Microglia Gone Rogue: Impacts on Psychiatric Disorders across the Lifespan

Abstract

Microglia are the predominant immune response cells and professional phagocytes of the central nervous system (CNS) that have been shown to be important for brain development and homeostasis. These cells present a broad spectrum of phenotypes across stages of the lifespan and especially in CNS diseases. Their prevalence in all neurological pathologies makes it pertinent to reexamine their distinct roles during steady-state and disease conditions. A major question in the field is determining whether the clustering and phenotypical transformation of microglial cells are leading causes of pathogenesis, or potentially neuroprotective responses to the onset of disease. The recent explosive growth in our understanding of the origin and homeostasis of microglia, uncovering their roles in shaping of the neural circuitry and synaptic plasticity, allows us to discuss their emerging functions in the contexts of cognitive control and psychiatric disorders. The distinct mesodermal origin and genetic signature of microglia in contrast to other neuroglial cells also make them an interesting target for the development of therapeutics. Here, we review the physiological roles of microglia, their contribution to the effects of environmental risk factors (e.g., maternal infection, early-life stress, dietary imbalance), and their impact on psychiatric disorders initiated during development (e.g., Nasu-Hakola disease (NHD), hereditary diffuse leukoencephaly with spheroids, Rett syndrome, autism spectrum disorders (ASDs), and obsessive-compulsive disorder (OCD)) or adulthood (e.g., alcohol and drug abuse, major depressive disorder (MDD), bipolar disorder (BD), schizophrenia, eating disorders and sleep disorders). Furthermore, we discuss the changes in microglial functions in the context of cognitive aging, and review their implication in neurodegenerative diseases of the aged adult (e.g., Alzheimer’s and Parkinson’s). Taking into account the recent identification of microglia-specific markers, and the availability of compounds that target these cells selectively in vivo, we consider the prospect of disease intervention via the microglial route.

Microglial subtypes: diversity within the microglial community

“…Differences in microglial number, morphology, and gene expression were also reported between sexes (Schwarz et al , ; Crain et al , ; Lenz et al , ; Pimentel‐Coelho et al , ; Butovsky et al , ; Dorfman et al , ; Hanamsagar et al , ; Krasemann et al , ). Adequate microglial functions are crucial for plasticity and behavioral adaptation to the environment (Salter & Stevens, ; Tay et al , ). Throughout life, microglia contribute to neurogenesis, neuronal circuit shaping, vascular formation and remodeling, and maintenance of homeostasis (Tay et al , ).…”

“…During aging and in diseases, these cells may become reactive or impaired in their surveillance and phagocytosis (Streit, ; Koellhoffer et al , ; Spittau, ). Microglial contribution to diseases is associated with compromised physiological roles (e.g., in synaptic maintenance and plasticity; Tay et al , ) and processes that are adaptive in the healthy brain, yet leading to cell death and tissue damage in pathological settings (e.g., excitotoxicity, oxidative stress, and inflammation; Weil et al , ). Microglial reaction can be triggered by any kind of insults or disturbances to the CNS.…”

Maternal thyroid autoimmunity associated with acute‐onset neuropsychiatric disorders and global regression in offspring

“…Epidemiological studies have reported a higher rate of maternal autoimmunity in children with ASD and Tourette syndrome . It has been hypothesized that maternal autoimmunity and other maternal immune factors may pose a risk to the fetus through ‘maternal immune activation’, whereby the inflammatory milieu in utero is thought to result in epigenetic alteration of expression of genes involved in neuronal development and/or activation of the resident immune cells of the brain, the microglia . Although there is robust animal model support for the maternal immune activation hypothesis, evidence in humans is lacking, and longitudinal studies are required.…”

Haploinsufficiency of the psychiatric risk gene Cyfip1 causes abnormal postnatal hippocampal neurogenesis through microglial and Arp2/3 mediated actin dependent mechanisms

“…The 15q11.2(BP1-BP2) deletion is not solely associated with schizophrenia, it also markedly increases risk for autism spectrum disorders 63 , ADHD and developmental delay 64 , and epilepsy 65 . Whether altered microglia functioning due to Cyfip1 haploinsufficiency, impacting on adult hippocampal neurogenesis, also plays a part in these disorders is an open question, but all have been associated with alterations in immune system and microglia functioning 66,67 . Moreover, as noted previously, a number of schizophrenia risk genes, including DISC1 37 , SREB2/GPR85 38 , CACNA1C 39,40 DGCR8 41 , and miR137 42 , have also been shown to modify adult hippocampal neurogenesis in model systems.…”