In addition, ALK inhibitor Wnt-5a treatment reduced the pool of previously surface biotinylated and internalized GABAARs, suggesting that increased clustering of GABAARs reflected enhanced recycling of endocytosed receptors. In support of this mechanism, treatment of neurons with a Wnt-5a-mimicking peptide (Foxy-5) that specifically activates noncanonical Wnt pathways replicated the Wnt-5a effect on GABAAR clustering. Moreover, cotreatment with Foxy-5 and pathway-specific pharmacological inhibitors allowed the conclusion that Wnt-5A-induced clustering of GABAARs

involved the noncanonical Wnt/Ca2+ pathway and CaMKII. The CaMKII targets that are phosphorylated in response to Wnt-5a have so far not been determined. In addition to the Wnt/Ca2+ pathway the canonical Wnt pathway is strongly implicated in the regulation of GABAergic inhibition by the aforementioned effects of Li+ and GSK3β on the stability and postsynaptic clustering of gephyrin (Tyagarajan et al., 2011). However, in apparent conflict with this study, the canonical Wnt ligand Wnt-7A and Li+ had no significant effect on GABAAR clustering in the study by Cuitino et al. (2010). There has been remarkable progress in understanding the mechanisms that regulate GABAergic transmission. Dynamic changes Selleckchem Afatinib in GABAAR trafficking

represent prevalent forms of GABAergic neural plasticity, although changes in subunit gene expression, Cl− reversal potential, and GABA release are also important, especially under pathological conditions. GABAAR-associated proteins and signaling factors involved in GABAAR trafficking are shared with other signal transduction pathways, thereby allowing for complex interactions among multiple neurotransmitter and signaling systems. Developmental imbalances between neural excitation and inhibition are broadly implicated in the etiology of the most prevalent neuropsychiatric disorders. Such imbalances may be further amplified by trafficking deficits in GABAARs, as suggested by activity and anoxia-induced loss of postsynaptic GABAARs (Mielke and Wang, 2005, Terunuma et al., 2008 and Arancibia-Cárcamo et al., 2009). PD184352 (CI-1040) Indeed, deficits in GABAergic transmission may

be central to the etiology of neuropsychiatric disorders such as major depressive disorder (Luscher et al., 2011), bipolar disorder (Craddock et al., 2010), and schizophrenia (Charych et al., 2009). Conversely, the cell surface trafficking and synaptic accumulation of GABAARs is modulated by Wnt pathway kinases (GSK3β, Akt) that are central to the therapeutic action of mood stabilizing and antidepressant drugs (Logan and Nusse, 2004, Okamoto et al., 2010 and Tyagarajan et al., 2011). Further progress in understanding of GABAAR trafficking mechanisms should provide better mechanistic insights into these disorders and facilitate the development of more effective drug therapies. Despite the recent progress, diverse aspects of GABAAR trafficking remain poorly understood.