior and its ionic basis.Completed studies have illustrated the effects of NE and muscarine on neocortical cells from adult animals. Those experiments also revealed that norepinephrine and muscarine decrease the same two K+ currents in neocortical cells by two apparently different second messenger systems. The proposed experiments will examine: (i) the effects of 5HT upon firing behavior in adult cats, (ii) the ontogeny of repetitive firing behavior and its modulation by extrathalamic transmitters, and (iii) the second messengers involved in modulation of Ca2+ and Ca-dependent K+ currents. These studies will answer fundamental questions concerning synaptic communication. In particular, the proposed experiments will test the hypothesis concerning the actions of neuromodulators during critical periods for cortical plasticity. The results of these experiments will facilitate formulation of hypotheses about epileptic mechanisms in neocortex and will contribute to the understanding of diseases such as Alzheimer's disease.
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