Elevated 5-HT 2A receptors in postmortem prefrontal cortex in major depression is associated with reduced activity of protein kinase A

Shelton, Richard C.; Sanders‐Bush, Elaine; Manier, D. Hal; Lewis, David

doi:10.1016/j.neuroscience.2008.11.036

Cited by 123 publications

(90 citation statements)

References 86 publications

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“…Our finding of a critical role for PKA shows that behavioral gregarization and classical forms of learning have coopted overlapping mechanisms from a conserved molecular toolbox for the transduction of environmental stimuli, in this case sensory cues from conspecifics, into phenotypic responses (15). Phase change in locusts, subordinate behavior following defeat (59,60), and clinical depression in humans (61) are all manifestations of a fundamental capacity for behavioral remodeling in response to social experience in which biogenic amines and altered PKA signaling have been strongly implicated. They encompass changes in the individual's interaction with the environment, including its social domain; this altered interaction in turn feeds back through the social environment onto the individual to reinforce the new behavioral state (62).…”

Section: Discussionmentioning

confidence: 86%

Critical role for protein kinase A in the acquisition of gregarious behavior in the desert locust

Ott

Verlinden

Rogers

et al. 2011

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

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The mechanisms that integrate genetic and environmental information to coordinate the expression of complex phenotypes are little understood. We investigated the role of two protein kinases (PKs) in the population density-dependent transition to gregarious behavior that underlies swarm formation in desert locusts: the foraging gene product, a cGMP-dependent PK (PKG) implicated in switching between alternative group-related behaviors in several animal species; and cAMP-dependent PK (PKA), a signal transduction protein with a preeminent role in different forms of learning. Solitarious locusts acquire key behavioral characters of the swarming gregarious phase within just 1 to 4 h of forced crowding. Injecting the PKA inhibitor KT5720 before crowding prevented this transition, whereas injecting KT5823, an inhibitor of PKG, did not. Neither drug altered the behavior of long-term gregarious locusts. RNAi against foraging effectively reduced its expression in the central nervous system, but this did not prevent gregarization upon crowding. By contrast, solitarious locusts with an RNAi-induced reduction in PKA catalytic subunit C1 expression behaved less gregariously after crowding, and RNAi against the inhibitory R1 subunit promoted more extensive gregarization following a brief crowding period. A central role of PKA is congruent with the recent discovery that serotonin mediates gregarization in locusts and with findings in vertebrates that similarly implicate PKA in the capacity to cope with adverse life events. Our results show that PKA has been coopted into effecting the wide-ranging transformation from solitarious to gregarious behavior, with PKAmediated behavioral plasticity resulting in an environmentally driven reorganization of a complex phenotype.phase change | phenotypic plasticity | Schistocerca gregaria H ow genetic information is integrated with environmental cues to control and coordinate complex phenotypes is a fundamental question in biology (1, 2). Environmental input can cause concerted changes in multiple traits to produce distinct phenotypic syndromes that are adaptive in particular conditions. Phase polyphenism in desert locusts (Schistocerca gregaria) is an extreme example. Locusts can reversibly transform between a solitarious phase and a gregarious phase that differ profoundly in morphology, physiology, and behavior (3-5). Solitarious locusts occur at low population densities and actively avoid conspecifics; they are cryptic in appearance and behavior; walk with a slow, creeping gait; and have restricted dietary preferences. The gregarious phase is characterized by increased activity and locomotion, an upright posture and gait, aposematic coloration, a broad dietary range, and, most critically, attraction to other locusts. Phase change is driven by huge changes in population density and is an adaptation to arid habitats where rains are infrequent and erratic. Transitory periods of verdure support rapid population growth, but after the rains cease, large numbers of solitarious locusts compete for...

