Deficient long-term synaptic depression in the rostral cerebellum correlated with impaired motor learning in phospholipase C β4 mutant mice

Long-term depression (LTD) at parallel fibre-Purkinje cell synapse of the cerebellum is thought to be a cellular substrate for motor learning. LTD requires activation of metabotropic glutamate receptor subtype 1 (mGluR1) and its downstream signalling pathways, which invariably involves phospholipase Cβs (PLCβs). PLCβs consist of four isoforms (PLCβ1-4) among which PLCβ4 is the major isoform in most Purkinje cells in the rostral cerebellum (lobule 1 to the rostral half of lobule 6). We studied mutant mice deficient in PLCβ4, and found that LTD was deficient in the rostral but not in the caudal cerebellum of the mutant. Basic properties of parallel fibre-Purkinje cell synapses and voltage-gated Ca ²⁺ channel currents appeared normal. The mGluR1-mediated Ca ²⁺ release induced by repetitive parallel fibre stimulation was absent in the rostral cerebellum of the mutant, suggesting that their LTD lesion was due to the defect in the mGluR1-mediated signalling in Purkinje cells. Importantly, the eyeblink conditioning, a simple form of discrete motor learning, was severely impaired in PLCβ4 mutant mice. Wild-type mice developed the conditioned eyeblink response, when pairs of the conditioned stimulus (tone) and the unconditioned stimulus (periorbital shock) were repeatedly applied. In contrast, PLCβ4 mutant mice could not learn the association between the conditioned and unconditioned stimuli, although their behavioural responses to the tone or to the periorbital shock appeared normal. These results strongly suggest that PLCβ4 is essential for LTD in the rostral cerebellum, which may be required for the acuisition of the conditioned eyeblink response.