GABA(A) receptor delta subunit deletion prevents neurosteroid modulation of inhibitory synaptic currents in cerebellar neurons.

The delta subunit of the GABA(A) receptor has been reported to play a pivotal role in neurosteroid modulation. We investigated the action of the neurosteroid THDOC on GABA(A) receptor-mediated spontaneous inhibitory postsynaptic currents (sIPSCs) recorded in cerebellar neurons from delta subunit knockout mice. We observed that the neurosteroid failed to prolong IPSCs in granule neurons in cerebellar slices from these mice. This was in contrast to robust potentiation observed in wild-type mice. However, in stellate neurons, naturally devoid of delta subunit, a significant reduction of neurosteroid action on sIPSCs recorded in the presence of tetrodotoxin (mIPSCs) was also observed in mice that lack the delta subunit. Given the reported role of intracellular protein kinase C modulation of neurosteroid activity, we investigated the action of THDOC by recording sIPSCs and mIPSCs from delta-deficient mice with intracellular perfusion of a kinase stimulator. Phorbol-12-myristate-13-acetate (PMA) completely restored the action of the neurosteroid on synaptic currents in both granule and stellate neurons.