고려대학교 생명과학대학 생명과학부/ 대학원 분자생명과학과

Intellectual disability is a mild mental retardation showing impaired intellectual ability with IQ below 70. Recent studies have revealed a series of synaptic proteins as factors related to the mild mental retardation. Cereblon is one of mild mental retardation related factor which is one of ATP-dependent Lon protease. The nonsense multation (R419X) of cereblon gene located in the human chromosome 3 (3p26.3) is thought to cause the intellectual disability in the patients with IQ 50-70. However the detailed mechanism of cereblon in synapse is mostly unclear yet. Here we studied the role of Cereblon in the synaptic structure and function using multiple model systems including mouse hippocampal slices and Drosophila neuromuscular junction. The knockout mouse lacking the expression of cereblon shows generally normal gross brain anatomy as well as spine density and length. However cereblon KO animal shows clear impairment in cognitive function analyzed by Y-maze test, passive avoidance test and novel object recognition test. The synaptic function in cereblon KO animal are intact in Schaffer-collateral synapse in hippocampus with normal input-output relationship, LTP, LTD, long-lasting LTP, and mGluR-induced LTD. Interestingly the paired-pulse ratio was altered in KO animal, implying the changes in presynaptic release function. To further confirm the function of cereblon and to identify its signaling mechanism, we monitored the synaptic function of Drosophila cereblon KO animal. The changes in paired-pulse ratio were also monitored in KO animal. Interestingly the mutants also showed the increased evoked excitatory postsynatpic currents and size of releasable neurotransmitter pool as well. These results suggest that the changes in presynaptic neurotransmitter release could be involved in the pathology of mild mental retardation in the patients with cereblon mutation.