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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, Representative traces of eEPSCs in LCIs recorded at −70 mV using Cs-Meth internal solution. The peak amplitude of the response was similar in LCIs from WT and R6/2 mice. B, Graph shows the input−output relationship of eEPSCs. No statistical differences in amplitude were observed. C, Striatal LCI (red) surrounded by EYFP terminals in a R6/2 mouse injected with ChR2 in the Cm/Pf nuclear complex. D, Optogenetic stimulation of thalamic afferents induced similar AMPA (top) and NMDA (bottom) receptor-mediated currents in LCIs from WT and R6/2 mice. E, Graphs show that the amplitude and charge of AMPA (top) and NMDA (bottom) responses were not significantly different.
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Figure 6: A, Representative traces of eEPSCs in LCIs recorded at −70 mV using Cs-Meth internal solution. The peak amplitude of the response was similar in LCIs from WT and R6/2 mice. B, Graph shows the input−output relationship of eEPSCs. No statistical differences in amplitude were observed. C, Striatal LCI (red) surrounded by EYFP terminals in a R6/2 mouse injected with ChR2 in the Cm/Pf nuclear complex. D, Optogenetic stimulation of thalamic afferents induced similar AMPA (top) and NMDA (bottom) receptor-mediated currents in LCIs from WT and R6/2 mice. E, Graphs show that the amplitude and charge of AMPA (top) and NMDA (bottom) responses were not significantly different.

Mentions: eEPSCs were recorded at −70 mV with QX314 in the internal pipette solution (Fig. 6A). Similar procedures to those described above were used to evoke synaptic currents in LCIs. Application of NBQX (10 μM) and APV (50 μM) completely blocked evoked currents. There were no statistically significant differences in peak amplitudes of LCIs from symptomatic R6/2 (n = 8, age 65 ± 1 d) compared with those from WTs (n = 6, age 66 ± 2 d) at all stimulation intensities (Fig. 6A,B).


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 eEPSCs in LCIs recorded at −70 mV using Cs-Meth internal solution. The peak amplitude of the response was similar in LCIs from WT and R6/2 mice. B, Graph shows the input−output relationship of eEPSCs. No statistical differences in amplitude were observed. C, Striatal LCI (red) surrounded by EYFP terminals in a R6/2 mouse injected with ChR2 in the Cm/Pf nuclear complex. D, Optogenetic stimulation of thalamic afferents induced similar AMPA (top) and NMDA (bottom) receptor-mediated currents in LCIs from WT and R6/2 mice. E, Graphs show that the amplitude and charge of AMPA (top) and NMDA (bottom) responses were not significantly different.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 6: A, Representative traces of eEPSCs in LCIs recorded at −70 mV using Cs-Meth internal solution. The peak amplitude of the response was similar in LCIs from WT and R6/2 mice. B, Graph shows the input−output relationship of eEPSCs. No statistical differences in amplitude were observed. C, Striatal LCI (red) surrounded by EYFP terminals in a R6/2 mouse injected with ChR2 in the Cm/Pf nuclear complex. D, Optogenetic stimulation of thalamic afferents induced similar AMPA (top) and NMDA (bottom) receptor-mediated currents in LCIs from WT and R6/2 mice. E, Graphs show that the amplitude and charge of AMPA (top) and NMDA (bottom) responses were not significantly different.
Mentions: eEPSCs were recorded at −70 mV with QX314 in the internal pipette solution (Fig. 6A). Similar procedures to those described above were used to evoke synaptic currents in LCIs. Application of NBQX (10 μM) and APV (50 μM) completely blocked evoked currents. There were no statistically significant differences in peak amplitudes of LCIs from symptomatic R6/2 (n = 8, age 65 ± 1 d) compared with those from WTs (n = 6, age 66 ± 2 d) at all stimulation intensities (Fig. 6A,B).

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