An acetylcholine alpha7 positive allosteric modulator rescues a schizophrenia-associated brain endophenotype in the 15q13.3 microdeletion, encompassing CHRNA7

Gass, Natalia; Weber‐Fahr, Wolfgang; Sartorius, Alexander; Becker, Robert E.; Didriksen, Michael; Stensbøl, Tine B.; Bastlund, Jesper F.; Meyer‐Lindenberg, Andreas; Schwarz, Adam J.

doi:10.1016/j.euroneuro.2016.03.013

Cited by 34 publications

(20 citation statements)

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“…Clinical studies suggest treatment of schizophrenia with α7 nAChR agonists and positive allosteric modulators has resulted in improved cognition and reduced negative symptoms (Freedman 2014). Studies in rodent models of neuropsychiatric and neurodegenerative disorders have also implicated the α7 nAChR (Gass et al 2016; Lykhmus et al 2015; Papouin et al 2017; Plitman et al 2017). In addition, α7 nAChRs have been shown to regulate aggression through activation of dentate granule cells (Lewis et al 2017).…”

Section: Discussionmentioning

confidence: 99%

The α7 nicotinic acetylcholine receptors regulate hippocampal adult-neurogenesis in a sexually dimorphic fashion

Otto

Yakel

2018

Brain Struct Funct

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Disruption in cholinergic signaling has been linked to many environmental and/or pathological conditions known to modify adult neurogenesis. The α7 nAChRs are in the family of cys-loop receptor channels which have been shown to be neuroprotective in adult neurons and are thought to be critical for survival and integration of immature neurons. However, in developing neurons, poor calcium buffering may cause α7 nAChR activation to be neurotoxic. To investigate whether the α7 nAChR regulates neurogenesis in the hippocampus, we used a combination of mouse genetics and imaging to quantify neural stem cell (NSC) densities located in the dentate gyrus of adult mice. In addition, we considered whether the loss of α7 nAChRs had functional consequences on a spatial discrimination task that is thought to rely on pattern separation mechanisms. We found that the loss of α7 nAChRs resulted in increased neurogenesis in male mice only, while female mice showed increased cell divisions and intermediate progenitors but no change in neurogenesis. Knocking out the α7 nAChR from nestin+ NSCs and their progeny showed signaling in these cells contributes to regulating neurogenesis. In addition, male, but not female, mice lacking α7 nAChRs performed significantly worse in the spatial discrimination task. This task was sexually dimorphic in wild-type mice, but not in the absence of α7 nAChRs. We conclude that α7 nAChRs regulate adult neurogenesis and impact spatial discrimination function in male, but not female mice, via a mechanism involving nestin+ NSCs and their progeny.

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Section: Discussionmentioning

confidence: 99%

The α7 nicotinic acetylcholine receptors regulate hippocampal adult-neurogenesis in a sexually dimorphic fashion

Otto

Yakel

2018

Brain Struct Funct

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“…This hypothesis is indeed tempting in view of the findings implicating genetic variations within the CHRNA7 gene in the etiology of psychiatric disorders with neurodevelopmental components, especially schizophrenia [49]. Additional evidence supporting this hypothesis stems from recent mouse studies demonstrating that Lu AF58801, a nAChA7 positive allosteric modulator, is capable of mitigating altered functional brain connectivity in a hemizygous 15q13.3 microdeletion mouse model (i.e., in Df[h15q13]−/+ mice) [19]. Based on the existing evidence, however, it should be noted that CHRNA7 alone is unlikely to explain the diverse phenotype of the 15q13.3 microdeletion syndrome [16,50].…”

Section: Discussionmentioning

confidence: 99%

“…Mice with a hemizygous deletion of the orthologous region of 15q13.3 (Df[h15q13]−/+mice) are characterized with neurophysiological changes relevant to the human 15q13.3 microdeletion syndrome [16][17][18]. In addition, they show abnormalities in functional brain connectivity and impairments in sustained attention [17,19]. Some of these abnormalities are more pronounced in 15q13.3 homozygous knockout mice (i.e., in Df [h15q13]−/− mice) [20], supporting a gene-dosage dependency in the 15q13.3 microdeletion syndrome.…”

Section: Introductionmentioning

confidence: 99%

Interactive effects between hemizygous 15q13.3 microdeletion and peripubertal stress on adult behavioral functions

