CRL4 antagonizes SCFFbxo7-mediated turnover of cereblon and BK channel to regulate learning and memory

Intellectual disability (ID), one of the most common human developmental disorders, can be caused by genetic mutations in Cullin 4B (Cul4B) and cereblon (CRBN). CRBN is a substrate receptor for the Cul4A/B-DDB1 ubiquitin ligase (CRL4) and can target voltage- and calcium-activated BK channel for ER retention. Here we report that ID-associated CRL4CRBNmutations abolish the interaction of the BK channel with CRL4, and redirect the BK channel to the SCFFbxo7ubiquitin ligase for proteasomal degradation. Glioma cell lines harbouring CRBN mutations record density-dependent decrease of BK currents, which can be restored by blocking Cullin ubiquitin ligase activity. Importantly, mice with neuron-specific deletion of DDB1 or CRBN express reduced BK protein levels in the brain, and exhibit similar impairment in learning and memory, a deficit that can be partially rescued by activating the BK channel. Our results reveal a competitive targeting of the BK channel by two ubiquitin ligases to achieve exquisite control of its stability, and support changes in neuronal excitability as a common pathogenic mechanism underlying CRL4CRBN–associated ID

Neuronal Responses to Lemniscal Stimulation in Laminar Brain Slices of the Inferior Colliculus

The central nucleus of the inferior colliculus (ICC) receives inputs from all parts of the auditory brainstem and transmits the information to the forebrain. Fibrodendritic laminae of the ICC provide a structural basis for a tonotopic organization, and the interaction of inputs within a single layer is important for ICC processing. Transverse slice planes of the ICC sever the layers and many of the ascending axons that enter through the lateral lemniscus. Consequently, the activity initiated within a lamina by a pure lemniscal stimulus is not well characterized. Here, we use a slice plane that maintains the integrity of the laminae in ICC and allows the axons in the lateral lemniscus to be stimulated at a distance from the ICC. We examined both the postsynaptic currents and potentials of the same neurons to lemniscal stimuli in this laminar brain slice. Our main finding is that lemniscal stimulation evokes prolonged synaptic potentials in ICC neurons. Synaptic potential amplitudes and durations increase with lemniscal shock strength. In ∼50% of ICC neurons, the postsynaptic potential is equal in duration to the postsynaptic current, whereas in the remaining neurons it is three to four times longer. Synaptic responses to single shocks or shock trains exhibit plateau potentials that enable sustained firing in ICC neurons. Plateau potentials are evoked by N-methyl-d-aspartate (NMDA) receptor activation, and their amplitudes and durations are regulated by both NMDA-R and gamma-aminobutyric acid A (GABA(A))-R activation. These data suggest that in the intact laminae of the ICC, lemniscal inputs initiate sustained firing through monosynaptic and polysynaptic NMDA-mediated synapses regulated by GABA(A) synapses