Purkinje cell BKchannel ablation induces abnormal rhythm in deep cerebellar nuclei and prevents LTD

Abstract

Purkinje cells (PC) control deep cerebellar nuclei (DCN), which in turn inhibit inferior olive nucleus, closing a positive feedback loop via climbing fibers. PC highly express potassium BK channels but their contribution to the olivo-cerebellar loop is not clear. Using multiple-unit recordings in alert mice we found in that selective deletion of BK channels in PC induces a decrease in their simple spike firing with a beta-range bursting pattern and fast intraburst frequency (~200 Hz). To determine the impact of this abnormal rhythm on the olivo-cerebellar loop we analyzed simultaneous rhythmicity in different cerebellar structures. We found that this abnormal PC rhythmicity is transmitted to DCN neurons with no effect on their mean firing frequency. Long term depression at the parallel-PC synapses was altered and the intra-burst complex spike spikelets frequency was increased without modification of the mean complex spike frequency in BK-PC−/− mice. We argue that the ataxia present in these conditional knockout mice could be explained by rhythmic disruptions transmitted from mutant PC to DCN but not by rate code modification only. This suggests a neuronal mechanism for ataxia with possible implications for human disease.

LINGO1 is a regulatory subunit of large conductance, Ca 2+ -activated potassium channels

“…Calcium-activated potassium (BK) channels are widely expressed, transmembrane proteins that govern smooth muscle (8) and neuronal excitability (9). Pharmacological blockade (10)(11)(12), or molecular ablation (13,14), of these channels also induces tremor. For example, ingestion of indole diterpenoids (11,12), the causative agents of "Rye Grass Staggers" (10), induces motor impairment and tremor (12).…”

“…For example, ingestion of indole diterpenoids (11,12), the causative agents of "Rye Grass Staggers" (10), induces motor impairment and tremor (12). Similarly, global null BK −/− (13) and cerebellar Purkinje cell-specific BK −/− mice (14) exhibit motor impairment and tremor. It is clear, therefore, that inhibition of BK channels, or enhanced expression of LINGO1, are both associated with motor disorders and tremor.…”

Cerebellar Cortex 4–12 Hz Oscillations and Unit Phase Relation in the Awake Rat

“…Besides, the 4–12 Hz rhythmicity also fits well with a recovery time constant of the channels CaV3.1 in those same neurons around 100 ms (Iftinca et al, 2006 ; De Schutter and Steuber, 2009 ; Tadayonnejad et al, 2010 ). Importantly as well, mutant mice that are without the calcium-sensitive BK channels in their Purkinje cells show strong firing rhythmicity in SSs (Chéron et al, 2009 ) but also in the deep cerebellar nuclei, in the beta range, showing a transmittable rhythmic influence (Chéron et al, 2018 ). Together, these elements paint a picture that a rhythmic influence could coordinate the activity in the overall cerebellar circuitry under certain conditions, such as in movement preparation (Courtemanche et al, 2013 ).…”

“…strong firing rhythmicity in SSs (Chéron et al, 2009) but also in the deep cerebellar nuclei, in the beta range, showing a transmittable rhythmic influence (Chéron et al, 2018). Together, these elements paint a picture that a rhythmic influence could coordinate the activity in the overall cerebellar circuitry under certain conditions, such as in movement preparation (Courtemanche et al, 2013).…”

Synergistic excitability plasticity in cerebellar functioning

“…Further, in this study, there is concern about changes in neuronal activity in the oculomotor circuit. Both global and PC‐specific BK‐null mice exhibited ataxia, motor performance deficits [256–258], and a periodic PC activity with abnormal complex spike discharges [258], which is similar to that of LTD‐deficient mice [259]. Therefore, more specific investigations in cell types and temporality are required for the validation of BK plasticity in motor learning.…”