Selective overexpression of Comt in prefrontal cortex rescues schizophrenia-like phenotypes in a mouse model of 22q11 deletion syndrome

Kimoto, Sohei; Muraki, Kazue; Toritsuka, Michihiro; Mugikura, S; Kajiwara, Kagemasa; Kishimoto, Toshifumi; Illingworth, Elizabeth; Tanigaki, Kenji

doi:10.1038/tp.2012.70

Cited by 39 publications

(21 citation statements)

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“…Similar to the Df1/+ mouse, 34 we found that Df(h22q11)/+ mice displayed increased locomotor activity in response to the NMDAr antagonists PCP and ketamine. Interestingly, the effect was age-dependent and only was observed after puberty (9-but not 7-week-old animals).…”

Section: Discussionmentioning

confidence: 50%

Persistent gating deficit and increased sensitivity to NMDA receptor antagonism after puberty in a new mouse model of the human 22q11.2 microdeletion syndrome: a study in male mice

Didriksen

Fejgin

Nilsson

et al. 2017

JPN

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IntroductionThe 22q11.2 hemizygous microdeletion confers very high risk for neurodevelopmental disorders, including autism and schizophrenia (22q11.2 deletion syndrome [22q11.2DS]). The estimated prevalence is approximately 1 in 2000.1 The International Consortium on Brain and Behaviour in 22q11.2 has recently reported the cumulated prevalence of schizophrenia to be 24% in adolescence and 41% in adulthood.2 Studies of patients with schizophrenia find that 22q11.2 deletion accounts for approximately 0.3% of the cases. Despite massive efforts there is still no coherent understanding of the etiology of schizophrenia -a highly heritable heterogeneous disorder with strong environmental influence. 4,5 Several neurotransmitters are implicated in the disorder: glutamate, 6 γ-aminobutyric acid (GABA), 7 dopamine (DA) 8 and acetylcholine signalling 9 have all been highlighted in the disease etiology and manifestation. The cognitive impairment and negative symptomatology have been related to dysfunction in regulation of glutamate-GABA transmission leading to excitatory-inhibitory imbalances.7 Like in individuals with schizophrenia, 10,11 cognition 12 and information processing is disrupted in children with 22q11.2 deletion, in whom schizophrenia has not (yet) developed.13,14 Given the highly increased risk for schizophrenia and the phenotypic overlap between schizophrenia and the 22q11.2DS, studying the consequence of the 22q11.2 deletion provides a unique opportunity to add to the understanding of the Background: The hemizygous 22q11.2 microdeletion is a common copy number variant in humans. The deletion confers high risk for neuro developmental disorders, including autism and schizophrenia. Up to 41% of deletion carriers experience psychotic symptoms. Methods: We present a new mouse model (Df(h22q11)/+) of the deletion syndrome (22q11.2DS) and report on, to our knowledge, the most comprehensive study undertaken to date in 22q11.2DS models. The study was conducted in male mice. Results: We found elevated postpubertal N-methyl-d-aspartate (NMDA) receptor antagonist-induced hyperlocomotion, age-independent prepulse inhibition (PPI) deficits and increased acoustic startle response (ASR). The PPI deficit and increased ASR were resistant to antipsychotic treatment. The PPI deficit was not a consequence of impaired hearing measured by auditory brain stem responses. The Df(h22q11)/+ mice also displayed increased amplitude of loudness-dependent auditory evoked potentials. Prefrontal cortex and dorsal striatal elevations of the dopamine metabolite DOPAC and increased dorsal striatal expression of the AMPA receptor subunit GluR1 was found. The Df(h22q11)/+ mice did not deviate from wild-type mice in a wide range of other behavioural and biochemical assays. Limitations: The 22q11.2 microdeletion has incomplete penetrance in humans, and the severity of disease depends on the complete genetic makeup in concert with environmental factors. In order to obtain more marked phenotypes reflecting the severe conditions related to 22q11.2DS it...

