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

Abstract

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 Cbetas (PLCbetas). PLCbetas consist of four isoforms (PLCbeta1-4) among which PLCbeta4 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 PLCbeta4, 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 Ca2+ channel currents appeared normal. The mGluR1-mediated Ca2+ 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 PLCbeta4 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, PLCbeta4 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 PLCbeta4 is essential for LTD in the rostral cerebellum, which may be required for the acuisition of the conditioned eyeblink response.

Conditioned eyeblink learning is formed and stored without cerebellar granule cell transmission

“…1a). The localization and underlying mechanisms of eyeblink conditioning have been extensively studied by different approaches including gene targeting (6)(7)(8)(9)(10)(11), lesioning (12)(13)(14)(15), mutant analysis (16), and pharmacological inactivation analyses (17)(18)(19)(20)(21)(22)(23). On the basis of these studies, one model proposes an essential role of the cerebellar Purkinje cell circuit in memory traces (24)(25)(26).…”

H2-K b and H2-D b regulate cerebellar long-term depression and limit motor learning

“…It follows that impaired PF LTD should diminish motor learning, whereas more robust PF LTD would improve motor learning. Several mutant mice with diminished cerebellar LTD do display impaired motor learning (34)(35)(36).…”

Type-1 metabotropic glutamate receptor in cerebellar Purkinje cells: a key molecule responsible for long-term depression, endocannabinoid signalling and synapse elimination

“…Hirono et al (2001a) confirmed the observation by Miyata et al by analysing the other strain of PLCb4 knockout mice. Importantly, Miyata et al (2001) showed that delay eyeblink conditioning was severely impaired in the PLCb4 knockout mice. Since lobule simplex or lobule HVI of Larsell, a part of the cerebellar cortex with rich PLCb4 expression in the Purkinje cells, is crucial for delay eyeblink conditioning (Hesslow & Yeo 1998), these results indicate that PLCb4 is crucial for LTD and discrete motor learning in the rostral cerebellum.…”

“…Miyata et al (2001) analysed the PLCb4 knockout mice and found that both mGluR1-mediated Ca 2C mobilization and LTD were deficient in the rostral cerebellum, whereas these responses were intact in the caudal cerebellum. Hirono et al (2001a) confirmed the observation by Miyata et al by analysing the other strain of PLCb4 knockout mice.…”