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The γ-aminobutyric acid (GABA) type A receptor (GABAAR) is the major inhibitory neurotransmitter receptor in the brain. Its multiple subunits show regional, developmental, and disease-related plasticity of expression; however, the regulatory networks controlling GABAAR subunit expression remain poorly understood. We report that the seizure-induced decrease in GABAAR α1 subunit expression associated with epilepsy is mediated by the Janus kinase (JAK)/signal transducer and activator of transcription (STAT) pathway regulated by brain-derived neurotrophic factor (BDNF). BDNF- and seizure-dependent phosphorylation of STAT3 cause the adenosine 3′,5′-monophosphate (cAMP) response element–binding protein (CREB) family member ICER (inducible cAMP early repressor) to bind with phosphorylated CREB at the Gabra1:CRE site. JAK/STAT pathway inhibition prevents the seizure-induced decrease in GABAAR α1 abundance in vivo and, given that BDNF is known to increase the abundance of GABAAR α4 in a JAK/STAT-independent manner, indicates that BDNF acts through at least two distinct pathways to influence GABAAR-dependent synaptic inhibition.