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Spironolactone alleviates schizophrenia-related reversal learning in Tcf4 transgenic mice subjected to social defeat
Marius Stephan1,2, Jonathan Schoeller1, Florian J Raabe1,2
1Department of Psychiatry and Psychotherapy, Laboratory of Molecular Neurobiology, University Hospital, LMU Munich, Munich, Germany.
Abstract:
Cognitive deficits are a hallmark of schizophrenia, for which no convincing pharmacological treatment option is currently available. Here, we tested spironolactone as a repurposed compound in Tcf4 transgenic mice subjected to psychosocial stress. In this '2-hit' gene by environment mouse (GxE) model, the animals showed schizophrenia-related cognitive deficits. We had previously shown that spironolactone ameliorates working memory deficits and hyperactivity in a mouse model of cortical excitatory/inhibitory (E/I) dysbalance caused by an overactive NRG1-ERBB4 signaling pathway. In an add-on clinical study design, we used spironolactone as adjuvant medication to the standard antipsychotic drug aripiprazole. We characterized the compound effects using our previously established Platform for Systematic Semi-Automated Behavioral and Cognitive Profiling (PsyCoP). PsyCoP is a widely applicable analysis pipeline based on the Research Domain Criteria (RDoC) framework aiming at facilitating translation into the clinic. In addition, we use dimensional reduction to analyze and visualize overall treatment effect profiles. We found that spironolactone and aripiprazole improve deficits of several cognitive domains in Tcf4tg x SD mice but partially interfere with each other's effect in the combination therapy. A similar interaction was detected for the modulation of novelty-induced activity. In addition to its strong activity-dampening effects, we found an increase in negative valence measures as a side effect of aripiprazole treatment in mice. We suggest that repurposed drug candidates should first be tested in an adequate preclinical setting before initiating clinical trials. In addition, a more specific and effective NRG1-ERBB4 pathway inhibitor or more potent E/I balancing drug might enhance the ameliorating effect on cognition even further.
Insights
Spironolactone and aripiprazole improve cognitive deficits in a schizophrenia mouse model. However, combination therapy showed interference, highlighting the need for preclinical testing of repurposed drugs for schizophrenia treatment.
Area of Science:
- Neuroscience
- Pharmacology
- Genetics
Background:
- Schizophrenia is characterized by cognitive deficits with limited treatment options.
- A '2-hit' gene by environment (GxE) mouse model using Tcf4 transgenic mice and psychosocial stress exhibits schizophrenia-related cognitive impairments.
- Spironolactone has previously shown efficacy in ameliorating cognitive deficits and hyperactivity in a mouse model of cortical excitatory/inhibitory (E/I) dysbalance.
Purpose of the Study:
- To evaluate spironolactone as a repurposed drug for schizophrenia-related cognitive deficits in a Tcf4 transgenic mouse model.
- To assess the effects of spironolactone as an adjuvant to aripiprazole in this preclinical model.
- To characterize treatment effects using the Platform for Systematic Semi-Automated Behavioral and Cognitive Profiling (PsyCoP) based on the Research Domain Criteria (RDoC) framework.
Main Methods:
- Utilized a '2-hit' gene by environment (GxE) mouse model (Tcf4 transgenic mice subjected to psychosocial stress).
- Administered spironolactone alone and in combination with aripiprazole.
- Employed the Platform for Systematic Semi-Automated Behavioral and Cognitive Profiling (PsyCoP) for behavioral and cognitive assessment.
- Applied dimensional reduction techniques for analyzing treatment effect profiles.
Main Results:
- Both spironolactone and aripiprazole improved cognitive deficits in multiple domains in the Tcf4tg x SD mice.
- Combination therapy revealed partial interference between spironolactone and aripiprazole effects on cognition and novelty-induced activity.
- Aripiprazole treatment exhibited side effects, including increased negative valence measures, in addition to activity-dampening effects.
Conclusions:
- Repurposed drug candidates like spironolactone show potential for treating schizophrenia-related cognitive deficits.
- Preclinical testing is crucial before initiating clinical trials for repurposed medications.
- Further research into specific NRG1-ERBB4 pathway inhibitors or more potent E/I balancing drugs may offer enhanced cognitive benefits.
