Histone deacetylase 2 cell autonomously suppresses excitatory and enhances inhibitory synaptic function in CA1 pyramidal neurons

Abstract

Histone deacetylase 2 (HDAC2) negatively regulates excitatory synapse number and memory performance. However, whether HDAC2 regulation of excitatory synapses occurs in a cell-autonomous manner and whether HDAC2 regulates inhibitory synaptic functions are not well understood. To examine these aspects of HDAC2 function, we used sparse transfection of rat hippocampal slice cultures and whole-cell recordings in pyramidal neurons. HDAC2 knockdown (KD) in single postsynaptic pyramidal neurons enhanced, whereas HDAC2 overexpression (OE) reduced, excitatory synaptic transmission. Postsynaptic KD of HDAC2 also facilitated expression of longterm potentiation induced by subthreshold induction stimuli, without altering long-term depression. In contrast, HDAC2 KD reduced, whereasHDAC2OEenhanced, inhibitory synaptic transmission. Alterations of postsynapticGABAA receptors(GABAARs) likely underlie the impact of HDAC2 on inhibitory transmission. Consistent with this, we observed reduced transcript and protein levels of the GABAAR α2 subunit and reduced surface expression of the γ2 subunit after HDAC2 KD. Furthermore, we observed a reduction in synaptic but not tonic GABAAR currents by HDAC2 KD, suggesting that HDAC2 selectively affects synaptic abundance of functional GABAARs. Immunostaining for postsynaptic GABAARs confirmed that HDAC2 KD and OE can regulate the synaptic abundance of these receptors. Together, these results highlight a role for HDAC2 in suppressing synaptic excitation and enhancing synaptic inhibition of hippocampal neurons. Therefore, a shift in the balance of synaptic excitation versus inhibition favoring excitation could contribute to the beneficial effects of reducing HDAC2 function in wild-type mice or of inhibiting HDACs in models of cognitive impairment. © 2013 the authors.