TY - JOUR
T1 - Electrophysiological Studies Support Utility of Positive Modulators of SK Channels for the Treatment of Spinocerebellar Ataxia Type 2
AU - Egorova, Polina A.
AU - Bezprozvanny, Ilya B.
N1 - Publisher Copyright:
© 2021, The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.
PY - 2022/10
Y1 - 2022/10
N2 - Spinocerebellar ataxia type 2 (SCA2) is an incurable hereditary disorder accompanied by cerebellar degeneration following ataxic symptoms. The causative gene for SCA2 is ATXN2. The ataxin-2 protein is involved in RNA metabolism; the polyQ expansion may interrupt ataxin-2 interaction with its molecular targets, thus representing a loss-of-function mutation. However, mutant ataxin-2 protein also displays the features of gain-of-function mutation since it forms the aggregates in SCA2 cells and also enhances the IP3-induced calcium release in affected neurons. The cerebellar Purkinje cells (PCs) are primarily affected in SCA2. Their tonic pacemaker activity is crucial for the proper cerebellar functioning. Disturbances in PC pacemaking are observed in many ataxic disorders. The abnormal intrinsic pacemaking was reported in mouse models of episodic ataxia type 2 (EA2), SCA1, SCA2, SCA3, SCA6, Huntington’s disease (HD), and in some other murine models of the disorders associated with the cerebellar degeneration. In our studies using SCA2-58Q transgenic mice via cerebellar slice recording and in vivo recording from urethane-anesthetized mice and awake head-fixed mice, we have demonstrated the impaired firing frequency and irregularity of PCs in these mice. PC pacemaker activity is regulated by SK channels. The pharmacological activation of SK channels has demonstrated some promising results in the electrophysiological experiments on EA2, SCA1, SCA2, SCA3, SCA6, HD mice, and also on mutant CACNA1A mice. In our studies, we have reported that the SK activators CyPPA and NS309 converted bursting activity into tonic, while oral treatment with CyPPA and NS13001 significantly improved motor performance and PC morphology in SCA2 mice. The i.p. injections of chlorzoxazone (CHZ) during in vivo recording sessions converted bursting cells into tonic in anesthetized SCA2 mice. And, finally, long-term injections of CHZ recovered the precision of PC pacemaking activity in awake SCA2 mice and alleviated their motor decline. Thus, the SK activation can be used as a potential way to treat SCA2 and other diseases accompanied by cerebellar degeneration.
AB - Spinocerebellar ataxia type 2 (SCA2) is an incurable hereditary disorder accompanied by cerebellar degeneration following ataxic symptoms. The causative gene for SCA2 is ATXN2. The ataxin-2 protein is involved in RNA metabolism; the polyQ expansion may interrupt ataxin-2 interaction with its molecular targets, thus representing a loss-of-function mutation. However, mutant ataxin-2 protein also displays the features of gain-of-function mutation since it forms the aggregates in SCA2 cells and also enhances the IP3-induced calcium release in affected neurons. The cerebellar Purkinje cells (PCs) are primarily affected in SCA2. Their tonic pacemaker activity is crucial for the proper cerebellar functioning. Disturbances in PC pacemaking are observed in many ataxic disorders. The abnormal intrinsic pacemaking was reported in mouse models of episodic ataxia type 2 (EA2), SCA1, SCA2, SCA3, SCA6, Huntington’s disease (HD), and in some other murine models of the disorders associated with the cerebellar degeneration. In our studies using SCA2-58Q transgenic mice via cerebellar slice recording and in vivo recording from urethane-anesthetized mice and awake head-fixed mice, we have demonstrated the impaired firing frequency and irregularity of PCs in these mice. PC pacemaker activity is regulated by SK channels. The pharmacological activation of SK channels has demonstrated some promising results in the electrophysiological experiments on EA2, SCA1, SCA2, SCA3, SCA6, HD mice, and also on mutant CACNA1A mice. In our studies, we have reported that the SK activators CyPPA and NS309 converted bursting activity into tonic, while oral treatment with CyPPA and NS13001 significantly improved motor performance and PC morphology in SCA2 mice. The i.p. injections of chlorzoxazone (CHZ) during in vivo recording sessions converted bursting cells into tonic in anesthetized SCA2 mice. And, finally, long-term injections of CHZ recovered the precision of PC pacemaking activity in awake SCA2 mice and alleviated their motor decline. Thus, the SK activation can be used as a potential way to treat SCA2 and other diseases accompanied by cerebellar degeneration.
KW - Chlorzoxazone
KW - Purkinje cells
KW - SK channels
KW - Spinocerebellar ataxia
KW - Transgenic mice
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UR - http://www.scopus.com/inward/citedby.url?scp=85122142867&partnerID=8YFLogxK
U2 - 10.1007/s12311-021-01349-1
DO - 10.1007/s12311-021-01349-1
M3 - Review article
C2 - 34978024
AN - SCOPUS:85122142867
SN - 1473-4222
VL - 21
SP - 742
EP - 749
JO - Cerebellum
JF - Cerebellum
IS - 5
ER -