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

Abstract

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.

Psycho-Behavioral Spiral of Disturbances in Prosocial Behavior, Stress Response, and Self-Regulation inSubstance-Related and Addictive Disorders

“…It is likely that M1 polarization of microglia is persistent under inhibition in the M2 state and that imbalance of M1/M2 microglia subsequently leads to disturbances in the DLPFC [5,6,7]. Taken together, imbalance between pro-and antiinflammatory subsets of microglia appears to mainly contribute to self-regulation system disturbances in mood disorders, ASD, and schizophrenia in contrast to SRADs.…”

“…It is also known that the hippocampus plays a pivotal role in HPA axis functions [85]. As mentioned above, there is functional interaction among the hippocampus, amygdala, NAc, VMPFC, and ACC which allows them to be regulated by DLPFC top-down processing [4,5,6,7]. Given this, it is likely that HPA axis function is initially controlled by the DLPFC and subsequently, with the development of SRADs, by the amygdala and hippocampus.…”

“…On the other hand, hyperactivation of possible initiating brain regions of mood disorders, ASD, and schizophrenia patients can induce M1 polarization of microglia which produces proinflammatory cytokines and chemokines including IL-6, TNF-α, and CC-chemokine ligand (CCL)-2 [5,6,7]. It is likely that M1 polarization of microglia is persistent under inhibition in the M2 state and that imbalance of M1/M2 microglia subsequently leads to disturbances in the DLPFC [5,6,7].…”

“…This regulation is crucial in humans for self-regulation of behavioral responses [4]. We have previously hypothesized that disturbances in the self-regulation system are a common feature of psychiatric conditions, and that they underlie the emotional and social cognitive abnormalities associated with mood disorders, schizophrenia, and ASD [5,6,7].…”

Microglial Intracellular Ca2+ Signaling in Synaptic Development and its Alterations in Neurodevelopmental Disorders

“…Although there is no clinical use of minocycline in ASDs, prenatal minocycline treatment can alter the expression of PSD-95 and ameliorate abnormal mother-infant communication in oxytocin receptor (Oxtr)-deficient mice (Miyazaki et al, 2016). This finding suggests that minocycline has a therapeutic potential for the development of OT/Oxtr-mediated ASD-like phenotypes (Nakagawa and Chiba, 2016). In addition, OT suppressed both the mRNA expression of TNFα, IL-1β, COX-2 and iNOS and the elevation of [Ca 2+ ]i in LPS-stimulated microglia cells (Yuan et al, 2016).…”