GABA is the key inhibitory neurotransmitter of the mature brain, and most synaptic inhibition is mediated by GABAA receptors. These receptors are chloride-permeable ion channels, which means that the strength of inhibition depends on the Cl– gradient across the membrane. Dysregulation of Cl– homeostasis has emerged as a key mechanism underlying several brain disorders, including autism spectrum disorders (ASDs). Blockade of the Cl– importer NKCC1, with the diuretic bumetanide, restores normal behavioral phenotypes in experimental models of ASD1 and has been shown to reduce autism childhood ratings in a randomized, controlled pilot study in children with ASD2, validating the restoration of Cl– homeostasis as a therapeutic strategy for ASDs.
Strategies focused on targeting NKCC1 are not ideal, however, as NKCC1 is not restricted to the CNS and, hence, are prone to undesirable side effects. However, the Cl- exporter, KCC2, is restricted to the CNS. Thus, the reverse strategy of enhancing KCC2 activity is a more promising approach. Yves De Koninck and Melanie Woodin aim to identify, characterize and validate novel KCC2 enhancers and evaluate their mechanisms of action.
De Koninck’s laboratory has previously developed small compounds that enhance KCC2 function, with evidence suggesting that these types of compounds operate through increasing KCC2 expression on the plasma membrane3. Further, Woodin’s laboratory has shown that KCC2 function critically depends on protein-protein interactions, including interactions with the kainate receptor subunit GluK2 and its auxiliary subunit Neto24.
De Koninck and Woodin aim to establish a more complete KCC2 protein interactome in order to systematically search for positive regulators of KCC2. The team will also determine the mechanisms by which KCC2 interacting proteins and existing KCC2 positive modulators affect KCC2 function. Successful completion of this proposal will aid in the development of novel potential therapeutic avenues for strengthening inhibition in ASD and other disorders where an imbalance in excitation/inhibition occurs.