Does microglial dysfunction play a role in autism and Rett syndrome?

M.I.N.D. (Medical Investigation of Neurodevelopmental Disorders) Institute and Department of Pathology and Laboratory Medicine, Sacramento, CA, USA.
Neuron Glia Biology (Impact Factor: 6.64). 04/2012; 7(1):85-97. DOI: 10.1017/S1740925X1200004X
Source: PubMed


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.

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    • "Proposed roles include “fine-tuning” CNS structure, promoting axonal growth, directing neuronal migration, determining neuronal phenotypes, interacting with oligodendrocytes in myelination, influencing vascularization, and disposing of debris and normally dying cells. Through epigenetic, structural, and other mechanisms, they may also contribute to developmental disruptions and subsequent neuropathology such as in fetal alcohol spectrum disorder, cerebral palsy, Down's syndrome, autism, and schizophrenia (Hao et al., 2001a,b; Aarum et al., 2003; McAllister and Miller, 2010; Maezawa et al., 2011; Paolicelli et al., 2011). There are many opportunities to test the ability of fractal analysis to contribute to our knowledge of early development. "
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    ABSTRACT: Glial cells consisting of oligodendrocytes, astrocytes, microglia, and NG2 positive cells are major cell populations in the central nervous system, number-wise. They function as effectors and modulators of neurodevelopment through a wide variety of neuron-glial cell interactions in brain development and functions. Glial cells can be affected by both genetic and environmental factors, leading to their dysfunctions in supporting neuronal development and functions. These in turn can affect neuronal cells, causing alterations at the circuitry level that manifest as behavioral characteristics associated with schizophrenia in late teens-early twenties. Glial cells are also involved in neuroinflammatory processes, which sometimes have deleterious effects on the normal brain development. If the glial involvement plays significant roles in schizophrenia, the processes involving glial cells can become possible therapeutic targets for schizophrenia. A number of known antipsychotics are shown to have beneficial effects on glial cells, but other drugs targeting glial cell functions may also have therapeutic effects on schizophrenia. The latter can be taken into consideration for future drug development for schizophrenia.
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