Blocking L-type Voltage-gated Ca Channels with Dihydropyridines Reduces -Aminobutyric Acid Type A Receptor Expression and Synaptic Inhibition*

-Aminobutyric acid type A receptors (GABAARs) are the major sites of fast inhibitory neurotransmission in the brain, and the numbers of these receptors at the cell surface can determine the strength of GABAergic neurotransmission. Chronic changes in neuronal activity lead to an adaptive modulation in the efficacy of GABAergic synaptic inhibition, brought about in part by changes in the number of synaptic GABAARs, a mechanismknown as homeostatic synaptic plasticity. Reduction in the number ofGABAARs in response to prolongedneuronal activity blockade is dependent on the ubiquitin-proteasome system. The underlying biochemical pathways linking chronic activity blockade to proteasome-dependent degradation of GABAARs are unknown. Here, we show that chronic blockade of L-type voltagegated calcium channels (VGCCs) with nifedipine decreases the numberofGABAARsatsynapticsitesbutnot theoverallnumberof inhibitory synapses. In parallel, blockade of L-type VGCCs decreases the amplitude but not the frequency ofminiature inhibitory postsynaptic currents or expression of the glutamic acid decarboxylase GAD65. We further reveal that the activation of L-typeVGCCsregulates the turnoverofnewly translatedGABAAR subunits in a mechanism dependent upon the activity of the proteasome and thus regulates GABAAR insertion into the plasma membrane. Together, these observations suggest that activation of L-type VGCCs can regulate the abundance of synaptic GABAARs and the efficacy of synaptic inhibition, revealing a potential mechanism underlying the homeostatic adaptation of fast GABAergic inhibition to prolonged changes in activity.