Deciphering the Roles of Kainate Receptors in Developing CNS Circuits

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SUMMARY Kainate receptor signaling is required for the appropriate development of the central nervous system. Children with de novo loss-of-function or missense mutations exhibit intellectual disability and other severe developmental phenotypes. Why this occurs is unknown, in part because we do not have a clear understanding of how aberrant kainate receptor function disrupts neural development. The objectives of this project are to (i) gain insight into normal neurodevelopmental roles played by kainate receptors and (ii) to determine the nature of circuit and behavioral disruptions when kainate receptor signaling is aberrant or completely lost in mouse models. We will pursue these objectives using comparative studies in mice that model known genetic variants causative for human disorders. These include a new mouse line generated in the Swanson laboratory, GluK2(A657T), that models a human de novo missense mutation in the Grik2 gene that causes intellectual disability (ID) and ataxia, as well as mice which model Grik2 haploinsufficiency which is associated with developmental delay and ID in human populations. The Contractor, Swanson and Savas laboratories will use these mice to test the hypotheses that kainate receptors establish an appropriate balance between excitation and inhibition in developing hippocampal circuits, are required for correct development of synapses, and regulate intrinsic excitability in the CNS. In the first Specific Aim, we will determine how missense or loss-of-function mutations in Grik2 alter synaptic connectivity, function, morphology and expression of the synaptic and non-synaptic proteome in brain regions associated with altered behaviors. In the second Specific Aim, we determine how intrinsic excitability is altered in kainate receptor mutant mice. In the third Specific Aim, we will carry out behavioral studies on kainate receptor mutant mice to determine the expanse of cognitive, social, habitual, and motor dysfunction, which will also inform the physiological studies in Aims 1 and 2. We anticipate these studies will reveal some of the underlying circuit disruptions that give rise to human cognitive and motor phenotypes. We therefore aim to develop a comprehensive and integrated understanding of the importance of kainate receptor signaling to establishment of appropriate neuronal function in the CNS and establish how aberrant signaling leads to maladaptive development and behaviors in mice that are correlates of the core symptoms of human developmental disorders.