Microglia in the pathogenesis of autism spectrum disorders

Koyama, Ryuta; Ikegaya, Yuji

doi:10.1016/j.neures.2015.06.005

Cited by 114 publications

(84 citation statements)

References 42 publications

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“…Therefore, it is highly possible that neuroinflammation mediated by M1 microglia is associated with symptoms of ASD based on imbalance of proinflammatory M1 and antiinflammatory M2 polarization states of microglia. Our view is along the lines of previous hypotheses that the imbalance of M1/M2 polarization of microglia is implicated in neuroinflammation and disruption of excitatory versus inhibitory balance in the brain of ASD (Gottfried et al, 2015;Koyama and Ikegaya, 2015).…”

Section: Downloaded Fromsupporting

confidence: 82%

Involvement of Neuroinflammation during Brain Development in Social Cognitive Deficits in Autism Spectrum Disorder and Schizophrenia

Nakagawa¹,

Chiba²

2016

Journal of Pharmacology and Experimental Therapeutics

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Development of social cognition, a unique and high-order function, depends on brain maturation from childhood to adulthood in humans. Autism spectrum disorder (ASD) and schizophrenia have similar social cognitive deficits, although age of onset in each disorder is different. Pathogenesis of these disorders is complex and contains several features, including genetic risk factors, environmental risk factors, and sites of abnormalities in the brain. Although several hypotheses have been postulated, they seem to be insufficient to explain how brain alterations associated with symptoms in these disorders develop at distinct developmental stages. Development of ASD appears to be related to cerebellar dysfunction and subsequent thalamic hyperactivation in early childhood. By contrast, schizophrenia seems to be triggered by thalamic hyperactivation in late adolescence, whereas hippocampal aberration has been possibly initiated in childhood. One of the possible culprits is metal homeostasis disturbances that can induce dysfunction of blood-cerebrospinal fluid barrier. Thalamic hyperactivation is thought to be induced by microglia-mediated neuroinflammation and abnormalities of intracerebral environment. Consequently, it is likely that the thalamic hyperactivation triggers dysregulation of the dorsolateral prefrontal cortex for lower brain regions related to social cognition. In this review, we summarize the brain aberration in ASD and schizophrenia and provide a possible mechanism underlying social cognitive deficits in these disorders based on their distinct ages of onset.

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Section: Downloaded Fromsupporting

confidence: 82%

Involvement of Neuroinflammation during Brain Development in Social Cognitive Deficits in Autism Spectrum Disorder and Schizophrenia

Nakagawa¹,

Chiba²

2016

Journal of Pharmacology and Experimental Therapeutics

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“…During brain development, the surveillant microglia rapidly phagocytose extra synapses and newborn cells undergoing apoptosis (Paolicelli et al, ). The deficiency of microglial phagocytosis results in neuropsychiatric disorders, including autism (Koyama & Ikegaya, ) and schizophrenia (Bernstein, Steiner, Guest, Dobrowolny, & Bogerts, ). In the adult brain, the surveillant microglia participate in the remodeling of neuronal circuits by phagocytosis of mature synapses (Bisht et al, ), and also regulate hippocampal neurogenesis and hippocampal‐dependent learning and memory (Sheridan et al, ; Sierra et al, ).…”

Section: Discussionmentioning

confidence: 99%

The ketone body metabolite β‐hydroxybutyrate induces an antidepression‐associated ramification of microglia via HDACs inhibition‐triggered Akt‐small RhoGTPase activation

Huang

Wang

et al. 2017

Glia

118

107

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Direct induction of macrophage ramification has been shown to promote an alternative (M2) polarization, suggesting that the ramified morphology may determine the function of immune cells. The ketone body metabolite β-hydroxybutyrate (BHB) elevated in conditions including fasting and low-carbohydrate ketogenic diet (KD) can reduce neuroinflammation. However, how exactly BHB impacts microglia remains unclear. We report that BHB as well as its producing stimuli fasting and KD induced obvious ramifications of murine microglia in basal and inflammatory conditions in a reversible manner, and these ramifications were accompanied with microglial profile toward M2 polarization and phagocytosis. The protein kinase B (Akt)-small RhoGTPase axis was found to mediate the effect of BHB on microglial shape change, as (i) BHB activated the microglial small RhoGTPase (Rac1, Cdc42) and Akt; (ii) Akt and Rac1-Cdc42 inhibition abolished the pro-ramification effect of BHB; (iii) Akt inhibition prevented the activation of Rac1-Cdc42 induced by BHB treatment. Incubation of microglia with other classical histone deacetylases (HDACs) inhibitors, but not G protein-coupled receptor 109a (GPR109a) activators, also induced microglial ramification and Akt activation, suggesting that the BHB-induced ramification of microglia may be triggered by HDACs inhibition. Functionally, Akt inhibition was found to abrogate the effects of BHB on microglial polarization and phagocytosis. In neuroinflammatory models induced by lipopolysaccharide (LPS) or chronic unpredictable stress (CUS), BHB prevented the microglial process retraction and depressive-like behaviors, and these effects were abolished by Akt inhibition. Our findings for the first time showed that BHB exerts anti-inflammatory actions via promotion of microglial ramification.

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“…Microglial function has been proposed to be implicated in ASD development . The number of activated microglia is higher in ASD patients compared to control subjects, and some data indicate that such increased microglia activation is already present in young children, suggesting that microglial activation could be a cause rather than a consequence of the disorder.…”

Section: The Microbiota and Cns Disordersmentioning

confidence: 99%

The role of the gut microbiota in development, function and disorders of the central nervous system and the enteric nervous system

Heiss

Olofsson

2019

J Neuroendocrinology

202

131

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The gut microbiota has emerged as an environmental factor that modulates the development of the central nervous system (CNS) and the enteric nervous system (ENS). Before obtaining its own microbiota, eutherian foetuses are exposed to products and metabolites from the maternal microbiota. At birth, the infants are colonised by microorganisms. The microbial composition in early life is strongly influenced by the mode of delivery, the feeding method, the use of antibiotics and the maternal microbial composition. Microbial products and microbially produced metabolites act as signalling molecules that have direct or indirect effects on the CNS and the ENS. An increasing number of studies show that the gut microbiota can modulate important processes during development, including neurogenesis, myelination, glial cell function, synaptic pruning and blood‐brain barrier permeability. Furthermore, numerous studies indicate that there is a developmental window early in life during which the gut microbial composition is crucial and perturbation of the gut microbiota during this period causes long‐lasting effects on the development of the CNS and the ENS. However, other functions are readily modulated in adult animals, including microglia activation and neuroinflammation. Several neurobehavioural, neurodegenerative, mental and metabolic disorders, including Parkinson disease, autism spectrum disorder, schizophrenia, Alzheimer's disease, depression and obesity, have been linked to the gut microbiota. This review focuses on the role of the microorganisms in the development and function of the CNS and the ENS, as well as their potential role in pathogenesis.

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Microglia in the pathogenesis of autism spectrum disorders

Cited by 114 publications

References 42 publications

Involvement of Neuroinflammation during Brain Development in Social Cognitive Deficits in Autism Spectrum Disorder and Schizophrenia

Involvement of Neuroinflammation during Brain Development in Social Cognitive Deficits in Autism Spectrum Disorder and Schizophrenia

The ketone body metabolite β‐hydroxybutyrate induces an antidepression‐associated ramification of microglia via HDACs inhibition‐triggered Akt‐small RhoGTPase activation

The role of the gut microbiota in development, function and disorders of the central nervous system and the enteric nervous system

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