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Mechanism-Based Reversal of Pathological Synaptic Plasticity in Obsessive-Compulsive Disorder as Strategy for Pharmacological Treatment

Applicant Simmler Linda
Number 174178
Funding scheme Ambizione
Research institution Dépt des Neurosciences Fondamentales Faculté de Médecine Université de Genève
Institution of higher education University of Geneva - GE
Main discipline Neurophysiology and Brain Research
Start/End 01.10.2017 - 30.09.2021
Approved amount 787'052.00
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All Disciplines (2)

Discipline
Neurophysiology and Brain Research
Pharmacology, Pharmacy

Keywords (8)

Striatum; OCD; Sapap3; Fiber photometry; Synaptic plasticity; Obsessive-compulsive disorder; Genetic mouse model; Optogenetics

Lay Summary (German)

Lead
Zwangsstörung ist eine relativ häufige psychische Erkrankung, die mit den momentan verfügbaren Medikamenten schlecht behandelbar ist. Ein besseres Verständnis der synaptischen Veränderungen in spezifischen Hirnregionen, welche Symptome der Zwangsstörung hervorrufen, ist zwingend, um bessere pharmakologische Therapien zu entwickeln.
Lay summary

Inhalt und Ziele des Forschungsprojekts

Ziel dieses Projektes ist es, im Mausmodell die Pathophysiologie der Zwangsstörung auf zellulärer Ebene besser zu verstehen und diese direkt mit Verhalten, das vergleichbar mit Symptomen der Zwangsstörung sind, in Verbindung zu setzten. Mit neurowissenschaftlichen Methoden wie Elektrophysiologie, Optogenetik und in-vivo Bestimmung der neuronalen Aktivitäten können neuronale Defizite im Maushirn mechanistisch erfasst werden. Aufbauend auf einem verbesserten Verständnis der Pathophysiologie werden wir pharmakologische Therapien, welche mechanistisch antagonistisch wirken könnten, in Verhaltenstests bei Mäusen erproben.  Wir werden dabei glutamaterge Substanzen, welche in der Klinik jetzt schon als schnellwirksame Antidepressiva angewendet werden, auf die Wirksamkeit bei Zwangsstörungen im Mausmodell testen.

Wissenschaftlicher und gesellschaftlicher Kontext des Forschungsprojekts

Zwangsstörung ist eine psychische Erkrankung die in schweren Fällen zu erheblichen Beeinträchtigungen im Alltag führen kann. Wobei Verhaltenstherapien und momentan verfügbare Psychopharmaka nur bedingt wirksam sind, war in den letzten Jahren die tiefe Hirnstimulation („deep brain stimulation“; DBS) als erfolgreiche Alternative aufgekommen. DBS erfordert jedoch ein operativ eingeführte und permanent implantierte Stimulationselektrode im Gehirn. Für viele Patienten ist DBS deshalb die Ultima Ratio. Da medikamentöse Therapien nach wie vor zugänglicher sind, möchten wir mit dem vorliegenden Projekt zur verbesserten pharmakologischen Therapie bei Zwangsstörung beitragen.

Direct link to Lay Summary Last update: 21.08.2017

Responsible applicant and co-applicants

Employees

Publications

Publication
Projection-specific deficits in synaptic transmission in adult Sapap3-knockout mice
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, 1.
Aberrant habit formation in the Sapap3-knockout mouse model of obsessive-compulsive disorder
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.
Neural circuits in goal-directed and habitual behavior: Implications for circuit dysfunction in obsessive-compulsive disorder
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.
The SERT Met172 Mouse: An Engineered Model To Elucidate the Contributions of Serotonin Signaling to Cocaine Action
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.
Monoamine Transporter and Receptor Interaction Profiles of Synthetic Cathinones
Simmler Linda D. (2018), Monoamine Transporter and Receptor Interaction Profiles of Synthetic Cathinones, in Zawilska Jolanta (ed.), Springer International Publishing, Cham, 97.
Pharmacology of MDMA- and Amphetamine-Like New Psychoactive Substances
Simmler Linda D., Liechti Matthias E. (2018), Pharmacology of MDMA- and Amphetamine-Like New Psychoactive Substances, Springer Berlin Heidelberg, Berlin, Heidelberg, NA.

Scientific events

Active participation

Title Type of contribution Title of article or contribution Date Place Persons involved
7th European Synapse Meeting Poster Acute reinforcement, but little adaptive behavior with ketamine 02.09.2019 Lausanne, Switzerland Simmler Linda;
12. Swiss Pharma Science Day Talk given at a conference Acute Reinforcement, But Little Adaptive Behavior With Ketamine 28.08.2019 Bern, Switzerland Simmler Linda;
optoDBS meeting 2019 Poster Aberrant habit formation in the Sapap3-KO mouse model of OCD 20.06.2019 Geneva, Switzerland Hadjas Lotfi; Simmler Linda;
15th Swiss meeting on cellular and molecular neurobiology of mental disease Talk given at a conference Acute reinforcement, but little adaptive behavior with ketamine 23.05.2019 Giessbach, Switzerland Simmler Linda;
NCCR-Synapsy Annual Meeting Poster Aberrant habit formation in the Sapap3-KO mouse model of OCD 21.03.2019 Villars, Switzerland Simmler Linda;
Annual Meeting of the Swiss Society for Neuroscience Poster Behavioral Hallmarks and Altered Synaptic Transmission in the Sapap3-/- Mouse Model of Obsessive-Compulsive Disorder 01.02.2019 Genève, Switzerland Hadjas Lotfi;
11th FENS Forum of Neuroscience Poster Behavioral phenotypes and input-specific synaptic plasticity in the Sapap3-KO mouse model of obsessive-compulsive disorder 07.07.2018 Berlin, Germany Simmler Linda;
14th Swiss meeting on cellular and molecular neurobiology of mental disease Talk given at a conference Behavior and input-specific synaptic plasticity assessed in the Sapap3-/- mouse model of obsessive-compulsive disorder 24.05.2018 Giessbach, Switzerland Simmler Linda;


Awards

Title Year
Poster Award 2019

Abstract

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.
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