Loss of the calcium channel ?4 subunit impairs parallel fibre volley and Purkinje cell firing in cerebellum of adult ataxic mice.

ABSTRACT: The auxiliary voltage-gated calcium channel subunit ?4 supports targeting of calcium channels to the cell membrane, modulates ionic currents and promotes synaptic release in the central nervous system. ?4 is abundant in cerebellum and its loss causes ataxia. However, the type of calcium channels and cerebellar functions affected by the loss of ?4 are currently unknown. We therefore studied the structure and function of Purkinje cells in acute cerebellar slices of the ?4 (-/-) ataxic (lethargic) mouse, finding that loss of ?4 affected Purkinje cell input, morphology and pacemaker activity. In adult lethargic cerebellum evoked postsynaptic currents from parallel fibres were depressed, while paired-pulse facilitation and spontaneous synaptic currents were unaffected. Because climbing fibre input was spared, the parallel fibre/climbing fibre input ratio was reduced. The dendritic arbor of adult lethargic Purkinje cells displayed fewer and shorter dendrites, but a normal spine density. Accordingly, the width of the molecular and granular layers was reduced. These defects recapitulate the impaired cerebellar maturation observed upon Cav 2.1 ataxic mutations. However, unlike Cav 2.1 mutations, lethargic Purkinje cells also displayed a striking decrease in pacemaker firing frequency, without loss of firing regularity. All these deficiencies appear in late development, indicating the importance of ?4 for the normal differentiation and function of mature Purkinje cells networks. The observed reduction of the parallel fibre input, the altered parallel fibre/climbing fibre ratio and the reduced Purkinje cell output can contribute to the severe motor impairment caused by the loss of the calcium channel ?4 subunit in lethargic mice.

SUBMITTER: Benedetti B 

PROVIDER: S-EPMC4949674 | biostudies-literature | 2016 Jun

REPOSITORIES: biostudies-literature