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Enhanced GABAergic Inputs Contribute to Functional Alterations of Cholinergic Interneurons in the R6/2 Mouse Model of Huntington's Disease.

Holley SM, Joshi PR, Parievsky A, Galvan L, Chen JY, Fisher YE, Huynh MN, Cepeda C, Levine MS - eNeuro (2015 Jan-Feb)

Bottom Line: In Huntington's disease (HD), a hereditary neurodegenerative disorder, striatal medium-sized spiny neurons undergo degenerative changes.They also displayed a higher frequency of spontaneous GABAergic inhibitory postsynaptic currents (IPSCs) and larger amplitude of electrically evoked IPSCs.In contrast, glutamatergic spontaneous or evoked postsynaptic currents were not affected.

View Article: PubMed Central - HTML - PubMed

Affiliation: Intellectual and Developmental Disabilities Research Center, Semel Institute for Neuroscience and Human Behavior, University of California at Los Angeles, Los Angeles, CA 90095.

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.

No MeSH data available.


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A, Representative traces of responses induced by bath application of increasing concentrations of GABA (10, 100, and 1000 μM) in large striatal neurons (presumably LCIs) from WT and symptomatic R6/2 mice. B, Graph shows no significant differences in peak current density (peak current divided by cell capacitance) of GABA responses. C, D, AMPA- and NMDA-induced peak current densities also were similar in R6/2 and WT mice.
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Figure 7: A, Representative traces of responses induced by bath application of increasing concentrations of GABA (10, 100, and 1000 μM) in large striatal neurons (presumably LCIs) from WT and symptomatic R6/2 mice. B, Graph shows no significant differences in peak current density (peak current divided by cell capacitance) of GABA responses. C, D, AMPA- and NMDA-induced peak current densities also were similar in R6/2 and WT mice.

Mentions: We also examined the frequency of GABAergic sIPSCs in WT (n = 12, age 65 ± 1 d) and symptomatic R6/2 animals (n = 13, age 64 ± 2 d) using a CsCl-based internal solution with the cell voltage-clamped at −70 mV and in the presence of glutamate receptor blockers. Mean sIPSC frequency was significantly greater in LCIs from R6/2 mice (p < 0.01; Fig. 3B and D, inset). The amplitude-frequency histogram showed that, except for the 10-20 pA bin, increased frequency occurred across all other amplitude bins (Fig. 3D), in particular IPSCs with amplitudes between 20-40 pA (p < 0.001). The cumulative interevent interval probability distribution also was significantly shifted to the left in LCIs from R6/2 mice (p < 0.001; Fig. 3F). Similar to results obtained with Cs-Meth solution, the frequency of mIPSCs in LCIs recorded with CsCl after TTX were not significantly different between WTs and R6/2s (Fig. 3H). The percent change in frequency after TTX was significantly reduced in LCIs from R6/2s (p = 0.02; Fig. 3H, right bar graph), indicating that more sIPSCs were dependent on presynaptic action potentials.


Enhanced GABAergic Inputs Contribute to Functional Alterations of Cholinergic Interneurons in the R6/2 Mouse Model of Huntington's Disease.

Holley SM, Joshi PR, Parievsky A, Galvan L, Chen JY, Fisher YE, Huynh MN, Cepeda C, Levine MS - eNeuro (2015 Jan-Feb)

A, Representative traces of responses induced by bath application of increasing concentrations of GABA (10, 100, and 1000 μM) in large striatal neurons (presumably LCIs) from WT and symptomatic R6/2 mice. B, Graph shows no significant differences in peak current density (peak current divided by cell capacitance) of GABA responses. C, D, AMPA- and NMDA-induced peak current densities also were similar in R6/2 and WT mice.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4507822&req=5

Figure 7: A, Representative traces of responses induced by bath application of increasing concentrations of GABA (10, 100, and 1000 μM) in large striatal neurons (presumably LCIs) from WT and symptomatic R6/2 mice. B, Graph shows no significant differences in peak current density (peak current divided by cell capacitance) of GABA responses. C, D, AMPA- and NMDA-induced peak current densities also were similar in R6/2 and WT mice.
Mentions: We also examined the frequency of GABAergic sIPSCs in WT (n = 12, age 65 ± 1 d) and symptomatic R6/2 animals (n = 13, age 64 ± 2 d) using a CsCl-based internal solution with the cell voltage-clamped at −70 mV and in the presence of glutamate receptor blockers. Mean sIPSC frequency was significantly greater in LCIs from R6/2 mice (p < 0.01; Fig. 3B and D, inset). The amplitude-frequency histogram showed that, except for the 10-20 pA bin, increased frequency occurred across all other amplitude bins (Fig. 3D), in particular IPSCs with amplitudes between 20-40 pA (p < 0.001). The cumulative interevent interval probability distribution also was significantly shifted to the left in LCIs from R6/2 mice (p < 0.001; Fig. 3F). Similar to results obtained with Cs-Meth solution, the frequency of mIPSCs in LCIs recorded with CsCl after TTX were not significantly different between WTs and R6/2s (Fig. 3H). The percent change in frequency after TTX was significantly reduced in LCIs from R6/2s (p = 0.02; Fig. 3H, right bar graph), indicating that more sIPSCs were dependent on presynaptic action potentials.

Bottom Line: In Huntington's disease (HD), a hereditary neurodegenerative disorder, striatal medium-sized spiny neurons undergo degenerative changes.They also displayed a higher frequency of spontaneous GABAergic inhibitory postsynaptic currents (IPSCs) and larger amplitude of electrically evoked IPSCs.In contrast, glutamatergic spontaneous or evoked postsynaptic currents were not affected.

View Article: PubMed Central - HTML - PubMed

Affiliation: Intellectual and Developmental Disabilities Research Center, Semel Institute for Neuroscience and Human Behavior, University of California at Los Angeles, Los Angeles, CA 90095.

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.

No MeSH data available.


Related in: MedlinePlus