Serotonin as a developmental signal

Whitaker‐Azmitia, Patricia M.; Druse, Mary J.; Walker, Paul D.; Lauder, Jean M.

doi:10.1016/0166-4328(96)00071-x

Cited by 320 publications

(211 citation statements)

References 84 publications

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“…We suggest here that altered forebrain 5-HT innervation, acting via 5-HT and glutamate receptor sites, disrupts the appropriate pruning of cortical axons and plasticity of cortical maps. The role of 5-HT as a morphogen in cerebral cortical development is well described [71,124], as are the interactions of 5-HT and glutamate on neuronal plasticity [72,79,80]. For example, application of 5-HT to cultured neonatal thalamic neurons caused neurite outgrowth and elaboration [79,80].…”

Section: Discussionmentioning

confidence: 99%

“…Serotonin is involved in neuronal growth and plasticity [71,124] and it likely exerts a modulatory role on cortical synaptic plasticity via regulation of glutamate receptors during both normal development and in disease states with serotonergic dysfunction. In addition, serotonin has a trophic influence on the morphogenesis of somatosensory cortex (SI) and the development of patterned glutamatergic thalamocortical connections [26,41,74,99].…”

Section: Introductionmentioning

confidence: 99%

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Modeling early cortical serotonergic deficits in autism

Boylan

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Höhmann

2007

Behavioural Brain Research

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Autism is a developmental brain disorder characterized by deficits in social interaction, language and behavior. Brain imaging studies demonstrate increased cerebral cortical volumes and micro-and macroscopic neuroanatomic changes in children with this disorder. Alterations in forebrain serotonergic function may underlie the neuroanatomic and behavioral features of autism. Serotonin is involved in neuronal growth and plasticity and these actions are likely mediated via serotonergic and glutamatergic receptors. Few animal models of autism have been described that replicate both etiology and pathophysiology. We report here on a selective serotonin (5-HT) depletion model of this disorder in neonatal mice that mimics neurochemical and structural changes in cortex and, in addition, displays a behavioral phenotype consistent with autism. Newborn male and female mice were depleted of forebrain 5-HT with injections of the serotonergic neurotoxin, 5,7-dihydroxytryptamine (5,7-DHT), into the bilateral medial forebrain bundle (mfb). Behavioral testing of these animals as adults revealed alterations in social, sensory and stereotypic behaviors. Lesioned mice showed significantly increased cortical width. Serotonin immunocytochemistry showed a dramatic long-lasting depletion of 5-HT containing fibers in cerebral cortex until postnatal day (PND) 60. Autoradiographic binding to high affinity 5-HT transporters was significantly but transiently reduced in cerebral cortex of 5,7-DHT-depleted mice. AMPA glutamate receptor binding was decreased at PND 15. We hypothesize that increased cerebral cortical volume and sensorimotor, cognitive and social deficits observed in both 5-HT-depleted animals and in individuals with autism, may be the result of deficiencies in timely axonal pruning to key cerebral cortical areas.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Modeling early cortical serotonergic deficits in autism

Boylan

Blue

Höhmann

2007

Behavioural Brain Research

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“…That SERT inactivation during development can have such profound effects is perhaps not surprising considering that serotonin is a major developmental signal (Sodhi and Sanders-Bush, 2004;Whitaker-Azmitia et al, 1996). The rodent neonatal period also corresponds to a time of high transient expression of SERT (but not other monoamine transporters) on non-serotonin neurons (Lebrand et al, 1998).…”

Section: Serotonin Reuptakementioning

confidence: 99%

Genetic variation in cortico-amygdala serotonin function and risk for stress-related disease

