In vivo analysis of cerebellar Purkinje cell activity in SCA2 transgenic mouse model

Abstract

Cerebellar Purkinje cells (PCs) are primarily affected in many spinocerebellar ataxias (SCA). In this study we investigated functional activity of PCs in transgenic mouse model of SCA2, a polyglutamine neurodegenerative hereditary disorder. In our studies we used extracellular single-unit recording method to compare spontaneous activity of PCs in age-matched wild-type mice and SCA2-58Q transgenic mice. We discovered that the fraction of PCs with bursting and an irregular pattern of spontaneous activity dramatically increases in aged SCA2-58Q mice compared with wild-type littermates. Small-conductance calcium-activated potassium (SK) channels play an important role in determining firing rate of PCs. Indeed, we demonstrated that intraperitoneal (IP) injection of SK channel inhibitor NS8593 induces an irregular pattern of PC activity in wild-type mice. Furthermore, we demonstrated that IP injection of SK channel-positive modulator chlorzoxazone (CHZ) decreases spontaneous firing rate of cerebellar PCs. Finally, we have shown that IP injections with CHZ normalize firing activity of cerebellar PCs from aging SCA2-58Q mice. We propose that alterations in PC firing patterns is one of potential causes of ataxic symptoms in SCA2 and in other SCAs and that positive modulators of SK channels can be used to normalize activity of PCs and alleviate ataxic phenotype in patients with SCA.

Inositol 1,4,5‐trisphosphate receptors and neurodegenerative disorders

“…In a recent study we compared the functional properties of PCs from the intact cerebella of aging WT and SCA2-58Q transgenic mice using an in vivo recording technique. We observed significant and agedependent loss of firing precision of PCs in SCA2-58Q mice [91]. The reason for loss of precision firing by SCA2-58Q PCs may be due to the toxic effects of mutant ataxin-2 leading to the dysregulation of IICR [7,57,91].…”

“…We observed significant and agedependent loss of firing precision of PCs in SCA2-58Q mice [91]. The reason for loss of precision firing by SCA2-58Q PCs may be due to the toxic effects of mutant ataxin-2 leading to the dysregulation of IICR [7,57,91].…”

IP3 receptor mutations and brain diseases in human and rodents

“…In vivo PC firings in SCA2‐58Q Tg mice also exhibit bursting and irregular patterns; intraperitoneal injection of an SK channel‐positive drug normalizes the PC firing in SCA2‐58Q Tg mice (Egorova et al . ). Although the relationship between enhanced Ca 2+ release from IP 3 R1 by Atx2–58Q and the bursting patterns of PC firing, and the target cells that the drug affects, are unknown, these results suggest the potential application of an SK modulator for the treatment of SCA2 and possibly other types of cerebellar ataxias.…”

Expression of mutant DISC1 in Purkinje cells increases their spontaneous activity and impairs cognitive and social behaviors in mice

“…Homozygous Staggerer mice ( sg/sg ) with functional loss of the transcription factor retinoid-related orphan receptor α (RORα) have anomalous passive electrical properties of PCs, parallel fibers-evoked EPSCs with faster kinetics and a slightly decreased paired pulse facilitation (Mitsumura et al, 2011). Expression of human mutant ataxin-2 under the PC-specific L7/pcp2 promoter increased the percentage of PCs with bursting and an irregular pattern of spontaneous activity (Egorova et al, 2016). PC pacemaker firing becomes disrupted and is accompanied by abnormal depolarization after the onset of motor dysfunction in SCA1 [82Q] mice (Dell'Orco et al, 2015).…”