| Type A gamma-aminobutyric acid receptors (GABAARs) mediate inhibitory synaptic transmission required for normal function of the central nervous system. A change in the number or kind of GABAAR has been implicated in multiple neurological diseases including temporal lobe epilepsy (TLE) where decreased levels of GABAAR alpha1, and increased alpha4 subunits, accompany abnormal excitability of dentate granule cells. Delivery of alpha1 to the dentate gyrus (DG) in a TLE animal model inhibits spontaneous seizures, supporting a direct role for GABAAR subunit composition in the disease process. We now show that altered a subunit levels and GABA AR function are associated with a decrease of alpha1gamma2-containing and an increase of alpha4gamma2-containing GABAARs in the DG of pilocarpine-treated rats 24 h after status epilepticus (SE). GABA AR alpha1 subunit gene (GABRA1) expression is under control of the CAMP response element binding protein (CREB) and the inducible CAMP early repressor (ICER).; Activation of protein kinase C (PKC), but not mitogen activated protein kinase, increases expression of GABRA1 through phosphorylation of CREB by activating the GABRA1 promoter (GABRA1p). However, activation of protein kinase A (PKA) decreases the levels of alpha1 mRNA and subunit protein even in the presence of phospho-CREB, and activation of PKA, not PKC, leads to induction of ICER. Inhibition of ICER expression by siRNAs inhibits the decrease in alpha1 subunit mRNA levels by PKA. In addition, transfection of primary cultured neurons with GABRA1p/reporter constructs, in combination with overexpressed CREB or ICER, demonstrates that CREB activates GABRA1 transcription only in the absence of ICER.; The signal transduction pathway(s) that alter alpha subunit expression after SE remain to be discovered. Here, we report that brain-derived neurotrophic factor (BDNF), whose levels increase markedly in TLE animal models, may be the extracellular signal that alters alpha1 expression in a PKA-independent manner. Downregulation of alpha1 subunits by BDNF occurs via the activation of Janus kinase and its selective control over ICER synthesis. Our findings taken together identify a new drug target for regulating inhibitory neurotransmission after brain insult and highlight the importance of ICER to expression of synaptic GABAARs in the CNS. |
