title: An acetylcholine alpha7 positive allosteric modulator rescues a schizophrenia-associated brain endophenotype in the 15q13.3 microdeletion, encompassing CHRNA7.
abstract: The 15q13.3 microdeletion copy number variation is strongly associated with schizophrenia and epilepsy. The CHRNA7 gene, encoding nicotinic acetylcholine alpha 7 receptors (nAChA7Rs), is hypothesized to be one of the main genes in this deletion causing the neuropsychiatric phenotype. Here we used a recently developed 15q13.3 microdeletion mouse model to explore whether an established schizophrenia-associated connectivity phenotype is replicated in a murine model, and whether positive modulation of nAChA7 receptor might pharmacologically normalize the connectivity patterns. Resting-state fMRI data were acquired from male mice carrying a hemizygous 15q13.3 microdeletion (N=9) and from wild-type mice (N=9). To study the connectivity profile of 15q13.3 mice and test the effect of nAChA7 positive allosteric modulation, the 15q13.3 mice underwent two imaging sessions, one week apart, receiving a single intraperitoneal injection of either 15mg/kg Lu AF58801 or saline. The control group comprised wild-type mice treated with saline. We performed seed-based functional connectivity analysis to delineate aberrant connectivity patterns associated with the deletion (15q13.3 mice (saline treatment) versus wild-type mice (saline treatment)) and their modulation by Lu AF58801 (15q13.3 mice (Lu AF58801 treatment) versus 15q13.3 mice (saline treatment)). Compared to wild-type mice, 15q13.3 mice evidenced a predominant hyperconnectivity pattern. The main effect of Lu AF58801 was a normalization of elevated functional connectivity between prefrontal and frontal, hippocampal, striatal, thalamic and auditory regions. The strongest effects were observed in brain regions expressing nAChA7Rs, namely hippocampus, cerebral cortex and thalamus. These effects may underlie the antiepileptic, pro-cognitive and auditory gating deficit-reversal effects of nAChA7R stimulation.
authors.affiliation: Research Group Translational Imaging, Department of Neuroimaging, Central Institute of Mental Health, Medical Faculty Mannheim, University of Heidelberg, Germany. Electronic address: natalia.gass@zi-mannheim.de.
authors.forename: Natalia
authors.initials: N
authors.lastname: Gass
authors.affiliation: Research Group Translational Imaging, Department of Neuroimaging, Central Institute of Mental Health, Medical Faculty Mannheim, University of Heidelberg, Germany.
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Weber-Fahr
authors.affiliation: Research Group Translational Imaging, Department of Neuroimaging, Central Institute of Mental Health, Medical Faculty Mannheim, University of Heidelberg, Germany; Department of Psychiatry and Psychotherapy, Central Institute of Mental Health, Medical Faculty Mannheim, University of Heidelberg, Germany.
authors.forename: Alexander
authors.initials: A
authors.lastname: Sartorius
authors.affiliation: Research Group Translational Imaging, Department of Neuroimaging, Central Institute of Mental Health, Medical Faculty Mannheim, University of Heidelberg, Germany.
authors.forename: Robert
authors.initials: R
authors.lastname: Becker
authors.affiliation: H. Lundbeck A/S, Valby, Denmark.
authors.forename: Michael
authors.initials: M
authors.lastname: Didriksen
authors.affiliation: H. Lundbeck A/S, Valby, Denmark.
authors.forename: Tine Bryan
authors.initials: TB
authors.lastname: Stensbøl
authors.affiliation: H. Lundbeck A/S, Valby, Denmark.
authors.forename: Jesper Frank
authors.initials: JF
authors.lastname: Bastlund
authors.affiliation: Department of Psychiatry and Psychotherapy, Central Institute of Mental Health, Medical Faculty Mannheim, University of Heidelberg, Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: Meyer-Lindenberg
authors.affiliation: Tailored Therapeutics - Neuroscience, Eli Lilly and Company, Indianapolis, IN, USA; Department of Psychological and Brain Sciences, Indiana University, Bloomington, IN, USA; Department of Radiology and Imaging Sciences, Indiana University, Indianapolis, IN, USA.
authors.forename: Adam J
authors.initials: AJ
authors.lastname: Schwarz
mesh_terms: D000818:Animals; D001921:Brain / Q000000981:diagnostic imaging / Q000187:drug effects* / Q000378:metabolism; D001931:Brain Mapping; D018678:Cholinergic Agents / Q000494:pharmacology*; D002872:Chromosome Deletion; D025063:Chromosome Disorders / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D002884:Chromosomes, Human, Pair 15 / Q000235:genetics / Q000378:metabolism; D003521:Cyclopropanes / Q000494:pharmacology; D004195:Disease Models, Animal; D058068:Endophenotypes; D008607:Intellectual Disability / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D008279:Magnetic Resonance Imaging; D008297:Male; D008822:Mice, Transgenic; D009434:Neural Pathways / Q000000981:diagnostic imaging / Q000187:drug effects / Q000378:metabolism; D010626:Phenylethyl Alcohol / Q000031:analogs & derivatives / Q000494:pharmacology; D012146:Rest; D012559:Schizophrenia / Q000188:drug therapy* / Q000378:metabolism; D012640:Seizures / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D064569:alpha7 Nicotinic Acetylcholine Receptor / Q000235:genetics / Q000378:metabolism*
chemical_list: D018678:Cholinergic Agents; C579166:Chrna7 protein, mouse; D003521:Cyclopropanes; C000588469:Lu AF58801; D064569:alpha7 Nicotinic Acetylcholine Receptor; D010626:Phenylethyl Alcohol
keywords: 15q13.3 Microdeletion; Mouse model; Resting-state fMRI; Schizophrenia