Striatum; OCD; Sapap3; Fiber photometry; Synaptic plasticity; Obsessive-compulsive disorder; Genetic mouse model; Optogenetics
Hadjas Lotfi C., Schartner Michael M., Cand Jennifer, Creed Meaghan C., Pascoli Vincent, Lüscher Christian, Simmler Linda D. (2020), Projection-specific deficits in synaptic transmission in adult Sapap3-knockout mice, in Neuropsychopharmacology
Hadjas Lotfi C., Lüscher Christian, Simmler Linda D. (2019), Aberrant habit formation in the Sapap3-knockout mouse model of obsessive-compulsive disorder, in Scientific Reports
, 9(1), 12061-12061.
Simmler Linda D., Ozawa Takaaki (2019), Neural circuits in goal-directed and habitual behavior: Implications for circuit dysfunction in obsessive-compulsive disorder, in Neurochemistry International
, 129, 104464-104464.
Simmler Linda D., Blakely Randy D. (2019), The SERT Met172 Mouse: An Engineered Model To Elucidate the Contributions of Serotonin Signaling to Cocaine Action, in ACS Chemical Neuroscience
, 10(7), 3053-3060.
Simmler Linda D. (2018), Monoamine Transporter and Receptor Interaction Profiles of Synthetic Cathinones, in Zawilska Jolanta (ed.), Springer International Publishing, Cham, 97.
Simmler Linda D., Liechti Matthias E. (2018), Pharmacology of MDMA- and Amphetamine-Like New Psychoactive Substances, Springer Berlin Heidelberg, Berlin, Heidelberg, NA.
Background: Obsessive-compulsive disorder (OCD) is a potentially debilitating psychiatric condition, manifested by obsessive thoughts and anxiety, along with behavior (e.g., excessive hand-washing) arising from aberrant formation of habits. High failure rates of pharmacological OCD treatments are typical. The development of improved, mechanism-based therapy is hampered by a deficient understanding of the pathophysiology of OCD. Imaging studies consistently implicated the cortico-striatal-thalamic-cortical (CSTC) circuit in OCD, but on a cellular and molecular level, pathological plasticity underlying abnormal CSTC circuit function is not well understood. We propose to employ a genetic mouse model of OCD to study circuit-based pathological plasticity. The Sapap3-knock-out (Sapap3-KO) mouse model exhibits OCD-like grooming and anxiety behaviors as well as striatal synaptic pathology. Using Sapap3-KO mice allows us to link plasticity to OCD-like habitual behavior. We further propose to investigate if and how normal plasticity in OCD-like mice can be restored by glutamatergic pharmacological substances, which have shown efficacy in alleviating obsessive symptoms in OCD patients, but the underlying mechanisms are not known. A potentiation of pathologically weak synaptic CSTC connections via AMPA-receptor protein synthesis is conceivable. Hypothesis: We hypothesize that pathological plasticity in the Sapap3-KO mouse model of OCD causes pathological neuronal signaling in the CSTC circuit, underlying inappropriate habitual behavior. Targeting the glutamate system pharmacologically could be effective to normalize pathological plasticity and consequently in restoring normal habit behavior. Aims: We aim to a) characterize pathological striatal plasticity from cortical inputs, and identify the major mechanism causing plasticity due to the knock-out of Sapap3, b) elucidate in vivo neuronal activity pattern during behavioral testing of habitual lever-pressing behavior in Sapap3-KO mice, and c) test the potential of glutamatergic agents to reverse CSTC circuit pathology on the level of neuronal activity in vivo and cellular function ex vivo. Experimental approach: We will use mice with a constitutive knock-out of Sapap3 and wild-type littermates as control, crossed with Drd1-, Drd2-, and Pvalb-Cre-lines for cell-specific viral gene transfer required for optogenetic and photometry techniques. Whole-cell recording in brain slices under consideration of input-specificity and cell identity will be used to elaborate pathological plasticity of Sapap3-KO mice. Operant tasks that reflect habit formation will serve as representative OCD-like behavior. During operant tasks, we will record in vivo activity of striatal neurons using fiber photometry, which is based on cell type-specific expression of a calcium indicator. Finally, we will test efficacy of pharmacological treatment to reverse pathological plasticity and neuronal activity patterns that underlie excessive habit formation. Relevance: A global understanding of CSTC circuit dysfunction in pre-clinical OCD-models will guide advancements in OCD treatment, with particular benefits for patients that experience insufficient response to standard OCD medication. Exploring the potential of glutamatergic agents to reverse pathological plasticity could enable novel strategies for mechanism-based pharmacological OCD treatment with improved efficacy and low unwanted side effects.