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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.


Related in: MedlinePlus

A, Infrared differential interference contrast optics was used to visualize LCIs (arrows) in WT and symptomatic R6/2 mice. B-D, Representative traces of tonic firing of LCIs in the cell-attached configuration. In WTs, more LCIs fired action potentials regularly (B). In R6/2s, some LCIs fired regularly (C) but a greater number of irregular and bursting cells (D) were recorded. E, High degree of autocorrelation reflected regular firing patterns of LCIs from WT mice. F, Although firing of some LCIs from R6/2 animals was highly autocorrelated, the autocorrelation coefficient (peak amplitude or coefficient value of the first lag interval) was lower than in LCIs from WTs. G, Low or no autocorrelations were observed in irregular firing and bursting LCIs, particularly from R6/2s. H, Spontaneous firing rates in LCIs from WT and R6/2 mice were almost identical. I, In contrast, the autocorrelation coefficient, a measure of firing regularity, was significantly decreased in LCIs from R6/2 mice. J, Scatter plots showing the correlation between firing frequency and coefficient of variation. There was a very good correlation between both in LCIs from WT mice. In contrast, this correlation was markedly reduced in cells from R6/2 mice. *p < 0.05.
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Figure 2: A, Infrared differential interference contrast optics was used to visualize LCIs (arrows) in WT and symptomatic R6/2 mice. B-D, Representative traces of tonic firing of LCIs in the cell-attached configuration. In WTs, more LCIs fired action potentials regularly (B). In R6/2s, some LCIs fired regularly (C) but a greater number of irregular and bursting cells (D) were recorded. E, High degree of autocorrelation reflected regular firing patterns of LCIs from WT mice. F, Although firing of some LCIs from R6/2 animals was highly autocorrelated, the autocorrelation coefficient (peak amplitude or coefficient value of the first lag interval) was lower than in LCIs from WTs. G, Low or no autocorrelations were observed in irregular firing and bursting LCIs, particularly from R6/2s. H, Spontaneous firing rates in LCIs from WT and R6/2 mice were almost identical. I, In contrast, the autocorrelation coefficient, a measure of firing regularity, was significantly decreased in LCIs from R6/2 mice. J, Scatter plots showing the correlation between firing frequency and coefficient of variation. There was a very good correlation between both in LCIs from WT mice. In contrast, this correlation was markedly reduced in cells from R6/2 mice. *p < 0.05.

Mentions: For electrophysiological studies LCIs were recorded primarily from the dorsolateral striatum. Representative IR-DIC images of visually identified LCIs from WT and R6/2 mice are shown in Fig. 2A. In whole-cell voltage-clamp mode, passive membrane properties were consistent with LCIs, displaying relatively high input resistance and fast decay time constant. No differences in membrane properties of LCIs from WT and presymptomatic R6/2 animals (n = 4 in each group, age 23 ± 1 d) were observed (Table 1). In symptomatic animals (n = 10, age 65 ± 1 d), LCIs displayed significantly lower mean capacitance (p = 0.038) and higher mean input resistance (p < 0.001) compared with WT animals (n = 14, age 65 ± 1 d).


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, Infrared differential interference contrast optics was used to visualize LCIs (arrows) in WT and symptomatic R6/2 mice. B-D, Representative traces of tonic firing of LCIs in the cell-attached configuration. In WTs, more LCIs fired action potentials regularly (B). In R6/2s, some LCIs fired regularly (C) but a greater number of irregular and bursting cells (D) were recorded. E, High degree of autocorrelation reflected regular firing patterns of LCIs from WT mice. F, Although firing of some LCIs from R6/2 animals was highly autocorrelated, the autocorrelation coefficient (peak amplitude or coefficient value of the first lag interval) was lower than in LCIs from WTs. G, Low or no autocorrelations were observed in irregular firing and bursting LCIs, particularly from R6/2s. H, Spontaneous firing rates in LCIs from WT and R6/2 mice were almost identical. I, In contrast, the autocorrelation coefficient, a measure of firing regularity, was significantly decreased in LCIs from R6/2 mice. J, Scatter plots showing the correlation between firing frequency and coefficient of variation. There was a very good correlation between both in LCIs from WT mice. In contrast, this correlation was markedly reduced in cells from R6/2 mice. *p < 0.05.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 2: A, Infrared differential interference contrast optics was used to visualize LCIs (arrows) in WT and symptomatic R6/2 mice. B-D, Representative traces of tonic firing of LCIs in the cell-attached configuration. In WTs, more LCIs fired action potentials regularly (B). In R6/2s, some LCIs fired regularly (C) but a greater number of irregular and bursting cells (D) were recorded. E, High degree of autocorrelation reflected regular firing patterns of LCIs from WT mice. F, Although firing of some LCIs from R6/2 animals was highly autocorrelated, the autocorrelation coefficient (peak amplitude or coefficient value of the first lag interval) was lower than in LCIs from WTs. G, Low or no autocorrelations were observed in irregular firing and bursting LCIs, particularly from R6/2s. H, Spontaneous firing rates in LCIs from WT and R6/2 mice were almost identical. I, In contrast, the autocorrelation coefficient, a measure of firing regularity, was significantly decreased in LCIs from R6/2 mice. J, Scatter plots showing the correlation between firing frequency and coefficient of variation. There was a very good correlation between both in LCIs from WT mice. In contrast, this correlation was markedly reduced in cells from R6/2 mice. *p < 0.05.
Mentions: For electrophysiological studies LCIs were recorded primarily from the dorsolateral striatum. Representative IR-DIC images of visually identified LCIs from WT and R6/2 mice are shown in Fig. 2A. In whole-cell voltage-clamp mode, passive membrane properties were consistent with LCIs, displaying relatively high input resistance and fast decay time constant. No differences in membrane properties of LCIs from WT and presymptomatic R6/2 animals (n = 4 in each group, age 23 ± 1 d) were observed (Table 1). In symptomatic animals (n = 10, age 65 ± 1 d), LCIs displayed significantly lower mean capacitance (p = 0.038) and higher mean input resistance (p < 0.001) compared with WT animals (n = 14, age 65 ± 1 d).

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