Association between <i>Tph2</i> gene polymorphism, brain tryptophan hydroxylase activity and aggressiveness in mouse strains

Куликов, А. В.; Osipova, Daria; Науменко, В. С.; Попова, Н. К.

doi:10.1111/j.1601-183x.2005.00145.x

Cited by 100 publications

(71 citation statements)

References 21 publications

(35 reference statements)

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“…This variant results in a reduction of enzyme activity by Ϸ50% when expressed in PC12 cells. Furthermore, expression of this Tph2 variant in these inbred mouse lines is associated with reduced brain 5-HT synthesis (15) and differences in aggressive behavior (45), premRNA editing of the 5-HT 2C receptor (46), as well as responsiveness to SSRIs (47,48). However, these studies can only be viewed as correlative because they were all conducted by comparing different strains of inbred mice and the potential contribution of other genetic variations in these mice cannot be ruled out.…”

Section: Discussionmentioning

confidence: 99%

Role of GSK3β in behavioral abnormalities induced by serotonin deficiency

Beaulieu¹,

Zhang²,

Rodriguiz

et al. 2008

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

337

317

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Dysregulation of brain serotonin (5-HT) neurotransmission is thought to underlie mental conditions as diverse as depression, anxiety disorders, bipolar disorder, autism, and schizophrenia. Despite treatment of these conditions with serotonergic drugs, the molecular mechanisms by which 5-HT is involved in the regulation of aberrant emotional behaviors are poorly understood. Here, we generated knockin mice expressing a mutant form of the brain 5-HT synthesis enzyme, tryptophan hydroxylase 2 (Tph2). This mutant is equivalent to a rare human variant (R441H) identified in few individuals with unipolar major depression. Expression of mutant Tph2 in mice results in markedly reduced (Ϸ80%) brain 5-HT production and leads to behavioral abnormalities in tests assessing 5-HT-mediated emotional states. This reduction in brain 5-HT levels is accompanied by activation of glycogen synthase kinase 3␤ (GSK3␤), a signaling molecule modulated by many psychiatric therapeutic agents. Importantly, inactivation of GSK3␤ in Tph2 knockin mice, using pharmacological or genetic approaches, alleviates the aberrant behaviors produced by 5-HT deficiency. These findings establish a critical role of Tph2 in the maintenance of brain serotonin homeostasis and identify GSK3␤ signaling as an important pathway through which brain 5-HT deficiency induces abnormal behaviors. Targeting GSK3␤ and related signaling events may afford therapeutic advantages for the management of certain 5-HT-related psychiatric conditions. GSK-3 ͉ mood disorders ͉ serotonin ͉ Tph2 ͉ functional polymorphism S erotonin (5-HT) is involved in multiple aspects of normal brain functions ranging from the regulation of mood to the control of appetite and social interactions (1-3). Several studies have suggested a contribution of abnormal 5-HT transmission in various human psychiatric conditions and drugs acting on 5-HT neurotransmission are commonly used for the management of major depression, anxiety disorder, obsessive-compulsive disorder, autism, and schizophrenia (1-3). Although drugs that influence the 5-HT system can affect histone acetylation, modulate production of brain-derived neurotrophic factor, increase neural progenitor cell proliferation, and inhibit glycogen synthase kinase 3␤ (GSK3␤) in certain brain areas (4, 5), the mechanisms underlying the regulation of behavior by 5-HT are still obscure.There are indications that pharmacologic manipulations of 5-HT levels by different classes of drugs can affect distinct neuronal signaling mechanisms (6-9). For instance, multiple classes of 5-HT drugs, including selective 5-HT reuptake inhibitors (SSRIs), tricyclic antidepressants, monoamine oxidase inhibitors, and atypical antipsychotics (5, 7, 9), inhibit brain GSK3␤ signaling. GSK3␤ is also inhibited in vivo by lithium (6, 10-12), which is often used in combination with antidepressants for the management of certain mood disorders (13). However, whether these changes in GSK3␤ are incidental or contribute to the regulation of 5-HT-related abnormal behaviors is unexplored (5...

