Deficient long-term synaptic depression in the rostral cerebellum correlated with impaired motor learning in phospholipase C beta 4 mutant mice

Long-term depression (LTD) at parallel fibre-Purkinje cell synapse of the c erebellum is thought to be a cellular substrate for motor learning. LTD req uires activation of metabotropic glutamate receptor subtype 1 (mGluR1) and its downstream signalling pathways, which invariably involves phospholipase C betas (PLC betas). PLC betas consist of four isoforms (PLC beta1-4) amon g which PLC beta4 is the major isoform in most Purkinje cells in the rostra l cerebellum (lobule 1 to the rostral half of lobule 6). We studied mutant mice deficient in PLC beta4, and found that LTD was deficient in the rostra l but not in the caudal cerebellum of the mutant. Basic properties of paral lel fibre-Purkinje cell synapses and voltage-gated Ca2+ channel currents ap peared normal. The mGluR1-mediated Ca2+ release induced by repetitive paral lel fibre stimulation was absent in the rostral cerebellum of the mutant, s uggesting that their LTD lesion was due to the defect in the mGluR1-mediate d signalling in Purkinje cells. Importantly, the eyeblink conditioning, a s imple form of discrete motor learning, was severely impaired in PLC beta4 m utant mice. Wild-type mice developed the conditioned eyeblink response, whe n pairs of the conditioned stimulus (tone) and the unconditioned stimulus ( periorbital shock) were repeatedly applied. In contrast, PLC beta4 mutant m ice could not learn the association between the conditioned and uncondition ed stimuli, although their behavioural responses to the tone or to the peri orbital shock appeared normal. These results strongly suggest that PLC beta 4 is essential for LTD in the rostral cerebellum, which may be required for the acuisition of the conditioned eyeblink response.