Stress-induced alternative splicing of acetylcholinesterase results in enhanced fear memory and long-term potentiation

Nijholt, Ingrid M.; Farchi, Noa; Kye, Min Jeong; Sklan, Ella H.; Shoham, Shai; Verbeure, B.; Owen, David J.; Hochner, Binyamin; Spiess, Joachim; Soreq, Hermona; Blank, Thomas

doi:10.1038/sj.mp.4001446

Cited by 121 publications

(108 citation statements)

References 42 publications

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“…The state-anxietypredictive value of the difference between observed and expected AChE activity is further compatible with our recent findings that the suppression of the stress-induced AChE-R variant obliterates conflict behavior (17) and the consolidation of fearful memories (39). In mammals, responses to anxiogenics can be modulated by cholinergic agents (40,41), and subacute intoxication with organophosphate insecticides induces anxiogenic effects (42).…”

Section: Discussionsupporting

confidence: 71%

Acetylcholinesterase/paraoxonase genotype and expression predict anxiety scores in Health, Risk Factors, Exercise Training, and Genetics study

Sklan

Lowenthal

Korner

et al. 2004

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

125

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Anxiety involves complex, incompletely understood interactions of genomic, environmental, and experience-derived factors, and is currently being measured by psychological criteria. Here, we report previously nonperceived interrelationships between expression variations and nucleotide polymorphisms of the chromosome 7q21-22 acetylcholinesterase-paraoxonase 1 (ACHE-PON1) locus with the trait-and state-anxiety measures of 461 healthy subjects from the Health, Risk Factors, Exercise Training, and Genetics Family Study. The AChE protein controls the termination of the stress-enhanced acetylcholine signaling, whereas the PON protein displays peroxidase-like activity, thus protecting blood proteins from oxidative stress damages. Serum AChE and PON enzyme activities were both found to be affected by demographic parameters, and showed inverse, reciprocal associations with anxiety measures. Moreover, the transient scores of state anxiety and the susceptibility score of trait anxiety both appeared to be linked to enzyme activities. This finding supported the notion of corresponding gene expression relationships. Parallel polymorphisms in the ACHE and PON1 genes displayed apparent associations with both trait-and state-anxiety scores. Our findings indicate that a significant source of anxiety feelings involves inherited and acquired parameters of acetylcholine regulation that can be readily quantified, which can help explaining part of the human variance for state and trait anxiety.

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Section: Discussionsupporting

confidence: 71%

Acetylcholinesterase/paraoxonase genotype and expression predict anxiety scores in Health, Risk Factors, Exercise Training, and Genetics study

Sklan

Lowenthal

Korner

et al. 2004

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

125

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“…As suggested by Overstreet et al [10] a decreased behavioral sensitivity to AMPH goes along with cholinergic hypersensitivity. It has recently been shown that exposure to cholinesterase inhibitors is followed weeks later by an increase in excitability of cholinergically innervated limbic structures and an exaggerated conditioned fear response [11,12]. It is possible then that treatment with CVP triggered the process leading to a persistent increase in the cholinergic tone, which might explain the results of the present experiment.…”

Section: Discussionsupporting

confidence: 76%

Exposure to Chlorphenvinphos, an Organophosphate Insecticide, Prevents from Behavioral Sensitization to Amphetamine

