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

Abstract

Cyclin D1 (Ccnd1){middle dot}Cdk4 complexes drive cell cycle progression through phosphorylation of pRb. Interestingly, Ccnd1 moves to the cytoplasm at the onset of differentiation in neuronal precursors. However, the cytoplasmic functions and targets of Ccnd1 in post-mitotic neurons are unknown. Here we identify the 4 subunit of gamma-aminobutyric acid (GABA) type A receptors (GABAARs) as an interactor and target of Ccnd1{middle dot}Cdk4. Ccnd1 binds to an intracellular loop in 4 and, together with Cdk4, phosphorylates the 4 subunit at threonine 423 and serine 431. These modifications increase the activity of 4-containing GABAARs, measured in whole-cell patch-clamp recordings, and upregulate its surface levels. In agreement with this role of Ccnd1{middle dot}Cdk4 in neuronal signaling, inhibition of Cdk4 decreases synaptic and extrasynaptic currents in the hippocampus of newborn rats. Moreover, CCND1 knockout mice display an altered pattern of dendritic spines, according to 4 functions in synaptic pruning. Overall, our findings molecularly link Ccnd1{middle dot}Cdk4 to GABAARs activity in the central nervous system and highlight a novel role for this G1 cyclin in neuronal signaling.