Does microglial dysfunction play a role in autism and Rett syndrome?
ABSTRACT Autism spectrum disorders (ASDs) including classic autism is a group of complex developmental disabilities with core deficits of impaired social interactions, communication difficulties and repetitive behaviors. Although the neurobiology of ASDs has attracted much attention in the last two decades, the role of microglia has been ignored. Existing data are focused on their recognized role in neuroinflammation, which only covers a small part of the pathological repertoire of microglia. This review highlights recent findings on the broader roles of microglia, including their active surveillance of brain microenvironments and regulation of synaptic connectivity, maturation of brain circuitry and neurogenesis. Emerging evidence suggests that microglia respond to pre- and postnatal environmental stimuli through epigenetic interface to change gene expression, thus acting as effectors of experience-dependent synaptic plasticity. Impairments of these microglial functions could substantially contribute to several major etiological factors of autism, such as environmental toxins and cortical underconnectivity. Our recent study on Rett syndrome, a syndromic autistic disorder, provides an example that intrinsic microglial dysfunction due to genetic and epigenetic aberrations could detrimentally affect the developmental trajectory without evoking neuroinflammation. We propose that ASDs provide excellent opportunities to study the influence of microglia on neurodevelopment, and this knowledge could lead to novel therapies.
SourceAvailable from: Herbert F JelinekFrontiers in Bioengineering and Biotechnology 04/2015; 3. DOI:10.3389/fbioe.2015.00051
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ABSTRACT: Oxytocin (OT) and arginine vasopressin (AVP) are neurohypophysial hormones. CD38 and cyclic ADP-ribose (cADPR) formation have been identified in the hypothalamus and are critical for OT, but not AVP, secretion, with profound consequential changes in social behaviors in mice. In the present study, we examined the immunolocalization of CD38, OT and AVP in different cell types in the hypothalamus and pituitary lobe of male mice. In the hypothalamus, CD38 immunoreactivity was found more commonly in OT neurons than AVP neurons. In the posterior pituitary lobe, the expression of CD38 was partly merged with OT and AVP, while pituicyte-like staining was also observed. In the CD38-deficient hypothalamus and posterior lobe, stronger staining of OT was observed, suggesting accumulation of OT due to lack of the releasing process, as reported previously. Co-expression of CD38 with glial cells showed that CD38 was rarely expressed in glial fibrillary acidic protein (GFAP)-positive astrocytes. However, expression of CD38 protein in microglia was detected and more expression of CD38 in microglia was observed in the lipopolysaccharide-injected mouse brain. The expression of CD38 in different cell types, especially in microglia, in the hypothalamus and pituitary may indicate functional roles of CD38 in brain's immune system as well as in neurohypophysial hormone release.03/2013; 2(1):54-61. DOI:10.1166/msr.2013.1021
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ABSTRACT: The autistic spectrum disorders (ASD) form a set of multi-faceted disorders with significant genetic, epigenetic and environmental determinants. Oxidative and nitrosative stress (O&NS), immuno-inflammatory pathways, mitochondrial dysfunction and dysregulation of the tryptophan catabolite (TRYCATs) pathway play significant interactive roles in driving the early developmental etiology and course of ASD. O&NS interactions with immuno-inflammatory pathways mediate their effects centrally via the regulation of astrocyte and microglia responses, including regional variations in TRYCATs produced. Here we review the nature of these interactions and propose an early developmental model whereby different ASD genetic susceptibilities interact with environmental and epigenetic processes, resulting in glia biasing the patterning of central interarea interactions. A role for decreased local melatonin and N-acetylserotonin production by immune and glia cells may be a significant treatment target.Current Neuropharmacology 03/2014; 12(2):148-67. DOI:10.2174/1570159X11666131120223757 · 2.35 Impact Factor