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Section: Discussionmentioning

confidence: 99%

Role of GSK3β in behavioral abnormalities induced by serotonin deficiency

Beaulieu¹,

Zhang²,

Rodriguiz

et al. 2008

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

337

317

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“…This is somewhat at variance with a number of earlier findings that in established territories C57BL/ 6J mice display highly levels of aggression and stable dominance relationships (see [10] for review). Thus, in resident-intruder tests, C57BL/6J mice were found to be more aggressive toward an intruder compared to DBA/2J strain [51] and to additional 7 inbred mouse strains [34]. Mondragon et al [47] found that following formation of group, C57BL/6J subordinates showed more submissive to dominants and less aggression to other subordinate males, compared to BALB/cJ strain.…”

Section: Specific Social Behaviorsmentioning

confidence: 98%

Colony formation of C57BL/6J mice in visible burrow system: Identification of eusocial behaviors in a background strain for genetic animal models of autism

Arakawa

Blanchard

2007

Behavioural Brain Research

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Deficits in social interaction are primary characteristics of autism, which has strong genetic components. Genetically-manipulated mouse models may provide a useful research tool to advance the investigation of genes associated with autism. To identify these genes using mouse models, behavioral assays for social relationships in the background strains must be developed. The present study examined colony formation in groups of one male and three female mice (Experiment 1) and, groups of three male mice (Experiment 2) of the C57BL/6J strain in a seminatural visible burrow system. For adult mixed-sex colonies, four-hour observations during both the dark and light cycles for 15 days demonstrated day-dependent increases in huddling together in the chamber accompanied by decreased frequencies of active social behaviors. Sequential analyses of social interactions indicated that approaches to the back of the approached animal typically elicited flight, while approaches to the front of the approached animal failed to do so. This was seen for female to female, and for female to male approaches, as well as male to female approaches, strongly counter indicating a view that rear approach/flight specifically reflects female responsivirity to unwanted male sexual approach. For adult male colonies, similar protocols found that these social behaviors were similar to those of adult mixed-sex colonies. These findings suggest two potentially useful measures of eusocial behavior in mice, of possible value for genetic mouse models of autism; that is, huddling together and approaches to the front but not the back, of conspecifics.

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“…Selective breeding is very effective in creating large line differences if the males are reared in isolation, but the line difference largely disappears when they are instead reared in groups (42)(43)(44). Recent inbred strain surveys (45)(46)(47)(48) used very different test methods and͞or different substrains, and they differed substantially in many details from the 1968 multiplestrain comparison by Southwick and Clark (25). The available data did not warrant a formal statistical comparison between studies, and we could not evaluate the stability of scores over decades.…”

mentioning

confidence: 99%

Stability of inbred mouse strain differences in behavior and brain size between laboratories and across decades

Wahłsten

Bachmanov

Finn

et al. 2006

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

260

220

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If we conduct the same experiment in two laboratories or repeat a classical study many years later, will we obtain the same results? Recent research with mice in neural and behavioral genetics yielded different results in different laboratories for certain phenotypes, and these findings suggested to some researchers that behavior may be too unstable for fine-scale genetic analysis. Here we expand the range of data on this question to additional laboratories and phenotypes, and, for the first time in this field, we formally compare recent data with experiments conducted 30 -50 years ago. For ethanol preference and locomotor activity, strain differences have been highly stable over a period of 40 -50 years, and most strain correlations are in the range of r ‫؍‬ 0.85-0.98, as high as or higher than for brain weight. For anxiety-related behavior on the elevated plus maze, on the other hand, strain means often differ dramatically across laboratories or even when the same laboratory is moved to another site within a university. When a wide range of phenotypes is considered, no inbred strain appears to be exceptionally stable or labile across laboratories in any general sense, and there is no tendency to observe higher correlations among studies done more recently. Phenotypic drift over decades for most of the behaviors examined appears to be minimal.agonistic behavior ͉ anxiety ͉ ethanol preference ͉ gene-environment interaction ͉ locomotor activity

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Association between Tph2 gene polymorphism, brain tryptophan hydroxylase activity and aggressiveness in mouse strains

Cited by 100 publications

References 21 publications

Role of GSK3β in behavioral abnormalities induced by serotonin deficiency

Role of GSK3β in behavioral abnormalities induced by serotonin deficiency

Colony formation of C57BL/6J mice in visible burrow system: Identification of eusocial behaviors in a background strain for genetic animal models of autism

Stability of inbred mouse strain differences in behavior and brain size between laboratories and across decades

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