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Section: Discussionmentioning

confidence: 50%

Persistent gating deficit and increased sensitivity to NMDA receptor antagonism after puberty in a new mouse model of the human 22q11.2 microdeletion syndrome: a study in male mice

Didriksen

Fejgin

Nilsson

et al. 2017

JPN

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“…Its gene has several polymorphisms: Val/Val homozygotes have a PFC enzyme activity 40% higher than Met/Met homozygotes, therefore have lower dopamine levels in this region (Chen et al, 2004). The most common polymorphism, a Met substitution at codon 158, reduces the activity of COMT enzyme to one-quarter, resulting in a higher dopamine level in PFC (Kimoto et al, 2012;Lachman et al, 1996). Val(158)Met polymorphism (also known as rs4680) has therefore been considered a cognitive function modulator (Bearden et al, 2004;Farrell, Tunbridge, Braeutigam, & Harrison, 2012).…”

Section: S Oc I Al Cog Ni Ti On R El a Ti Onsh I P S Wi Th Sp E Ci mentioning

confidence: 99%

Genetic and clinical features of social cognition in 22q11.2 deletion syndrome

Lattanzi

Buzzanca

Frascarelli

et al. 2018

J of Neuroscience Research

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22q11.2 deletion syndrome (22q11.2 DS) is widely known as one of the most compelling genetic models of schizophrenia so far, being almost 40% of the carriers affected by psychotic symptoms. Moreover, most of these subjects also show impairment in social cognition, which is a comprehensive array of function that guides social interaction with the others, leading as well to the acquisition of new cognitive and social skills. In the last decade researchers have argued whether social cognition dysfunctions could be underlined by specific genetic alterations, and whether these are linked to specific clinical features. Some valid candidate genes are RTN4R, that encodes a protein which inhibits axonal sprouting, DGCR8, crucial in mRNA processing, or catechol-O-methyltransferase (COMT) and proline oxydase 1 (PRODH), involved in catecholamine metabolism in frontal cortex. This is the first article to address the topic of social cognition in 22q11.2 DS from a wide perspective, with a highlight on its genetic characteristics. We will provide a narrative review of the most recent findings and we will point out new directions on this research path, in order to achieve an effective characterization of the neurobiological system underlying social behavior.

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“…Schizophrenia-relevant sensory and psychomotor behaviors have been reported as disrupted in several of these models. The Df(16)A +/− mouse model has been shown to display baseline hyperactivity and an anxiogenic phenotype ( Stark et al 2008 ) while increased hyperactivity in response to MK-801 was reported in the Df/+ model ( Kimoto et al 2012 ). Similar to human carriers ( Sobin et al 2005 ) the Df(16)A +/− , Df1/+ and LgDel models displayed reduced prepulse inhibition ( Paylor et al 2001 ; Long et al 2006 ; Stark et al 2008 ) while the Df1/+ mutant had a increased acoustic startle response ( Paylor et al 2001 ).…”

Section: Introductionmentioning

confidence: 99%

Assessing the Cognitive Translational Potential of a Mouse Model of the 22q11.2 Microdeletion Syndrome

Nilsson¹,

Fejgin

Gastambide

et al. 2016

Cereb. Cortex

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A chromosomal microdeletion at the 22q11.2 locus is associated with extensive cognitive impairments, schizophrenia and other psychopathology in humans. Previous reports indicate that mouse models of the 22q11.2 microdeletion syndrome (22q11.2DS) may model the genetic basis of cognitive deficits relevant for neuropsychiatric disorders such as schizophrenia. To assess the models usefulness for drug discovery, a novel mouse (Df(h22q11)/+) was assessed in an extensive battery of cognitive assays by partners within the NEWMEDS collaboration (Innovative Medicines Initiative Grant Agreement No. 115008). This battery included classic and touchscreen-based paradigms with recognized sensitivity and multiple attempts at reproducing previously published findings in 22q11.2DS mouse models. This work represents one of the most comprehensive reports of cognitive functioning in a transgenic animal model. In accordance with previous reports, there were non-significant trends or marginal impairment in some tasks. However, the Df(h22q11)/+ mouse did not show comprehensive deficits; no robust impairment was observed following more than 17 experiments and 14 behavioral paradigms. Thus -within the current protocols -the 22q11.2DS mouse model fails to mimic the cognitive alterations observed in human 22q11.2 deletion carriers. We suggest that the 22q11.2DS model may induce liability for cognitive dysfunction with additional "hits" being required for phenotypic expression.

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Selective overexpression of Comt in prefrontal cortex rescues schizophrenia-like phenotypes in a mouse model of 22q11 deletion syndrome

Cited by 39 publications

References 55 publications

Persistent gating deficit and increased sensitivity to NMDA receptor antagonism after puberty in a new mouse model of the human 22q11.2 microdeletion syndrome: a study in male mice

Persistent gating deficit and increased sensitivity to NMDA receptor antagonism after puberty in a new mouse model of the human 22q11.2 microdeletion syndrome: a study in male mice

Genetic and clinical features of social cognition in 22q11.2 deletion syndrome

Assessing the Cognitive Translational Potential of a Mouse Model of the 22q11.2 Microdeletion Syndrome

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