Postsynaptic γ-aminobutyric acid A receptors (GABAARs) mediate most fast synaptic inhibition in the forebrain. GABAARs are heteromeric protein complexes composed of multiple subunits that form ligand-gated, anion-selective channels whose properties are modulated by barbiturates, benzodiazepines, zinc, ethanol, anesthetics, and neurosteroids. There are several different GABAAR subunit families, and multiple subtypes exist within each classification (α1–6, β1–4, γ1–3, δ, ε, π, and ∏). The most common GABAAR is the α1β2γ2 subtype, but subtype combinations vary in different brain regions and cell types, and during different times in development (Laurie et al., 1992; Rudolph & Mohler, 2006; Sieghart, 2006). Subunit composition of GABAARs determines the intrinsic properties of each channel, including GABA affinity, kinetics, conductance, allosteric modulation, probability of channel opening, interaction with modulatory proteins, and subcellular distribution (Pritchett et al., 1989; Macdonald & Olsen, 1994; Mehta & Ticku, 1999; Mohler, 2006; Sieghart, 2006). For example, alterations in the α-subtype results in differences in GABAAR modulation by benzodiazepines, neurosteroids, and zinc (Pritchett et al., 1989; Vicini, 1991; Nusser & Mody, 2002; Smith et al., 2007). Alterations in GABAAR subunit composition occur during epileptogenesis in animal models of epilepsy (Brooks-Kayal et al., 1998;Lauren et al., 2003; Peng et al., 2004; Sperk et al., 2004; Zhang et al., 2007; Feng et al., 2008; Lund et al., 2008). Status epilepticus (SE) results in changes in the expression and membrane localization (i.e., extrasynaptic vs. synaptic) of several GABAAR subunits (e.g., α1, α4, γ2, and δ) in hippocampal dentate granule cell neurons (DGNs). Beginning soon after the prolonged seizures of SE and continuing at least until the animals become epileptic, these alterations are associated with changes in phasic and tonic GABAAR-mediated inhibition, and in GABAAR pharmacology (Buhl et al., 1996; Gibbs et al., 1997; Cohen et al., 2003). After pilocarpine-induced SE, GABAAR α1 subunit messenger RNA (mRNA) expression decreases, GABAAR α4 subunit mRNA expression increases, and animals develop recurrent spontaneous seizures (Brooks-Kayal et al., 1998, 2001). Changes in GABAAR function and subunit expression have also been observed in neurons from surgically resected hippocampus of patients with intractable temporal lobe epilepsy (TLE) (Brooks-Kayal et al., 1999; Sperk et al., 2009). These alterations are associated with an increased abundance of α4γ2-containing receptors, a reduction in α1γ2-containing receptors in dentate gyrus (Lund et al., 2008), and a shift of γ2-containing receptors from synaptic to perisynaptic locations, likely as part of α4βxγ2 receptors (Zhang et al., 2007). This provides additional support for the concept that during epileptogenesis, altered expression and localization of α-subunits leads to changes in synaptic GABAAR composition that may underlie previously reported impairments in synaptic inhibition in DGNs, including diminished benzodiazepine sensitivity, enhanced zinc sensitivity, reduced neurosteroid modulation, and diminished phasic inhibition in dendrites (Buhl et al., 1996; Gibbs et al., 1997; Cohen et al., 2003; Sun et al., 2007). To directly address the relevance GABAAR subunit alterations to epileptogenesis, viral-mediated gene transfer in adult rodents was used to mitigate changes in GABAAR subunit expression, and the effect on epilepsy development was examined. A bicistronic RNA containing the coding information for the α1 subunit and the yellow enhanced fluorescent protein was delivered under control of the α4 subunit promoter, a promoter that is markedly activated in the dentate gyrus after SE. Delivery of this transgene using an adenoassociated viral vector (AAV) prior to SE resulted in a robust increase in expression of GABAARα1 after SE, a threefold increase in the mean time to the first spontaneous seizure, and only 39% of AAV-α1–injected rats were observed to develop spontaneous seizures in the first 4 weeks after SE compared to 100% of rats receiving sham injections (Raol et al., 2006). Together, these data support a role for GABAAR α subunit changes in the process of epileptogenesis. This article elucidates our current understanding of the molecular mechanisms that regulate aberrant GABAAR subunit expression in dentate gyrus associated with epilepsy and discusses potential therapeutic targets that this research has identified.