Modulation of synaptic GABA(A) receptor function by PKA and PKC in adult hippocampal neurons

Several protein kinases are known to phosphorylate Ser/Thr residues of cert ain GABA(A) receptor subunits. Yet, the effect of phosphorylation on GABA(A ) receptor function in neurons remains controversial, and the functional co nsequences of phosphorylating synaptic GABA(A) receptors of adult CNS neuro ns are poorly understood. We used whole-cell patch-clamp recordings of GABA (A) receptor-mediated miniature IPSCs (mIPSCs) in CA1 pyramidal neurons and dentate gyrus granule cells (GCs) of adult rat hippocampal slices to deter mine the effects of cAMP-dependent protein kinase (PKA) and Ca2+/phospholip id-dependent protein kinase (PKC) activation on the function of synaptic GA BA(A) receptors. The mIPSCs recorded in CA1 pyramidal cells and in GCs were differentially affected by PKA and PKC. In pyramidal cells, PKA reduced mI PSC amplitudes and enhanced the fraction of events decaying with a double e xponential, whereas PKC was without effect. In contrast, in GCs PKA was ine ffective, but PKC increased the peak amplitude of mIPSCs and also favored d ouble exponential decays. Intracellular perfusion of the phosphatase inhibi tor microcystin revealed that synaptic GABA(A) receptors of pyramidal cells , but not those of GCs, are continually phosphorylated by PKA and conversel y, dephosphorylated, most likely by phosphatase 1 or 2A. This differential, brain region-specific phosphorylation of GABA(A) receptors may produce a w ide dynamic range of inhibitory synaptic strength in these two regions of t he hippocampal formation.