Symptomatic and preventive effects of the novel phosphodiesterase-9 inhibitor BI 409306 in an immune-mediated model of neurodevelopmental disorders

Joseph Scarborough,Urs Meyer,Juliet Richetto,Daniele Mattei,Roberto Arban,Holger Rosenbrock,Cornelia Dorner-Ciossek,Michael Sand

doi:10.1038/s41386-021-01016-3

Abstract

BI 409306, a phosphodiesterase-9 inhibitor under development for treatment of schizophrenia and attenuated psychosis syndrome (APS), promotes synaptic plasticity and cognition. Here, we explored the effects of BI 409306 treatment in the polyriboinosinic-polyribocytidilic acid (poly[I:C])-based mouse model of maternal immune activation (MIA), which is relevant to schizophrenia and APS. In Study 1, adult offspring received BI 409306 0.2, 0.5, or 1 mg/kg or vehicle to establish an active dose. In Study 2, adult offspring received BI 409306 1 mg/kg and/or risperidone 0.025 mg/kg, risperidone 0.05 mg/kg, or vehicle, to evaluate BI 409306 as add-on to standard therapy for schizophrenia. In Study 3, offspring received BI 409306 1 mg/kg during adolescence only, or continually into adulthood to evaluate preventive effects of BI 409306. We found that BI 409306 significantly mitigated MIA-induced social interaction deficits and amphetamine-induced hyperlocomotion, but not prepulse inhibition impairments, in a dose-dependent manner (Study 1). Furthermore, BI 409306 1 mg/kg alone or in combination with risperidone 0.025 mg/kg significantly reversed social interaction deficits and attenuated amphetamine-induced hyperlocomotion in MIA offspring (Study 2). Finally, we revealed that BI 409306 1 mg/kg treatment restricted to adolescence prevented adult deficits in social interaction, whereas continued treatment into adulthood also significantly reduced amphetamine-induced hyperlocomotion (Study 3). Taken together, our findings suggest that symptomatic treatment with BI 409306 can restore social interaction deficits and dopaminergic dysfunctions in a MIA model of neurodevelopmental disruption, lending preclinical support to current clinical trials of BI 409306 in patients with schizophrenia. Moreover, BI 409306 given during adolescence has preventive effects on adult social interaction deficits in this model, supporting its use in people with APS.

Highlights

INTRODUCTION Abnormal glutamatergic neurotransmission related toN-methyl-Daspartate (NMDA) receptor hypofunction is implicated in the etiology of neuropsychiatric disorders, including schizophrenia [1,2,3]
BI 409306 has been shown to increase cyclic guanosine monophosphate (cGMP) in brain tissue and cerebrospinal fluid (CSF), promote synaptic plasticity, improve episodic memory, and reverse working memory deficits induced by acute pharmacological blockade of NMDA receptors
Since the main objective of Study 1 was to perform a dose–response study in maternal immune activation (MIA) offspring to identify the optimal dosage for our subsequent experiments (Study 2 and 3), we focused on the one-way analysis of variance (ANOVA) or RM-ANOVAs in the analysis and in the main text of this article in order to present all treatment groups in the MIA offspring

Summary

Introduction

INTRODUCTION Abnormal glutamatergic neurotransmission related toN-methyl-Daspartate (NMDA) receptor hypofunction is implicated in the etiology of neuropsychiatric disorders, including schizophrenia [1,2,3]. BI 409306 is a novel PDE9 inhibitor, a class of compounds that are thought to promote NMDA receptor-related glutamatergic transmission by elevating postsynaptic levels of cGMP in neurons [4, 5]. PDE9 inhibition with BI 409306 may provide benefits for patients with neurodevelopmental disorders by facilitating synaptic stabilization and plasticitydependent NMDA receptor function. On this basis, ongoing clinical trials are investigating the potential of BI 409306 for the prevention of relapse in patients with schizophrenia treated with antipsychotic medications (NCT03351244), and for early intervention in patients with attenuated psychosis syndrome (APS) (NCT03230097)

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