mGluR5 Is Substitutable for mGluR1 in Cerebellar Purkinje Cells for Motor Coordination, Developmental Synapse Elimination, and Motor Learning

Abstract

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.

Dataset of eyeblink conditioning in mice treated with the selective mGluR1 antagonist JNJ16259685

“…It is used as a behavioral task to study the neural structures and mechanisms underlying learning and memory [2 , 3] . Various studies over several decades have provided evidence that metabotropic glutamate receptor type 1 (mGluR1) is required for this type of motor learning in rodents [4] , [5] , [6] , [7] , [8] . These findings have been mainly observed in gene knockout studies or theoretical modeling research.…”

Targeting mGlu1 Receptors in the Treatment of Motor and Cognitive Dysfunctions in Mice Modeling Type 1 Spinocerebellar Ataxia

“…The developmental pattern of expression of mGlu1 and mGlu5 receptors is complementary in cerebellar Purkinje cells, and endogenous activation of mGlu1 receptors down-regulates the expression of mGlu5 receptors through an epigenetic mechanism [ 36 ]. A recent article published in this SI on Cells demonstrates that transgene-induced expression of mGlu5 receptors in Purkinje cells rescued the pathological phenotype in mGlu1 knock-out mice, suggesting that mGlu1 and Glu5 receptors behave similarly in Purkinje cells [ 37 ]. Interestingly, mGlu5 receptors are re-expressed in Purkinje cells of SCA1 mice [ 33 ], perhaps as a result of mGlu1 receptor down-regulation.…”