Support for involvement of neuregulin 1 in schizophrenia pathophysiology

Petryshen, Tracey L.; Middleton, Frank A.; Kirby, Andrew; Aldinger, Kimberly A.; Purcell, Shaun; Tahl, A R; Morley, Christopher P.; McGann, L; Gentile, Karen L.; Rockwell, Graham N.; Medeiros, Helena; Carvalho, Célia Barreto; Macedo, António; Dourado, Ana; Valente, J.; Ferreira, Carlos Paz; Patterson, Nick; Azevedo, Maria Helena Pinto de; Daly, Mark J.; Pato, Carlos N.; Pato, Michele T.; Sklar, Pamela

doi:10.1038/sj.mp.4001608

Cited by 164 publications

(86 citation statements)

References 48 publications

(67 reference statements)

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“…The HapICE risk haplotype is associated with increased expression of NRG1 in the brain (Weickert et al, 2012). Moreover, mRNA and protein of NRG1 are increased in the prefrontal cortex (PFC) and hippocampus of schizophrenia patients (Chong et al, 2008; Hashimoto et al, 2004; Law et al, 2006; Petryshen et al, 2005). The increase did not correlate with antipsychotics treatment (Chong et al, 2008; Law et al, 2006), suggesting an association with the disorder instead of medication.…”

Section: Introductionmentioning

confidence: 99%

Reversal of Behavioral Deficits and Synaptic Dysfunction in Mice Overexpressing Neuregulin 1

Yin

Chen

et al. 2013

Neuron

113

110

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Summary Neuregulin 1 (Nrg1) is a susceptibility gene of schizophrenia, a disabling mental illness that affects 1% of the general population. Here we show that ctoNrg1 mice, which mimic high levels of NRG1 observed in forebrain regions of schizophrenic patients, exhibit behavioral deficits and hypofunction of glutamatergic and GABAergic pathways. Intriguingly, these deficits were diminished when NRG1 expression returned to normal in adult mice that had been symptomatic, suggesting that damage which occurred during development is recoverable. Conversely, increase of NRG1 in adulthood was sufficient to cause glutamatergic impairment and behavioral deficits. We found that the glutamatergic impairment by NRG1 overexpression required LIM domain kinase 1 (LIMK1), which was activated in mutant mice, identifying a novel pathological mechanism. These observations demonstrate that synaptic dysfunction and behavioral deficits require continuous NRG1 abnormality in adulthood, suggesting that relevant schizophrenia may benefit from therapeutic intervention to restore NRG1 signaling.

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Section: Introductionmentioning

confidence: 99%

Reversal of Behavioral Deficits and Synaptic Dysfunction in Mice Overexpressing Neuregulin 1

Yin

Chen

et al. 2013

Neuron

113

110

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“…Separate follow-up studies in Scottish, Irish, mixed United Kingdom, and Dutch populations confirmed the genetic association between schizophrenia and NRG1 by using markers within the same core haplotype (11)(12)(13)(14) or with overlapping markers in the 5Ј region (15,16). Studies in four Asian populations also showed a strong association between schizophrenia and NRG1 polymorphisms at the 5Ј (17)(18)(19)(20) and 3Ј end of the gene (19).…”

mentioning

confidence: 74%

Neuregulin 1 transcripts are differentially expressed in schizophrenia and regulated by 5′ SNPs associated with the disease

Law

Lipska

Weickert

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

369

214

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Genetic variation in neuregulin 1 (NRG1) is associated with schizophrenia. The disease-associated SNPs are noncoding, and their functional implications remain unknown. We hypothesized that differential expression of the NRG1 gene explains its association to the disease. We examined four of the disease-associated SNPs that make up the original risk haplotype in the 5 upstream region of the gene for their effects on mRNA abundance of NRG1 types I-IV in human postmortem hippocampus. Diagnostic comparisons revealed a 34% increase in type I mRNA in schizophrenia and an interaction of diagnosis and genotype (SNP8NRG221132) on this transcript. Of potentially greater interest, a single SNP within the risk haplotype (SNP8NRG243177) and a 22-kb block of this core haplotype are associated with mRNA expression for the novel type IV isoform in patients and controls. Bioinformatic promoter analyses indicate that both SNPs lead to a gain͞loss of putative binding sites for three transcription factors, serum response factor, myelin transcription factor-1, and High Mobility Group Box Protein-1. These data implicate variation in isoform expression as a molecular mechanism for the genetic association of NRG1 with schizophrenia.genetics ͉ mRNA ͉ human postmortem brain ͉ hippocampus ͉ ErbB

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“…Furthermore, genetic linkage and association studies led to the identification of two additional susceptibility factors related to schizophrenia, such as neuregulin-1 ( NRG1 ) and its receptor ErbB4 [226,227]. NRG1 is a family of trophic factors that is synthesized as trans-membrane proteins displaying an extracellular epidermal growth factor (EGF)-like domain that is essential for ErbB4 receptor binding.…”

Section: Mtor Modulation Of Dopamine Transmission In Methamphetamimentioning

confidence: 99%

mTOR-Related Brain Dysfunctions in Neuropsychiatric Disorders

Ryskalin

Limanaqi

Frati

et al. 2018

IJMS

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The mammalian target of rapamycin (mTOR) is an ubiquitously expressed serine-threonine kinase, which senses and integrates several intracellular and environmental cues to orchestrate major processes such as cell growth and metabolism. Altered mTOR signalling is associated with brain malformation and neurological disorders. Emerging evidence indicates that even subtle defects in the mTOR pathway may produce severe effects, which are evident as neurological and psychiatric disorders. On the other hand, administration of mTOR inhibitors may be beneficial for a variety of neuropsychiatric alterations encompassing neurodegeneration, brain tumors, brain ischemia, epilepsy, autism, mood disorders, drugs of abuse, and schizophrenia. mTOR has been widely implicated in synaptic plasticity and autophagy activation. This review addresses the role of mTOR-dependent autophagy dysfunction in a variety of neuropsychiatric disorders, to focus mainly on psychiatric syndromes including schizophrenia and drug addiction. For instance, amphetamines-induced addiction fairly overlaps with some neuropsychiatric disorders including neurodegeneration and schizophrenia. For this reason, in the present review, a special emphasis is placed on the role of mTOR on methamphetamine-induced brain alterations.

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Support for involvement of neuregulin 1 in schizophrenia pathophysiology

Cited by 164 publications

References 48 publications

Reversal of Behavioral Deficits and Synaptic Dysfunction in Mice Overexpressing Neuregulin 1

Reversal of Behavioral Deficits and Synaptic Dysfunction in Mice Overexpressing Neuregulin 1

Neuregulin 1 transcripts are differentially expressed in schizophrenia and regulated by 5′ SNPs associated with the disease

mTOR-Related Brain Dysfunctions in Neuropsychiatric Disorders

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