The dorsolateral striatum integrates convergent cortical and thalamic input to control action initiation and termination Multiple disorders including obsessive compulsive disorder (OCD), autism spectrum disorders (ASDs), and Tourette syndrome have altered function or maladaptive rearrangements of triatal circuits, resulting in aberrant perseverative and repetitive behaviors. The spiny projection neurons (SPNs) make up approximately 90% of all the neurons in the striatum and are strictly divided by their incorporation and contribution to the direct pathway (important for action initiation) and the indirect pathway (involved in action termination In particular, two glutamate receptor types, Group 1 metabotropic glutamate receptors (mGluRs) and kainate receptors (KARs) are important in regulating activity of both the direct pathway SPNs (dSPNs) and indirect pathway neurons (iSPNs). Each of these receptors have multiple overlapping cellular functions, yet it remains unclear how each receptor type contributes precisely to establishing and modulating synapses, and affecting excitability of SPNs in the dorsolateral striatum. We have developed novel mice in which each of these receptors are ablated conditionally in either dSPN or iSPNs. These mice demonstrate interesting behavioral phenotypes that suggest divergent and dichotomous roles for each glutamate receptor type in the striatum. In this proposal we will take a comprehensive approach to map the cellular to circuit function of mGluRs and KARs, and determine how each of them has distinct roles in regulating striatal output. The goal is to determine how each of the receptor types regulates synaptic and intrinsic properties of the SPNs, and how contribute to the balanced output of this circuit that is vital to appropriate behavioral actions. Thus, in the first aim we will determine the cellular roles of mGluRs and KARs in each of the SPN types. In the second aim we will determine how each of the glutamate receptor types contributes to the balanced activity of the striatal circuit. Finally, in the third aim we will use in vivo imaging of SPN activity during the initiation of motor and habitual actions to determine whether imbalanced SPN function is evident during aberrant and maladaptive behaviors when glutamate receptors are ablated in SPNs. Together these studies will take a comprehensive and integrative approach to determine the cellular and circuit roles played by glutamate receptors in regulating striatal circuits, and will inform us about how these receptors contribute to disorders with maladaptive and compulsive behaviors.

Public Health Relevance

The dorsolateral striatum plays an important role in action initiation and termination, and disorders in which striatal activity is disrupted, such as obsessive compulsive disorder, lead to inappropriate and maladaptive repetitive and perseverative behaviors. Glutamate-gated neurotransmitter receptors are central to synaptic signaling and plasticity in the striatum, and determining how they regulate striatal circuits is critical to understanding the pathophysiology of striatal disorders. Using gene targeted mice we will determine how glutamate receptors modulate striatal circuits and ultimately affect habitual and compulsive behavior.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project (R01)
Project #
5R01MH099114-07
Application #
9649250
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Kim, Douglas Sun-IL
Project Start
2012-09-17
Project End
2023-01-31
Budget Start
2019-02-01
Budget End
2020-01-31
Support Year
7
Fiscal Year
2019
Total Cost
Indirect Cost
Name
Northwestern University at Chicago
Department
Physiology
Type
Schools of Medicine
DUNS #
005436803
City
Chicago
State
IL
Country
United States
Zip Code
60611
Banala, Sambashiva; Arvin, Matthew C; Bannon, Nicholas M et al. (2018) Photoactivatable drugs for nicotinic optopharmacology. Nat Methods 15:347-350
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
Nomura, Toshihiro; Musial, Timothy F; Marshall, John J et al. (2017) Delayed Maturation of Fast-Spiking Interneurons Is Rectified by Activation of the TrkB Receptor in the Mouse Model of Fragile X Syndrome. J Neurosci 37:11298-11310
Straub, Christoph; Noam, Yoav; Nomura, Toshihiro et al. (2016) Distinct Subunit Domains Govern Synaptic Stability and Specificity of the Kainate Receptor. Cell Rep 16:531-544
Nomura, Toshihiro; Oyamada, Yoshihiro; Fernandes, Herman B et al. (2016) Subchronic phencyclidine treatment in adult mice increases GABAergic transmission and LTP threshold in the hippocampus. Neuropharmacology 100:90-7
Koranda, Jessica L; Krok, Anne C; Xu, Jian et al. (2016) Chronic Nicotine Mitigates Aberrant Inhibitory Motor Learning Induced by Motor Experience under Dopamine Deficiency. J Neurosci 36:5228-40
Fernandes, Herman B; Riordan, Sean; Nomura, Toshihiro et al. (2015) Epac2 Mediates cAMP-Dependent Potentiation of Neurotransmission in the Hippocampus. J Neurosci 35:6544-53
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
Contractor, Anis (2013) Broadening roles for FMRP: big news for big potassium (BK) channels. Neuron 77:601-3

Showing the most recent 10 out of 11 publications