Obsessive-compulsive disorder (OCD) is a common psychiatric disorder affecting 2-3 % of the population. The causes for these disorders are not well understood, as such, effective treatments are lacking. In preliminary studies I have found that knockout of one class of the glutamate receptor family, the kainate receptors leads to OCD-like behaviors in mice. My working hypothesis is that deleting KAR impairs corticostriatal synaptic transmission, leading to robust OCD-like behavior in mice. In light of this, a better understanding of KAR's role in corticostriatal synaptic transmission will provide key insight into pathogenesis of OCD. In the proposed experiments, I will combine electrophysiological recording and two-photon laser- scanning microscopy (2PLSM), complemented with mechanistic biochemical studies to determine the function and association of synaptic kainate receptors in corticostriatal synapses.
In Specific Aim 1, I will determine the contribution of kainate receptors to corticostriatal synapses. Kainate receptors can be presynaptic modulators of transmitter release or postsynaptic mediators of synaptic transmission. I will perform electrophysiological recording from spiny neurons to determine whether postsynaptic kainate receptors contribute to synaptic integration. In the second part of this aim I will determine whether presynaptic kainate receptors modulate neurotransmitter release at corticostriatal synapses. For this purpose I will make use of a novel presynaptic activity sensor (Sph4X) that we recently developed to interrogate presynaptic activity in kainate receptor knockout mice. Viral mediated transduction of cortical neurons followed by two-photon laser scanning microscopy (2PLSM) of presynaptic terminals in striatum will be used to determine whether kainate receptors modulate corticostriatal synapses.
In Specific Aim 2, I will determine whether kainate receptor scaffolding protein interactions in the striatum contribute corticostriatal synaptic function. A previous study has demonstrated that loss of a scaffolding protein SAPAP3 in the striatum results in OCD like phenotype similar to that in kainate receptor knockout mice. I hypothesize that kainate receptors are stabilized at striatal synapses through an interaction with SAPAP proteins. In preliminary findings I demonstrate that kainate receptor subunits co- immunoprecipitate with SAPAP proteins from brain lysate suggesting they are in the same signaling complex. In this aim I will determine how kainate receptors interact with SAPAP and whether this interaction is important for functions of kainate receptors at striatal synapses. In summary, these studies are designed to elucidate the important roles of kainate receptors in regulating synaptic transmission at corticostriatal synapses. The use of novel animal models will provide important insight into the roles of kainate receptors in pathogenesis of OCD.
Obsessive-compulsive disorder (OCD) is a common psychiatric disorder affecting 2~3 % of total populations. In my preliminary studies I have discovered robust OCD-like behaviors in mutant mice lacking kainate receptor genes. In this proposal I will study the mechanisms of how these kainate receptors are involved in the development of OCD disorder.
|Marshall, John J; Xu, Jian; Contractor, Anis (2018) Kainate Receptors Inhibit Glutamate Release Via Mobilization of Endocannabinoids in Striatal Direct Pathway Spiny Projection Neurons. J Neurosci 38:3901-3910|
|Xu, Jian; Marshall, John J; Fernandes, Herman B et al. (2017) Complete Disruption of the Kainate Receptor Gene Family Results in Corticostriatal Dysfunction in Mice. Cell Rep 18:1848-1857|
|Xu, Jian; Antion, Marcia D; Nomura, Toshihiro et al. (2014) Hippocampal metaplasticity is required for the formation of temporal associative memories. J Neurosci 34:16762-73|
|Xu, Jian; Zhu, Yongling; Kraniotis, Stephen et al. (2013) Potentiating mGluR5 function with a positive allosteric modulator enhances adaptive learning. Learn Mem 20:438-45|