Postsynaptic P/Q-type Ca ²⁺ channel in Purkinje cell mediates synaptic competition and elimination in developing cerebellum

Abstract

Neural circuits are initially redundant but rearranged through activity-dependent synapse elimination during postnatal development. This process is crucial for shaping mature neural circuits and for proper brain function. At birth, Purkinje cells (PCs) in the cerebellum are innervated by multiple climbing fibers (CFs) with similar synaptic strengths. During postnatal development, a single CF is selectively strengthened in each PC through synaptic competition, the strengthened single CF undergoes translocation to a PC dendrite, and massive elimination of redundant CF synapses follows. To investigate the cellular mechanisms of this activity-dependent synaptic refinement, we generated mice with PC-selective deletion of the Ca v 2.1 P/Q-type Ca 2+ channel, the major voltage-dependent Ca 2+ channel in PCs. In the PC-selective Ca v 2.1 knockout mice, Ca 2+ transients induced by spontaneous CF inputs are markedly reduced in PCs in vivo. Not a single but multiple CFs were equally strengthened in each PC from postnatal day 5 (P5) to P8, multiple CFs underwent translocation to PC dendrites, and subsequent synapse elimination until around P12 was severely impaired. Thus, P/Q-type Ca 2+ channels in postsynaptic PCs mediate synaptic competition among multiple CFs and trigger synapse elimination in developing cerebellum.

Glutamate transporter GLAST controls synaptic wrapping by Bergmann glia and ensures proper wiring of Purkinje cells

“…This wiring pattern is analogous to that observed in the developing cerebellum, where a single strengthened CF is not yet strong enough to eliminate the other weaker CFs from PC somata (7), and PF synapses cover the entire dendritic tree (45). To establish CF monoinnervation and segregated PF/CF territories, proper activations of P/Q-type Ca 2+ channels and the type 1 metabotropic glutamate receptor-Gαq-PLCβ4-protein kinase Cγ signaling pathway by glutamatergic inputs are crucial (8,(15)(16)(17). Therefore, one factor likely contributing to the impaired synaptic competition in GLAST-KO mice is the elevated [Glu] e , which may alter the balance of activation between glutamatergic synapses in favor of the inputs that should normally be eliminated over the ones that should remain or be further strengthened.…”

“…The strengthened CF starts dendritic translocation, whereas the other weaker CFs remain in the soma until they are eliminated (6,7). In this process, P/Q-type voltage-dependent Ca 2+ channels promote functional differentiation and dendritic translocation of the strengthened CF, and propel the early phase of CF synapse elimination (8). The late phase of CF synapse elimination critically depends on PF synapse formation, in which the GluD2-Cbln1-neurexin adhesion system ensures structural connectivity of PF-PC synapses (9-11), whereas the type 1 metabotropic glutamate receptor-protein kinase Cγ signaling pathway mediates the activity of PF-PC synapses for CF synapse elimination (12)(13)(14)(15)(16).…”

Synaptic Refinement of an Inhibitory Topographic Map in the Auditory Brainstem Requires Functional CaV1.3 Calcium Channels

“…This is best known for calcium-permeable NMDA receptors in the hippocampus (Bliss and Collingridge, 1993), yet it was also reported for L-type channels in the hippocampus (Kasyanov et al, 2004), NMDA receptors in the brainstem (Rudhard et al, 2003), NMDA receptors and L-type channels in the superior colliculus (Lo and Mize, 2000;Zhao et al, 2006) and Ca V 1.1 L-type channels in the neuromuscular system (Chen et al, 2011), as well as Ca V 2.1 P/Q-type channels in the cerebellum (Hashimoto et al, 2011). To regulate the transcription machinery, calcium signals have to be conveyed from the site of their generation in the cytoplasm to the cell nucleus.…”

Territories of heterologous inputs onto Purkinje cell dendrites are segregated by mGluR1-dependent parallel fiber synapse elimination

“…The strengthened ("winner") CF starts dendritic translocation, whereas the other weaker ("loser") CFs remaining on the soma are eliminated (6)(7)(8). In this process, P/Q-type voltage-dependent Ca 2+ channels (VDCCs) promote functional differentiation and dendritic translocation of winner CFs, and the early phase of CF synapse elimination (9)(10)(11), whereas the late phase of CF synapse elimination is critically dependent on the formation of parallel fiber (PF) synapses and activation of the type 1 metabotropic glutamate receptor (mGluR1)-protein kinase Cγ (PKCγ) pathway (12)(13)(14)(15)(16)(17).…”