Activity-Dependent Repression of Cbln1 Expression: Mechanism for Developmental and Homeostatic Regulation of Synapses in the Cerebellum

Abstract

Cbln1, which belongs to the C1q/tumor necrosis factor superfamily, is released from cerebellar granule cells and plays a crucial role in forming and maintaining excitatory synapses between parallel fibers (PFs; axons of granule cells) and Purkinje cells not only during development but also in the adult cerebellum. Although neuronal activity is known to cause morphological changes at synapses, how Cbln1 signaling is affected by neuronal activity remains unclear. Here, we show that chronic stimulation of neuronal activity by elevating extracellular K ϩ levels or by adding kainate decreased the expression of cbln1 mRNA within several hours in mature granule cells in a manner dependent on L-type voltage-dependent Ca 2ϩ channels and calcineurin. Chronic activity also reduced Cbln1 protein levels within a few days, during which time the number of excitatory synapses on Purkinje cell dendrites was reduced; this activity-induced reduction of synapses was prevented by the addition of exogenous Cbln1 to the culture medium. Therefore, the activity-dependent downregulation of cbln1 may serve as a new presynaptic mechanism by which PF-Purkinje cell synapses adapt to chronically elevated activity, thereby maintaining homeostasis. In addition, the expression of cbln1 mRNA was prevented when immature granule cells were maintained in high-K ϩ medium. Since immature granule cells are chronically depolarized before migrating to the internal granule layer, this depolarization-dependent regulation of cbln1 mRNA expression may also serve as a developmental switch to facilitate PF synapse formation in mature granule cells in the internal granule layer.

SAM68 Regulates Neuronal Activity-Dependent Alternative Splicing of Neurexin-1

“…When granule cells were maintained under depolarizing conditions, the response to NL1B-expressing cells was strongly increased and responses to GluD2 were reduced (Figure 2D, F and Figure S2E). Interestingly, this reduction in GluD2 responses is likely due to both, a change in Nrxn1 alternative splicing but also reduced expression of Cbln1, a critical component of the tripartite NRX-Cbln1-GluD2 complex (Figure S2E and see (Iijima et al, 2009)).…”

“…Our results demonstrate that the depolarization-dependent Nrxn isoform switch upregulates transsynaptic signaling via NL1B and at the same time, reduces the response to GluD2 which interacts through CBLN1 with NRX 4(+) variants (Uemura et al, 2010). Notably, Cbln1 expression in granule cells is itself down-regulated by neuronal activity (Iijima et al, 2009) and the reduction in Cbln1 levels also contribute to the loss of GluD2 responses. Therefore, depolarization-dependent alternative splicing of Nrxn1 and downregulation of Cbln1 synergize to mediate a trans-synaptic ligand switch from interactions with GluD2 towards NL1B.…”

Autism gene Ube3a and seizures impair sociability by repressing VTA Cbln1

“…Cbln1 mRNA is also repressed by increased neuronal activity in cerebellum in culture after depolarization and in vivo after status epilepticus 24 . Therefore, we tested whether recurrent seizures can concurrently repress Cbln1 and sociability.…”

The metamorphosis of the developing cerebellar microcircuit

“…Interestingly, the secretion of Cbln1 is regulated in an activity-dependent manner. An overall increase in neural activity results in decreased expression of Cbln1, and a reduction in the number of excitatory synapses on PC dendrites [72]. The activity-dependent regulation of Cbln1 release may function homeostatically to stabilize activity levels in the developing cerebellum.…”