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Group I metabotropic glutamate receptors (mGluRs) include mGluR1 and mGluR5, which are coupled to the Gq family of heterotrimeric G-proteins and readily activated by their selective agonist 3,5-dihydroxyphenilglycine (DHPG). mGluR1 and mGluR5 exhibit nearly complementary distributions spatially or temporally in the central nervous system (CNS). In adult cerebellar Purkinje cells (PCs), mGluR1 is a dominant group I mGluR and mGluR5 is undetectable. mGluR1 expression increases substantially during the first three weeks of postnatal development and remains high throughout adulthood. On the other hand, mGluR5 expression is observed during the first two postnatal weeks and then decreases. However, functional differences between mGluR1 and mGluR5 in the CNS remains to be elucidated. To address this issue, we generated "mGluR5-rescue" mice in which mGluR5 is specifically expressed in PCs in global mGluR1-knockout (KO) mice. mGluR5-rescue mice exhibited apparently normal motor coordination, developmental elimination of redundant climbing fiber (CF)-PC synapses, and delay eyeblink conditioning, which were severely impaired in mGluR1-KO mice. We concluded that mGluR5 is functionally comparable with mGluR1 in cerebellar PCs. [ABSTRACT FROM AUTHOR]

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 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 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 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. [ABSTRACT FROM AUTHOR]

Abstract: We previously demonstrated that metabotropic glutamate receptor-subtype 1 knockout [mGluR1 (−/−)] mice showed ataxic gait, deficient long-term depression and impaired synapse elimination and these phenotypes were rescued by introduction of an mGluR1 transgene with Purkinje cell-specific promoter (mGluR1-rescue mice). However, roles of mGluR1 in the adult brain remain elusive, mainly due to lack of conventional and reproducible method to block mGluR1 expression at a certain developmental stage. Here, we established a versatile mouse line, mGluR1 conditional knockout (cKO) mice using the tetracycline-controlled gene expression system to understand the roles of mGluR1 in the adult brain. The mGluR1 cKO mice express mGluR1 only in Purkinje cells and show normal motor coordination. Blockade of expression of mGluR1 in the adult mGluR1 cKO mice led to impaired motor coordination, suggesting that mGluR1 is essential for cerebellar function in mice not only during postnatal development but also in adulthood. [Copyright &y& Elsevier]

The cerebellum is essential for the control, coordination, and learning of movements, and for certain aspects of cognitive function. Purkinje cells are the sole output neurons in the cerebellar cortex and therefore play crucial roles in the diverse functions of the cerebellum. The type 1 metabotropic glutamate receptor (mGluR1) is prominently enriched in Purkinje cells and triggers downstream signaling pathways that are required for functional and structural plasticity, and for synaptic responses. To understand how mGluR1 contributes to cerebellar functions, it is important to consider not only the operational properties of this receptor, but also its spatial organization and the molecular interactions that enable its proper functioning. In this review, we highlight how mGluR1 and its related signaling molecules are organized into tightly coupled microdomains to fulfill physiological functions. We also describe emerging evidence that altered mGluR1 signaling in Purkinje cells underlies cerebellar dysfunction in ataxias of human patients and mouse models. • mGluR1 signaling in Purkinje cells is crucial for various cerebellar functions. • mGluR1 triggers intracellular pathways for neural plasticity and modulation. • mGluR1 and its interacting partners are arranged into tightly coupled microdomains. • mGluR1 signaling is a promising therapeutic target for cerebellar dysfunctions. [ABSTRACT FROM AUTHOR]