Roles of Glutamate Receptor δ2 Subunit (GluRδ2) and Metabotropic Glutamate Receptor Subtype 1 (mGluR1) in Climbing Fiber Synapse Elimination during Postnatal Cerebellar Development

Abstract

Climbing fiber (CF) synapse formation onto cerebellar Purkinje cells (PCs) is critically dependent on the synaptogenesis from parallel fibers (PFs), the other input to PCs. Previous studies revealed that deletion of the glutamate receptor delta2 subunit (GluRdelta2) gene results in persistent multiple CF innervation of PCs with impaired PF synaptogenesis, whereas mutation of the metabotropic glutamate receptor subtype 1 (mGluR1) gene causes multiple CF innervation with normal PF synaptogenesis. We demonstrate that atypical CF-mediated EPSCs (CF-EPSCs) with slow rise times and small amplitudes coexisted with typical CF-EPSCs with fast rise times and large amplitudes in PCs from GluRdelta2 mutant cerebellar slices. CF-EPSCs in mGluR1 mutant and wild-type PCs had fast rise times. Atypical slow CF responses of GluRdelta2 mutant PCs were associated with voltage-dependent Ca(2+) signals that were confined to PC distal dendrites. In the wild-type and mGluR1 mutant PCs, CF-induced Ca(2+) signals involved both proximal and distal dendrites. Morphologically, CFs of GluRdelta2 mutant mice extended to the superficial regions of the molecular layer, whereas those of wild-type and mGluR1 mutant mice did not innervate the superficial one-fifth of the molecular layer. It is therefore likely that surplus CFs of GluRdelta2 mutant mice form ectopic synapses onto distal dendrites, whereas those of wild-type and mGluR1 mutant mice innervate proximal dendrites. These findings suggest that GluRdelta2 is required for consolidating PF synapses and restricting CF synapses to the proximal dendrites, whereas the mGluR1-signaling pathway does not affect PF synaptogenesis but is involved in eliminating surplus CF synapses at the proximal dendrites.

Essential role of postsynaptic NMDA receptors in developmental refinement of excitatory synapses

“…Activities of corticothalamic neurons are likely to be altered in SERT-Grin1 −/− mice. In the cerebellum, the refinement of climbing fiber-Purkinje cell synapse is disrupted by changes of parallel fiber inputs (40,41). Therefore, it is possible that a reduction of corticothalamic inputs disrupts the refinement of thalamic relay synapses.…”

The axonal chemorepellant semaphorin 3A is increased in the cerebellum in schizophrenia and may contribute to its synaptic pathology

“…Furthermore, many genes apart from sema3A contribute to the formation and maintenance of synapses in the cerebellum, [68][69][70] and these will need to be investigated, along with those involved in reelin signalling, for a fuller picture to emerge. Finally, since synaptic pathology 71 and decreased reelin expression 30,67 may also occur in bipolar disorder, it will be of interest to establish whether sema3A plays a role in that disorder as well.…”

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

“…In the adult cerebellum, parallel fibres and a climbing fibre normally make synapses on distal and proximal dendrites, respectively. In the GluRd2 knockout mice, climbing fibres invade into the distal dendrites and form ectopic synapses there (Hashimoto et al 2001a;Ichikawa et al 2002). These ectopic climbing fibre synapses appear around P10 when parallel fibre synapse formation and Purkinje cell dendritic arborization occur most vigorously.…”