Cyclin D1-Cdk4 regulates neuronal activity through phosphorylation of GABAA receptors

Nuclear Cyclin D1 (Ccnd1) is a main regulator of cell cycle progression and cell proliferation. Interestingly, Ccnd1 moves to the cytoplasm at the onset of differentiation in neuronal precursors. However, cytoplasmic functions and targets of Ccnd1 in post-mitotic neurons are unknown. Here we identify the & alpha;4 subunit of gamma-aminobutyric acid (GABA) type A receptors (GABAARs) as an interactor and target of Ccnd1-Cdk4. Ccnd1 binds to an intracellular loop in & alpha;4 and, together with Cdk4, phosphorylates the & alpha;4 subunit at threonine 423 and serine 431. These modifications upregulate & alpha;4 surface levels, increasing the response of & alpha;4-containing GABAARs, measured in whole-cell patch-clamp recordings. In agreement with this role of Ccnd1-Cdk4 in neuronal signalling, inhibition of Cdk4 or expression of the non-phosphorylatable & alpha;4 decreases synaptic and extra-synaptic currents in the hippocampus of newborn rats. Moreover, according to & alpha;4 functions in synaptic pruning, CCND1 knockout mice display an altered pattern of dendritic spines that is rescued by the phosphomimetic & alpha;4. Overall, our findings molecularly link Ccnd1-Cdk4 to GABAARs activity in the central nervous system and highlight a novel role for this G1 cyclin in neuronal signalling.

Automated summary

In this study, Nuclear Cyclin D1 is found to interact with and phosphorylate the α4 subunit of GABA A receptors, increasing the surface levels of α4-containing GABA A receptors and enhancing their response. This molecular link between D1-Cdk4 and GABA A receptors activity highlights a novel role for this G1 cyclin in neuronal signalling.