GABAA receptors play key roles in cortical development. Early in development, GABAA receptors are excitatory due to a high intracellular chloride concentration and provide the main excitatory drive onto immature neural cells (Lee et al., 2005). This early excitatory function is important for normal corticogenesis, cell proliferation, and synaptic formation (Wang and Kriegstein, 2009). Because GABAA subunit stoichiometry affects channel properties (Olsen and Sieghart, 2009), we speculate that the genotype-associated differences in GABAA subunit expression may impact GABA signaling effects on cellular connectivity during development. Reported associations of GABRA2 genetic variation with EEG beta frequency oscillations (Edenberg et al., 2004, Lydall et al., 2011), increased activation of the insula (Villafuerte et al., 2012) and nucleus accumbens (Heitzeg et al., 2014) during reward anticipation, and differences in the activation of reward pathways by alcohol cues (Kareken et al., 2010) are consistent with a developmental model of the effects of the AD-associated GABRA2 genetic variant rather than an alteration in ligand binding.
