GABAA receptors are Cl? permeable ion channels that mediate hyperpolarizing fast synaptic inhibition in the adult brain, while in immature developing neurons GABAA receptors depolarize and excite neurons. This shift in the signaling of GABAA receptors is due to the postnatal increase in the activity of KCC2, the neuron-specific K+/Cl- co-transporter. KCC2 is the major protein mechanism that allows neurons to pump Cl? out of the cell. In rodents KCC2 expression is evident at birth and increases substantially during the critical periods of early brain development between postnatal days 7 and 14. Deficits in KCC2 activity in humans lead to epilepsy, and are strongly implicated in chronic pain and developmental disorders such as Fragile X and Rett syndromes. Therefore, understanding the mechanisms by which neurons determine the proper postnatal increase of KCC2 activity and its maintenance in adults is clinically significant. KCC2 function is dynamically controlled by signals within neurons that can rapidly and reversibly modify its structure. Modification of KCC2's structure in one region increases its activity, while modification of KCC2's structure in another region decreases its activity. Our overarching hypothesis is that the correct balance between these opposing modifications contributes to the proper early postnatal development and adult maintenance of synaptic inhibition in the brain. To address this issue we have created two new genetic tools that can prevent the modification of KCC2's structure. Importantly, one of the genetic tools is the first of its kind to allow scientists to increase the function of KCC2, and so our proposal constitutes the first test of the theory which states that increasing KCC2 function can be utilized as a therapy. To date, no medications exist that can directly and rapidly increase the function of KCC2.
The aims of our proposal are threefold: 1) demonstrate that preventing the modification of KCC2's structure is critical during early brain development; 2) examine the mechanisms by which disease causing factors influence the structure of KCC2 both in immature and more mature neurons; and 3) demonstrate that increasing the function of KCC2 can reduce the likelihood and severity of epileptic seizures. Our study will provide new insights on how KCC2 structure and function is controlled under normal conditions and during disease states. This information may aid in the development of new and improved treatments to alleviate the burdens of a range of neurological disorders.
Several neurological disorders in children and adults are due to deficits in the ability of the brain to constrain hyperactivity. Our proposal focuses on a critical protein, called KCC2, which loses its function in severe neurological disorders. Here we examine a new way in which to rescue KCC2 function as a possible therapeutic strategy.
| Hines, Rochelle M; Maric, Hans Michael; Hines, Dustin J et al. (2018) Developmental seizures and mortality result from reducing GABAA receptor ?2-subunit interaction with collybistin. Nat Commun 9:3130 |
| Moore, Yvonne E; Deeb, Tarek Z; Chadchankar, Heramb et al. (2018) Potentiating KCC2 activity is sufficient to limit the onset and severity of seizures. Proc Natl Acad Sci U S A 115:10166-10171 |
