Cerebellin

Cerebellin refers to a family of small secreted proteins that function as synaptic organizers in the brain, with the strongest expression in the cerebellum. The family includes cerebellin-1 (Cbln1) and related proteins Cbln2–Cbln4, encoded by the CBLN genes. Cbln1 is the best characterized member and is produced by cerebellar granule cells and other neuronal populations. These proteins are secreted glycoproteins that assemble into hexameric complexes and contain a C1q-like globular domain, a structural motif shared with other members of the C1q/TNF superfamily.

Cerebellins act as trans-synaptic signaling molecules by engaging presynaptic neurexins and the postsynaptic receptor GRID2 (glutamate receptor delta-2), effectively bridging the presynaptic and postsynaptic elements at certain excitatory synapses. This bridging supports the organization and maintenance of synapses, particularly the parallel fiber–Purkinje cell synapses in the cerebellum.

Physiological role and evidence: In mice, Cbln1 is essential for proper development and maintenance of parallel fiber–Purkinje cell synapses. Disruption of Cbln1, neurexins, or GRID2 can lead to reductions in synaptic density, morphological abnormalities, and motor coordination deficits, highlighting the importance of the cerebellin–neurexin–GRID2 pathway for cerebellar circuitry.

Clinical and research context: Altered cerebellin signaling has been investigated in relations to cerebellar dysfunction and neurodevelopmental disorders. The cerebellin–neurexin–GRID2 axis continues to be studied as a model of trans-synaptic organization with potential therapeutic implications, though human disease associations remain an area of active research.