Behavioral and cellular consequences of increasing serotonergic activity during brain development: a role in autism?

Whitaker‐Azmitia, Patricia M.

doi:10.1016/j.ijdevneu.2004.07.022

Cited by 252 publications

(201 citation statements)

References 114 publications

Supporting

Mentioning

192

Contrasting

Order By: Relevance

“…Another recent rodent model lends support to our hypothesis of the role played by early serotonergic innervation in the etiology of autism. Although Whitaker-Azmitia and colleagues [66,123] propose a hyperserotonemic model of autism, their hypothesis is ultimately consistent with our own. In their studies, perinatal rat pups were exposed to a serotonergic agonist from mid-gestation to PND 20.…”

Section: Discussionsupporting

confidence: 87%

“…Although somewhat variable, a number of recent reports indicate an association between variations in the gene that encodes SERT and a susceptibility to autism [33,43,112]. Whitaker-Azmitia and colleagues [66,123] propose a perinatal hyperserotonemic animal model for the pathophysiology of autism. They suggest that the excessively high 5-HT from the blood of the growing fetus crosses the forming blood brain barrier, gains access to the developing brain, and ultimately causes a loss of 5-HT terminals in cerebral cortex via a negative feedback system mediated by 5-HT receptors.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Modeling early cortical serotonergic deficits in autism

Boylan

Blue

Höhmann

2007

Behavioural Brain Research

View full text Add to dashboard Cite

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.

show abstract

Section: Discussionsupporting

confidence: 87%

Section: Introductionmentioning

confidence: 99%

Modeling early cortical serotonergic deficits in autism

Boylan

Blue

Höhmann

2007

Behavioural Brain Research

View full text Add to dashboard Cite

show abstract

“…In this way, increased 5-HTergic activity during development causes loss of 5-HT terminals in the adult. 169 Several drug treatment studies have shown this negative feedback of 5-HT on development of 5-HTergic neurons. [170][171][172][173][174][175][176][177][178][179][180] Alterations in 5-HTT function 181 and hypothalamic 5-HT levels 182 may be in part responsible for altered HPA axis activity in adult PS offspring.…”

Section: Stressmentioning

confidence: 99%

“…168 In addition to influencing the development of target regions, 5-HT also has a negative feedback effect on the developing fetal 5-HT neurons. 169 As 5-HT neurons develop, 5-HT levels increase until a point is reached at which the growth is curtailed through a negative feedback mechanism. 169 When 5-HT levels are high early in development, when the blood-brain barrier is not fully formed yet, 5-HT can enter the brain of a developing fetus and thus cause loss of serotonin terminals through negative feedback.…”

Section: Stressmentioning

confidence: 99%

“…169 As 5-HT neurons develop, 5-HT levels increase until a point is reached at which the growth is curtailed through a negative feedback mechanism. 169 When 5-HT levels are high early in development, when the blood-brain barrier is not fully formed yet, 5-HT can enter the brain of a developing fetus and thus cause loss of serotonin terminals through negative feedback. In this way, increased 5-HTergic activity during development causes loss of 5-HT terminals in the adult.…”

Section: Stressmentioning

confidence: 99%

See 1 more Smart Citation

Serotonergic vulnerability and depression: assumptions, experimental evidence and implications

et al. 2006

View full text Add to dashboard Cite

In recent years, the term serotonergic vulnerability (SV) has been used in scientific literature, but so far it has not been explicitly defined. This review article attempts to elucidate the SV concept. SV can be defined as increased sensitivity to natural or experimental alterations of the serotonergic (5-HTergic) system. Several factors that may disrupt the 5-HTergic system and hence contribute to SV are discussed, including genetic factors, female gender, personality characteristics, several types of stress and drug use. It is explained that SV can be demonstrated by means of manipulations of the 5-HTergic system, such as 5-HT challenges or acute tryptophan depletion (ATD). Results of 5-HT challenge studies and ATD studies are discussed in terms of their implications for the concept of SV. A model is proposed in which a combination of various factors that may compromise 5-HT functioning in one person can result in depression or other 5-HT-related pathology. By manipulating 5-HT levels, in particular with ATD, vulnerable subjects may be identified before pathology initiates, providing the opportunity to take preventive action. Although it is not likely that this model applies to all cases of depression, or is able to identify all vulnerable subjects, the strength of the model is that it may enable identification of vulnerable subjects before the 5-HT related pathology occurs. Molecular Psychiatry ( Keywords: serotonin; mood disorders; stress; genetics; sex; tryptophan Involvement of serotonin in depressionMood disorders are one of the most prevalent forms of mental illness. 1 According to the DSM-IV, the lifetime risk for major depressive disorder is between 10 and 25% for women and between 5 and 12% for men. 2 Depression has been studied intensively during the last few decades, but the psychological and neurobiological determinants of depression have not yet been precisely defined. Although several factors are known to contribute to the etiology of depression, it is not clear how these factors cause depression, and why some subjects become depressed while others remain unaffected. In terms of biological factors in the etiology of depression, there are several hypotheses. These include neurotransmitter dysfunctions (serotonin, 5-HT; dopamine, DA; norepinephrine, NE); dysregulations in hypothalamic-pituitary-adrenal (HPA) axis activity; and immune system imbalance. The aim of this article is not to discuss all of these hypotheses in detail, but to evaluate the role that serotonin may play within these hypothesized mechanisms.It is widely accepted that diminished serotonergic (5-HTergic) function is involved in the onset and course of depression. 3,4 The 5-HTergic system is a large and complex system. Although nearly all cell bodies of 5-HTergic neurons are located in the raphe nuclei in the brain stem, the axons of these neurons innervate almost the entire brain. The actions of 5-HT are mediated by 16 types and subtypes of receptors. 5 As the 5-HTergic system is assumed to be a modulatory system, the exact func...

show abstract