Giovanoli

Werge

Mortensen

et al. 2018

Neuropsychopharmacol

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15q13.3 microdeletion is one of several gene copy number variants (CNVs) conferring increased risk of psychiatric and neurological disorders. This microdeletion gives rise to a variable spectrum of pathological phenotypes, ranging from asymptomatic to severe clinical outcomes. The reasons for these varying phenotypic outcomes remain unknown. Using a mouse model of hemizygous deletion of the orthologous region of 15q13.3, the present study examined whether exposure to stressful life events might interact with hemizygous 15q13.3 microdeletion in the development of behavioral dysfunctions. We show that hemizygous 15q13.3 microdeletion alone induces only limited effects on adult behaviors, but when combined with psychological stress in pubescence (postnatal days 30-40), it impairs sensorimotor gating and increases the sensitivity to the psychostimulant drug, amphetamine, at adult age. Stress exposure in adolescence (postnatal days 50-60) did not induce similar interactions with 15q13.3 microdeletion, but led to impaired emotional learning and memory and social behavior regardless of the genetic background. The present study provides the first evidence for interactive effects between hemizygous 15q13.3 microdeletion and exposure to stressful life events, and at the same time, it emphasizes an important influence of the precise timing of postnatal stress exposure in these interactions. Our findings suggest that hemizygous 15q13.3 microdeletion can act as a "disease primer" that increases the carrier's vulnerability to the detrimental effects of peripubertal stress exposure on adult behaviors.

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Section: Functional Connectivity Mapping In Genetic Models Of Autismmentioning

confidence: 99%

“…Compared to wild-type mice, 15q13.3 mice showed widespread patterns of hyper-connectivity along the hippocampal-prefrontal axis, a network commonly affected in schizophrenic patients (Gass et al, 2016). Notably, Gass and colleagues also showed that aberrant functional connectivity could be acutely rescued by pharmacological stimulation of nicotinic acetylcholine alpha 7 receptors, in keeping with a contribution of this mechanism to the development of schizophrenia-related phenotypes in these mice (Gass et al, 2016). Although the phenotypic traits of this mouse line appear to be more closely related to schizophrenia rather than to ASD (Fejgin et al, 2014), the results of this study are important as they show that CNVs and genetic alterations with partial penetrance to ASD could produce divergent connectional phenotypes (e.g., hyper- and hypo-connectivity), suggesting a plausible contribution of genetic heterogeneity to some of the discrepant imaging findings in humans.…”

Section: Functional Connectivity Mapping In Genetic Models Of Autismmentioning

confidence: 99%

Can Mouse Imaging Studies Bring Order to Autism Connectivity Chaos?

Liska

Gozzi

2016

Front. Neurosci.

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Functional Magnetic Resonance Imaging (fMRI) has consistently highlighted impaired or aberrant functional connectivity across brain regions of autism spectrum disorder (ASD) patients. However, the manifestation and neural substrates of these alterations are highly heterogeneous and often conflicting. Moreover, their neurobiological underpinnings and etiopathological significance remain largely unknown. A deeper understanding of the complex pathophysiological cascade leading to aberrant connectivity in ASD can greatly benefit from the use of model organisms where individual pathophysiological or phenotypic components of ASD can be recreated and investigated via approaches that are either off limits or confounded by clinical heterogeneity. Despite some obvious limitations in reliably modeling the full phenotypic spectrum of a complex developmental disorder like ASD, mouse models have played a central role in advancing our basic mechanistic and molecular understanding of this syndrome. Recent progress in mouse brain connectivity mapping via resting-state fMRI (rsfMRI) offers the opportunity to generate and test mechanistic hypotheses about the elusive origin and significance of connectional aberrations observed in autism. Here we discuss recent progress toward this goal, and illustrate initial examples of how the approach can be employed to establish causal links between ASD-related mutations, developmental processes, and brain connectional architecture. As the spectrum of genetic and pathophysiological components of ASD modeled in the mouse is rapidly expanding, the use of rsfMRI can advance our mechanistic understanding of the origin and significance of the connectional alterations associated with autism, and their heterogeneous expression across patient cohorts.

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An acetylcholine alpha7 positive allosteric modulator rescues a schizophrenia-associated brain endophenotype in the 15q13.3 microdeletion, encompassing CHRNA7

Cited by 34 publications

References 50 publications

The α7 nicotinic acetylcholine receptors regulate hippocampal adult-neurogenesis in a sexually dimorphic fashion

The α7 nicotinic acetylcholine receptors regulate hippocampal adult-neurogenesis in a sexually dimorphic fashion

Interactive effects between hemizygous 15q13.3 microdeletion and peripubertal stress on adult behavioral functions

Can Mouse Imaging Studies Bring Order to Autism Connectivity Chaos?

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