Lutz¹,

Wiaderna²,

Gralewicz³

et al. 2006

International Journal of Occupational Medicine and Environmental Health

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Objectives: Exposure to organophosphorus (OP) pesticides, irreversible inhibitors of acetylcholinesterase (AChE), may result in long-lasting alterations in the functional state of the central nervous system. In earlier studies, we found that a single exposure of the rat to chlorphenvinphos (CVP), an OP pesticide, made the animal hyposensitive to amphetamine (AMPH) three weeks posttreatment. A repeated administration of AMPH is known to result in a progressive increase in the behavioral sensitivity to the psychostimulant. It makes it likely that treatment with AMPH after the CVP exposure may result in amelioration of the CVP-induced hyposensitivity to the psychostymulant. The purpose of the present experiment was to check out this supposition. Materials and Methods: At the first stage, the relationship between the CVP dose and the effect on sensitivity to AMPH was tested. The rats were given CVP once intraperitoneally (i.p.) at a dose of 0.0, 1.0 or 3.0 mg/kg. Three weeks later their open field behavior was assessed before and after i.p. administration of 0.25, 0.5 or 1.0 mg/kg of AMPH. At the subsequent stage, the susceptibility of the CVP-treated rats to AMPH sensitization by repeated AMPH treatment was investigated. For this purpose each of the rats was repeatedly treated with AMPH in its home cage (one injection/day for five days). At stage two, the daily AMPH dose received by each animal was of the same magnitude as that received at stage one. Two weeks after the last AMPH treatment dose, the motor response to a test AMPH dose (0.5 mg/kg) was measured in all rats. Results: The results of stage one confirmed a significant reduction of behavioral sensitivity to AMPH in the CVP-treated rats. The results of stage two indicated that the CVP-induced decrease in sensitivity to AMPH was not ameliorated by a repeated treatment with AMPH at any of the used doses. In fact, in the rats exposed to the high CVP dose, repeated treatment with AMPH resulted, dose dependently, in augmenting of the depressive effect of the pesticide. Conclusions: It appears then that treatment to an OP pesticide reduces the rat's sensitivity to AMPH and makes the animal resistant to sensitization by repeated treatment with the psychostimulant.

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“…These ACHE isoforms result from the differential assembly of structural and catalytic enzymatic subunits, the latter of which arise from alternative splicing of a single gene giving rise to ACHE splice variants containing either the T subunit and/or the hydrophobic H subunit [reviewed in 47,74]. Stressinduced alternative splicing of acetylcholinesterase in the hippocampus has been demonstrated to alter both its ability to associate with the neuronal membrane and interact with the structural subunit of the active enzyme [60]. There is also mounting evidence, especially from other tissues, that ACHE may function in the regulation of cellular differentiation and adhesion [25].…”

Section: Discussionmentioning

confidence: 99%

Social defeat, a paradigm of depression in rats that elicits 22-kHz vocalizations, preferentially activates the cholinergic signaling pathway in the periaqueductal gray

Kroes¹,

Burgdorf²,

Otto³

et al. 2007

Behavioural Brain Research

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Gene expression profiles in the periaqueductal gray (PAG) of adult Long-Evans rats as a function of a stressful social defeat in inter-male fighting encounters were examined. This social subordination model mimics prototypical behavioral changes that parallel aspects of clinical depression, has been postulated to simulate early changes in the onset of depression in the losers, and has been successfully utilized for the evaluation of antidepressant activity. 22-kHz ultrasonic vocalizations (USVs) have been shown to reflect negative emotional states akin to anxiety and depression. Social defeat is the most robust and reliable method of eliciting these calls. The PAG has been shown to be a key brain region for the generation of 22-kHz ultrasonic vocalizations, and 22-kHz USVs have been shown to be controlled by the mesolimbic cholinergic system. In this present study we examined gene expression changes in the PAG of social subordinate rats compared to dominant rats (that do not exhibit 22-kHz USVs). We found that social defeat significantly altered the genes associated with cholinergic synaptic transmission in the PAG. The most robust of these were the increased expression of the β2 subunit of the nicotinic acetylcholine receptor (CHRNB2) and the T-subunit of acetylcholinesterase (ACHE) in the subordinate animals. These changes were corroborated by qRT-PCR and found to be exclusive to the PAG compared to seven other brain regions examined. These data suggest that cholinergic transmission in the PAG is involved in the generation of 22-kHz USVs and provide potential therapeutic targets for the treatment of affective disorders.

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Stress-induced alternative splicing of acetylcholinesterase results in enhanced fear memory and long-term potentiation

Cited by 121 publications

References 42 publications

Acetylcholinesterase/paraoxonase genotype and expression predict anxiety scores in Health, Risk Factors, Exercise Training, and Genetics study

Acetylcholinesterase/paraoxonase genotype and expression predict anxiety scores in Health, Risk Factors, Exercise Training, and Genetics study

Exposure to Chlorphenvinphos, an Organophosphate Insecticide, Prevents from Behavioral Sensitization to Amphetamine

Social defeat, a paradigm of depression in rats that elicits 22-kHz vocalizations, preferentially activates the cholinergic signaling pathway in the periaqueductal gray

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