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Section: Discussionmentioning

confidence: 86%

Critical role for protein kinase A in the acquisition of gregarious behavior in the desert locust

Ott

Verlinden

Rogers

et al. 2011

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

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“…In line with these findings, a recent meta-analysis confirmed a significant association of the rs6311 HTR2A polymorphism with schizophrenia [21]. Previous postmortem studies have observed changed HTR2A levels in brains from individuals with major depression (in prefrontal cortex and hippocampus) [4,22], and suicide victims (in frontopolar and prefrontal cortex, hippocampus and amygdala) [23][24][25][26].…”

Section: Discussionmentioning

confidence: 64%

“…The serotonin 2A receptor (HTR2A) is a serotonin receptor subtype, which plays an important role in the modulation of anxiety and mood [4,5]. Furthermore, the HTR2A gene has been implicated by genetic studies in neuropsychiatric disorders as schizophrenia, depression, anxiety, OCD and eating disorders [6,7].…”

Section: Introductionmentioning

confidence: 99%

Region-Specific Regulation of the Serotonin 2a Receptor Expression in Development and Aging in Postmortem Human Brain

Marinova

Monoranu

Fetz

et al. 2016

European Neuropsychopharmacology

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AIMS The serotonin 2A receptor (HTR2A) is widely expressed in the brain and involved in the modulation of fear, mood, anxiety and other symptoms. HTR2A and HTR2A gene variations are implicated in depression, schizophrenia, anxiety and obsessive-compulsive disorder. To understand HTR2A signalling changes in psychiatric or neurodegenerative disorders, its normal pattern of brain expression and region specificity during development and aging needs to be clarified. The aim of the present study was to assess HTR2A expression through developmental and aging stages in six brain regions in postmortem human brain samples from individuals with no clinical or neuropathological evidence of neuropsychiatric disorders and to investigate the interaction with the rs6311 HTR2A promoter polymorphism. METH-ODS DNA, RNA and protein were isolated from postmortem brain samples including six regions (frontal cortex, striatum, amygdala, thalamus, brain stem and cerebellum) from 55 individuals. HTR2A mRNA levels were assessed using quantitative real time RT-PCR, and HTR2A protein levels -with western blot. The rs6311 HTR2A polymorphism was analyzed with genotyping. RESULTS We found that HTR2A mRNA and protein levels are differentially regulated with age in different brain regions studied, but are not affected by gender. Significant changes in HTR2A expression with age were found in frontal cortex, amygdala, thalamus, brain stem, and cerebellum. CONCLUSIONS Our results show plasticity and region specificity of HTR2A expression regulation in human brain with age, which may be important for the interaction with other neurotransmitter systems and for the occurrence of developmental periods with increased vulnerability to neuropsychiatric or neurodegenerative disorders. This article has been accepted for publication and undergone full peer review but has not been through the copyediting, typesetting, pagination and proofreading process, which may lead to differences between this version and the Version of Record. Please cite this article as doi: 10.1111/nan.12167 Accepted ArticleThis article is protected by copyright. All rights reserved. Significant changes in HTR2A expression with age were found in frontal cortex, amygdala, thalamus, brain stem, and cerebellum. Conclusions: Our results show plasticity and region specificity of HTR2A expression regulation in human brain with age, which may be important for the interaction with other neurotransmitter systems and for the occurrence of developmental periods with increased vulnerability to neuropsychiatric or neurodegenerative disorders.

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“…In MDD patients, the neurobiological alterations of the Fp were described in many previous studies, including difference in serotonin receptor densities [37] and reductions of the GMV [12]. Moreover, Bludau and his colleagues found a significantly smaller GMV of left Fp2 in MDD patients using cytoarchitectonically informed VBM [19].…”

Section: Discussionmentioning

confidence: 83%

Electroconvulsive Therapy Modulates the Structural and Functional Architecture of Frontal Pole in Major Depressive Disorder

Xu¹,

Wang²,

Xu³

et al. 2018

Neuropsychiatry

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Elevated 5-HT 2A receptors in postmortem prefrontal cortex in major depression is associated with reduced activity of protein kinase A

Cited by 123 publications

References 86 publications

Critical role for protein kinase A in the acquisition of gregarious behavior in the desert locust

Critical role for protein kinase A in the acquisition of gregarious behavior in the desert locust

Region-Specific Regulation of the Serotonin 2a Receptor Expression in Development and Aging in Postmortem Human Brain

Electroconvulsive Therapy Modulates the Structural and Functional Architecture of Frontal Pole in Major Depressive Disorder

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