Abstract
In Huntington's disease (HD), a hereditary neurodegenerative disorder, striatal medium-sized spiny neurons undergo degenerative changes. In contrast, large cholinergic interneurons (LCIs) are relatively spared. However, their ability to release acetylcholine (ACh) is impaired. The present experiments examined morphological and electrophysiological properties of LCIs in the R6/2 mouse model of HD. R6/2 mice show a severe, rapidly progressing phenotype. Immunocytochemical analysis of choline acetyltransferase-positive striatal neurons showed that, although the total number of cells was not changed, somatic areas were significantly smaller in symptomatic R6/2 mice compared to wildtype (WT) littermates, For electrophysiology, brain slices were obtained from presymptomatic (3-4 weeks) and symptomatic (>8 weeks) R6/2 mice and their WT littermates. Striatal LCIs were identified by somatic size and spontaneous action potential firing in the cell-attached mode. Passive and active membrane properties of LCIs were similar in presymptomatic R6/2 and WT mice. In contrast, LCIs from symptomatic R6/2 animals displayed smaller membrane capacitance and higher input resistance, consistent with reduced somatic size. In addition, more LCIs from symptomatic mice displayed irregular firing patterns and bursts of action potentials. They also displayed a higher frequency of spontaneous GABAergic inhibitory postsynaptic currents (IPSCs) and larger amplitude of electrically evoked IPSCs. Selective optogenetic stimulation of somatostatin- but not parvalbumin-containing interneurons also evoked larger amplitude IPSCs in LCIs from R6/2 mice. In contrast, glutamatergic spontaneous or evoked postsynaptic currents were not affected. Morphological and electrophysiological alterations, in conjunction with the presence of mutant huntingtin in LCIs, could explain impaired ACh release in HD mouse models.
Highlights
Huntington’s disease (HD) is a fatal, hereditary, neurodegenerative disorder characterized by abnormal movements, cognitive impairment, and psychiatric disturbances (Bates et al, 2002)
large cholinergic interneurons (LCIs) somatic areas are reduced in R6/2 mice Reduced medium-sized spiny neurons (MSNs) somatic area and dendritic elaboration have been previously shown in symptomatic R6/2 mice (Levine et al, 1999; Klapstein et al, 2001)
We examined the frequency of GABAergic spontaneous IPSCs (sIPSCs) in WT (n ϭ 12, age 65 Ϯ 1 d) and symptomatic R6/2 animals (n ϭ 13, age 64 Ϯ 2 d) using a CsCl-based internal solution with the cell voltage-clamped at Ϫ70 mV and in the presence of glutamate receptor blockers
Summary
Huntington’s disease (HD) is a fatal, hereditary, neurodegenerative disorder characterized by abnormal movements (chorea), cognitive impairment, and psychiatric disturbances (Bates et al, 2002). Medium-sized spiny neurons (MSNs), the main projection neurons, undergo degenerative changes and, in animal models of HD, display a range of abnormal morphological and electrophysiological properties. These include decreased somatic areas (Levine et al, 1999) and loss of dendritic spines (Klapstein et al, 2001), as well as alterations in both passive and active membrane properties and synaptic activity (Klapstein et al, 2001; Cepeda et al, 2003; Cepeda et al, 2007). Cell swelling (an early sign of excitotoxicity) induced by prolonged application of NMDA produces a time-dependent increase in somatic area in MSNs, whereas it produces negligible changes in LCIs (Cepeda et al, 2001). Another possibility is the fact that huntingtin nuclear inclusions form more gradually and are less abundant in LCIs compared with MSNs (Fusco et al, 1999; Kosinski et al, 1999; Meade et al, 2002)
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