Considerable neurophysiological data have indicated that the spontaneous activity of the spiny projection neurons within the striatum, is driven primarily by excitatory synaptic barrages from neocortex. This input produces abrupt, prolonged shifts in membrane potential from a hyperpolarized resting state to a near-threshold depolarized state from which spike discharges of variable latency and frequency can arise. Thus, the membrane potential of spiny neurons shifts between hyperpolarized and depolarized states as a function of the absence or presence of coordinated excitatory synaptic input. Evidence suggests that the efficacy of synaptic input, as well as the limits placed on the amplitude of these membrane potential shifts depend on inwardly- and outwardly-rectifying currents. The hyperpolarized state has been postulated to be determined by a pronounced inwardly-rectifying K= current which is prominent at membrane potentials near rest. In contrast,t he limits placed on the depolarized state are governed by outward K+ currents which may include the fast and slow, transient A-currents, as well as non-inactivating K+ currents as they are available in this region of subthreshold membrane potentials. In addition, the interaction between the excitatory cortical input and these membrane conductances determine the probability, rate, and pattern of spike discharge of spiny neurons. Thus, the primary focus of the proposed experiments is to characterize the specific biophysical properties of these K+ currents in spiny projection neurons, and then to investigate the manner in which these currents govern the unique subthreshold membrane potential shifts and firing properties of these cells. The goals of the of the present proposal are threefold. First, the biophysical and pharmacological properties of the inwardly-rectifying currents and the outward K+ currents will be characterized using whole-cell voltage-clamp recording from acutely-dissociated, identified spiny projection neurons. Second, knowledge of the voltage- and time-dependence of these inward and outward K+ currents recorded in isolation will be used to predict how these currents are expressed in the subthreshold voltage responses and suprathreshold discharge properties of spiny cells in a corticostriatal slice preparation. Third, the potential for modulation of these currents by dopamine, acetylcholine, and the neuropeptides enkephalin and Substance P will be investigated in dissociated cells, and the expression of such modulation on the sub- and suprathreshold responses of spiny neurons will be explored in the slice preparation. Numerous electrophysiological studies have shown that changes in the rate and/or pattern of activity of striatal neurons is correlated with sensory, initiative, and executive aspects of a variety of motor behaviors. In contrast, disruption of the normal patterns of activity of striatal neurons is associates with disorders of movement, such as Parkinson's disease. The present experiments will determine the contribution of intrinsic membrane properties to the susceptibility of striatal neurons to be recruited to discharge by excitatory input, as well s to the characteristics of such discharge. In addition, an understanding of the modulatory influence on these membrane conductances by neurotransmitter systems which are known to innervate spiny cells and to be altered in Parkinson's disease should provide insights into neurophysiological underpinnings of this disorder.
| Gabel, L A; Nisenbaum, E S (1999) Muscarinic receptors differentially modulate the persistent potassium current in striatal spiny projection neurons. J Neurophysiol 81:1418-23 |
| Nisenbaum, E S; Mermelstein, P G; Wilson, C J et al. (1998) Selective blockade of a slowly inactivating potassium current in striatal neurons by (+/-) 6-chloro-APB hydrobromide (SKF82958). Synapse 29:213-24 |
| Gabel, L A; Nisenbaum, E S (1998) Biophysical characterization and functional consequences of a slowly inactivating potassium current in neostriatal neurons. J Neurophysiol 79:1989-2002 |
| Nisenbaum, E S; Wilson, C J; Foehring, R C et al. (1996) Isolation and characterization of a persistent potassium current in neostriatal neurons. J Neurophysiol 76:1180-94 |
