The role and modulation of NMDA receptor-mediated membrane properties in motor pattern generation in the mammalian spinal cord

Abstract

Nonlinear membrane properties are nearly ubiquitous in motor pattern generating neural systems and can result in rhythmic oscillations of membrane voltage. N-methyl-D-aspartate (NMDA) receptor activation is capable of producing rhythmic motor activity, a nonlinear current voltage relationship and voltage oscillations in mammalian spinal neurons (Smith and Feldman 1987; Douglas et al 1993; Hochman et al 1994a,b). The first section of the thesis tests the hypothesis that NMDA-induced voltage oscillations produced by intrinsic membrane properties can be recruited by synaptic events. I report here that the ability of spinal cord lumbar motoneurons to generate NMDA receptor-dependent nonlinear behaviors (plateau potentials and voltage oscillations) is not limited to motoneurons which are synaptically isolated, as the same properties can be elicited in motoneurons under the influence of functionally intact circuitry. The second section of this thesis tests the hypothesis that NMDA receptor-dependent nonlinear membrane properties are modulated by serotonin. The production of rhythmic voltage oscillations in synaptically isolated spinal motoneurons requires both NMDA and 5-HT receptor activation. The third section of this thesis tests the hypothesis that serotonin promotes NMDA receptor-dependent voltage oscillations by decreasing the efficacy of the voltage-dependent Mg2+ blockade of the NMDA channel. In addition, whether the nonlinear membrane property imparted by the voltage- dependent Mg2+ blockade of the NMDA channel is necessary for locomotion, was examined. Voltage clamp recordings demonstrated that 5-HT shifts the voltage for activation of the negative slope conductance to more hyperpolarized potentials. The effect of 5-HT on the NMDA receptor-dependent negative slope conductance was mimicked by decreasing the concentration of extracellular Mg2+. These experiments have provided evidence that the rhythm-generating spinal network may call upon NMDA-dependent nonlinear membrane properties. In addition, an endogenous transmitter (5-HT) is capable of modulating NMDA-dependent nonlinearity and promoting oscillatory behavior. Because of the deleterious effect on pattern generation produced by abolishment of the region of negative slope conductance, via removal of Mg2+, enhancement of the region of negative slope conductan e by 5-HT application is expected to help promote stable locomotor network activity as has been reported (Cowley and Schmidt 1994; Kjaerulff et al 1994). (Abstract shortened by UMI.)