Holmes

2008

Neuroscience & Biobehavioral Reviews

249

166

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The serotonin system is strongly implicated in the pathophysiology and therapeutic alleviation of stress-related disorders such as anxiety and depression. Serotonergic modulation of the acute response to stress and the adaptation to chronic stress is mediated by a myriad of molecules controlling serotonin neuron development (Pet-1), synthesis (tryptophan hydroxylase 1 and 2 isozymes), packaging (vesicular monoamine transporter 2), actions at presynaptic and postsynaptic receptors (5-HT1A, 5-HT1B, 5-HT2A, 5-HT2C, 5-HT3A, 5-HT4, 5-HT5A, 5-HT6, 5-HT7), reuptake (serotonin transporter), and degradation (monoamine oxidase A). A growing body of evidence from preclinical rodents models, and especially genetically modified mice and inbred mouse strains, has provided significant insight into how genetic variation in these molecules can affect the development and function of a key neural circuit between the dorsal raphe nucleus, medial prefrontal cortex and amygdala. By extension, such variation is hypothesized to have a major influence on individual differences in the stress response and risk for stress-related disease in humans. The current article provides an update on this rapidly evolving field of research.

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“…Serotonin is one of the earliest appearing neurotransmitters in the developing brain and is important for cellular proliferation, neuronal migration, neurite outgrowth, growth cone motility, and the differentiation of neuronal phenotypes [164,176]. Relatively high doses of MDMA to adults decrease 5-HT and the 5-HT metabolite 5-hydroxyindole acetic acid (5-HIAA).…”

Section: Indoleaminementioning

confidence: 99%

A developmental comparison of the neurobehavioral effects of ecstasy (MDMA)

Piper

2007

Neurotoxicology and Teratology

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The entactogen ±3,4-methylenedioxymethamphetamine (MDMA or ecstasy) is a popular recreational drug among college, high school, and, occasionally, middle school students. Preclinical research examining the acute and long-term effects of MDMA has predominately been conducted in reproductively mature subjects but there has been increasing interest in adolescent and in utero exposure. This review examines the acute and long-term responses to MDMA during perinatal, adolescent, and adult periods. The ability of MDMA to alter core body temperature emerges gradually during ontogeny while a reduction in body weight is evident at all ages. Learning and workingmemory are also altered independent of the developmental stage of exposure. Current evidence suggests adults are more sensitive to the long-term serotonin depletions following MDMA but younger ages also exhibit substantial and rapid neuroplasticity. Sexually dimorphic MDMA responses have been identified for the acute hyperthermic and motoric effects of MDMA with pubescent males being especially susceptible. Several physiological, behavioral, and neurochemical MDMA issues requiring further study are also outlined. Keywords±3; 4-methylenedioxymethamphetamine; Adolescence; Anxiety; Depression; Learning; SerotoninThe phenylethylamine ±3,4-methylenedioxymethamphetamine (MDMA) is a popular recreational drug best known as ecstasy. MDMA has several other street names including Adam, baby slits, chocolate chips, clarity, doctor, essence, kleenex, and roll [77]. Although ecstasy has some similarities with both stimulants and hallucinogens, MDMA is an entactogen. Entactogen means "touching within" based on the drug's subjective effects [110]. MDMA also causes long term changes in several markers of the integrity of the serotonin (5-HT) neurotransmitter system [58]. There have been several excellent recent reviews on MDMA toxicology, pharmacokinetics, pharmacodynamics, and neurobehavioral consequences [30,37,113,157], but none have systematically addressed the intricate effects of MDMA during development.Ecstasy use is not restricted to limited subpopulations, that is fans of techno music and "raves" [173] or male homosexuals [73,81], as MDMA has expanded into the general population [124,148,170] and especially young people [52,78,170,172]. Over one hundred pregnant women in Toronto called a substance abuse helpline between 1998 and 2000 to inquire Corresponding Author: Brian J. Piper, Neuroscience and Behavior Program, University of Massachusetts, Amherst, MA 01003-7710, Tel: (413) 545-0996, bpiper@nsm.umass.edu Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers...

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Serotonin as a developmental signal

Cited by 320 publications

References 84 publications

Modeling early cortical serotonergic deficits in autism

Modeling early cortical serotonergic deficits in autism

Genetic variation in cortico-amygdala serotonin function and risk for stress-related disease

A developmental comparison of the neurobehavioral effects of ecstasy (MDMA)

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