Microglia and Neurodevelopmental Disorders

Abstract

Mounting evidence indicates that microglia, which are the resident immune cells of the brain, play critical roles in a diverse array of neurodevelopmental processes required for proper brain maturation and function. This evidence has ultimately led to growing speculation that microglial dysfunction may play a role in neurodevelopmental disorder (NDD) pathoetiology. In this review, we first provide an overview of how microglia mechanistically contribute to the sculpting of the developing brain and neuronal circuits. To provide an example of how disruption of microglial biology impacts NDD development, we also highlight emerging evidence that has linked microglial dysregulation to autism spectrum disorder pathogenesis. In recent years, there has been increasing interest in how the gut microbiome shapes microglial biology. In the last section of this review, we put a spotlight on this burgeoning area of microglial research and discuss how microbiota-dependent modulation of microglial biology is currently thought to influence NDD progression.

Keywords: Rett syndrome; autism; microbiome; microglia; neurodevelopmental disorders.

Figure 1

Microglia in circuit development relevant to neurodevelopmental disorders. During development, microglia regulate salient aspects of circuit development, including (a) inducing neuronal demise through NGF, superoxide ion, and TNF-alpha; (b) mediating neuronal survival through IGF-1 and fractalkine (CX3CL1-CX3CR1) signaling; (c) facilitating synapse formation and elimination through complement, Trem2, P2RY12, and CD47 signaling; and (d) conducting cell and ECM clearance through TAM family receptors, fractalkine signaling, DAP12, complement, and IL-33-IL-1R1 signaling. Abbreviations: CX3CL1, C-X3-C motif chemokine ligand 1; CX3CR1, C-X3-C motif chemokine receptor 1; DAP12, DNAX-activating protein of 12 kDa; ECM, extracellular matrix; IGF-1, Insulin growth factor 1; NGF, neurotrophic growth factor; P2RY12, metabotropic purinergic receptor 12; TAM, TYRO3, AXL, and MERTK family receptors; TNF-alpha, tumor necrosis factor alpha; TREM2, Triggering Receptor Expressed On Myeloid Cells 2.

Figure 2

Effects of the microbiome on microglial development and function. The microbiome can alter microglial development and function by three main mechanisms. (a) In the first mechanism, metabolites generated by commensal microbes such as short-chain fatty acids (SCFAs) and p-cresol can influence microglial maturation and activation status. (b) In the second mechanism, calibration of peripheral immune responses by the microbiome can lead to downstream effects on microglial biology. Cytokine production by immune cells in the periphery can potently modulate microglia morphology, numbers, and function. The microbiome is critically involved in the education and calibration of the peripheral immune system, where alterations in microbial landscape can directly impact cytokine production and immune cell numbers. T cells contribute to proper maturation of microglia under homeostatic conditions. Type I interferon (IFN) secretion and production of the proinflammatory cytokine IL-17a by T cells can promote the development of autism spectrum disorder (ASD)-related behavioral abnormalities in mice, and this is often accompanied by dysregulated microglial activation. (c) In the third mechanism, the microbiome can signal through the vagus nerve to modulate microglial biology. Stimulation of the vagus nerve potently dampens the production of proinflammatory cytokines (e.g., IL-1β and IL-6) by microglia. The gut commensal bacteria Lactobacillus reuteri (L. reuteri) has been shown to provide protection against the development of neurodevelopmental disorders in multiple experimental models, and these protective effects conferred by L. reuteri supplementation are dependent on vagus nerve signaling.