It has recently been suggested that neuronal degeneration may occur as a secondary phenomenon in response to neuronal dysfunction in HD. In support of this idea, recent reports have indicated that electrophysiological abnormalities occur in the brains of HD transgenic animals. These abnormalities include altered somatic discharge, broadening of the excitatory postsynaptic potential and failure to induce long term potentiation following high frequency stimulation. These abnormalities precede neurobehavioral and neuropathological alterations suggesting to some researchers that cytoplasmic functions including neurotransmitter regulation of ion channels and regulation of intracellular Ca2+ may play a role in this disease. If this is in fact the case, then understanding neuronal dysfunction in HD may be critical to the development of rational treatment strategies and early intervention programs. An extrinisic mechanism such as glutamate excitotoxicity has been proposed to account for the ultimate degeneration of medium spiny neostriatal neurons, therefore, we hypothesized that changes in the membrane properties of the cortical projection neurons which provide input to the medium spiny neostriatal neurons might be important in HD. This idea, while intriguing, has not been fully investigated using the newly available animal models of HD. We present preliminary data to support this idea and demonstrate that electrophysiological abnormalities occur in the presynaptic corticostriatal projection neurons in HD transgenic mice. Since the electrical activity of a neuron is regulated by its own intrinsic cytoplasmic properties as well as its synaptic inputs, it will be important to conduct a thorough study of these alterations in the electrophysiological properties of the presynaptic cortical projection neurons in HD. These electrophysiological abnormalities in corticostriatal projection neurons may contribute to neuronal dysfunction and the subsequent neuropathology observed in HD. This hypothesis will be tested in acutely isolated, identified cortical projection neurons obtained from HD mouse models in which expression of mutant huntingtin has been induced. Techniques employed include patch-clamp recording methods, single-cell RT-PCR and immunohistochemistry. This proposal has 3 Specific Aims: 1) To define the physiological properties of pharmacologically isolated HVA Ca2+ channels, voltage-gated Na+ channels and voltage-gated K+ channels in acutely isolated corticostriatal projection neurons from HD transgenic mouse models. 2) To determine the molecular mechanisms underlying the observed increase in HVA Ca2+ channel activity in corticostriatal neurons from R6/2 transgenic mice. 3) To expand our studies to include other classes of cortical projection neurons. These studies will provide valuable information for the elucidation and treatment of a variety of motor deficits and neurodegeneration observed in HD and a host of other neurological disorders.
