Alterations in Cortical Excitation and Inhibition in Genetic Mouse Models of Huntington's Disease

• DOI: 10.1523/jneurosci.1592-09.2009
• Publication Date: 2009-08-19T17:40:25Z
• Authors: Damian M. Cummings; Véronique M. André; Besim O. Uzgil; Steven M. Gee; Yvette E. Fisher; Carlos Cepeda; Michael S. Levine
• Keywords: Cerebral Cortex; Male; 0303 health sciences; Pyramidal Cells; Mice, Transgenic; Neural Inhibition; Synaptic Potentials; Mice, Inbred C57BL; Disease Models, Animal; Mice; 03 medical and health sciences; Huntington Disease; Mice, Inbred CBA; Animals; Female

Previously, we identified progressive alterations in spontaneous EPSCs and IPSCs in the striatum of the R6/2 mouse model of Huntington's disease (HD). Medium-sized spiny neurons from these mice displayed a lower frequency of EPSCs, and a population of cells exhibited an increased frequency of IPSCs beginning at ∼40 d, a time point when the overt behavioral phenotype begins. The cortex provides the major excitatory drive to the striatum and is affected during disease progression. We examined spontaneous EPSCs and IPSCs of somatosensory cortical pyramidal neurons in layers II/III in slices from three different mouse models of HD: the R6/2, the YAC128, and the CAG140 knock-in. Results revealed that spontaneous EPSCs occurred at a higher frequency, and evoked EPSCs were larger in behaviorally phenotypic mice whereas spontaneous IPSCs were initially increased in frequency in all models and subsequently decreased in R6/2 mice after they displayed the typical R6/2 overt behavioral phenotype. Changes in miniature IPSCs and evoked IPSC paired-pulse ratios suggested altered probability of GABA release. Also, in R6/2 mice, blockade of GABAAreceptors induced complex discharges in slices and seizuresin vivoat all ages. In conclusion, altered excitatory and inhibitory inputs to pyramidal neurons in the cortex in HD appear to be a prevailing deficit throughout the development of the disease. Furthermore, the differences between synaptic phenotypes in cortex and striatum are important for the development of future therapeutic approaches, which may need to be targeted early in the development of the phenotype.