, 2009 and Sequeira et al., 2009). Such changes are predicted to disrupt the subunit composition of GABAARs and are consistent with the GABAergic

deficit hypothesis of major depression (Luscher et al., 2011). The neural response to GABAAR activation depends on the Cl− equilibrium (ECl) potential, which determines the electrochemical driving force for Cl−. ECl is determined chiefly by the relative expression of the Cl− transporters KCC2 and NKCC1, which increase and decrease, respectively, during animal development and neural differentiation (for reviews see Ben-Ari, 2002, Fiumelli and Woodin, 2007 and Andäng and Lendahl, 2008). The ensuing hyperpolarizing shift in ECl leads to a gradual conversion of GABAergic depolarization in immature neurons to mainly hyperpolarizing function in mature neurons. This Pfizer Licensed Compound Library in vitro switch in the function of GABAARs is essential for structural and

functional maturation of neurons (Tozuka et al., 2005, Ge et al., 2006 and Cancedda et al., 3-Methyladenine mw 2007) and for termination of interneuron migration in the developing neocortex (Bortone and Polleux, 2009). Recent evidence further suggests that the ECl of mature neurons may be subject to synaptic input-specific modulation by the voltage- and Cl−-sensitive Cl− channel ClC-2 (Földy et al., 2010). The proposed function of ClC-2 is to prevent excessive accumulation of intracellular Cl− following strong GABAergic stimulation. While crotamiton GABAergic inputs to mature neurons are mostly inhibitory, depolarizing GABAergic effects are also common (reviewed by Marty and Llano, 2005 and Kahle et al., 2008). In particular, the aforementioned

axo-axonic synapses at the axon initial segment of cortical pyramidal cells (Szabadics et al., 2006), at hippocampal mossy fiber terminals (Jang et al., 2006), and on parallel fibers of the cerebellum (Stell et al., 2007 and Pugh and Jahr, 2011) are depolarizing and excitatory due to the local absence of KCC2 (Szabadics et al., 2006). Moreover, dynamic changes in the functional expression of KCC2 can lead to pathophysiological adaptations of neural excitability. For example, chronic stress-induced downregulation of KCC2 results in a depolarizing shift of the chloride reversal potential of neurons in the paraventricular nucleus of the hypothalamus, which renders GABA inputs ineffective (Hewitt et al., 2009). This posttranslational mechanism is thought to contribute to hypothalamus-pituitary-adrenal (HPA) axis hyperactivity and to the neuropathology of stress-associated neuropsychiatric disorders. Moreover, KCC2 mRNA and/or protein expression is downregulated following focal ischemia (Jaenisch et al., 2010) and status epilepticus (Pathak et al., 2007). The sustained loss of GABAergic inhibition observed following status epilepticus has been proposed to underlie injury-induced long-term increases in seizure susceptibility.