Past research has often highlighted the effects that immune activation in pregnant women can have on the development of human embryos, for instance increasing the risk of a child developing psychiatric disorders later in life.
The neural mechanisms underpinning these effects, however, remain largely unclear.
Researchers at New York Medical College have recently carried out a study investigating the impact that the activation of microglia (i.e., a specialized cell population that removes damaged neurons or infections) can have on an embryo’s development of a specific class of neurons that regulates information processing, known as cortical interneurons.
Their findings, published in Nature Neuroscience, suggest that activated microglia can cause metabolic disruptions that adversely impact the development of cortical interneurons.
Interestingly, in individuals diagnosed with schizophrenia these disruptions could persist when the microglia are no longer activated.
“While we now known that cortical interneurons are affected by maternal immune activation, the mechanism through which they are affected is still poorly understood,” Sangmi Chung, one of the researchers who carried out the study, told Medical Xpress.
“Since the human embryo is not accessible for mechanistic studies, we used iPSC-derived human cortical interneurons to investigate how inflammation during development affects this vulnerable population of neurons.”
Chung and her colleagues generated cortical interneurons using induced pluripotent stem cells (iPSCs), a technological tool that allows neuroscientists to reprogram cells that are extracted from human tissue samples.
Past studies have found that individuals with schizophrenia present abnormal patterns in the functioning of cortical interneurons.
The researchers hoped that their study would enhance the present understanding of the neural mechanisms that may lead to the development of Schizophrenia or other neuropsychiatric disorders.
The cortical interneurons used in their experiments were thus generated both from people with no psychiatric disorders and from patients diagnosed with schizophrenia.
After they created these cells, Chung and her colleagues co-cultured them either with or without activated microglial cells and observed the effects that these two procedures had on cortical interneurons generated from the tissue of healthy subjects and on those derived from that of patients with schizophrenia.
Co-culture is a technique that enables the simultaneous cultivation of two or more different types of cells. The researchers specifically used a method called tissue culture insert, which allowed the signals released from microglia to reach the cortical interneurons they created through a membrane that was inserted between them, which is permeable but does not allow cells to pass through.
“We found that the metabolism of cortical interneurons is compromised under inflammatory condition during development, which showed prolonged impact in cortical interneurons derived from schizophrenia iPSCs but not healthy control iPSCs,” Chung said. “Our findings highlight the existence of interactions between schizophrenia genetic backgrounds and environmental risk factors.”
The findings gathered by Chung and her colleagues could inform future studies investigating the neural mechanisms that link prenatal immune activation with the risk of developing schizophrenia or other neuropsychiatric disorders.
Most notably, it suggests that the activation of microglia, the cells that protect the nervous system against diseases and carry out immune responses, can cause metabolic disruptions in developmental cortical interneurons.
Moreover, the researchers found that in the cortical interneurons generated from the tissue of individuals with no neuropsychiatric disorders, these metabolic deficits were no longer present after the activated microglia were removed, while they persisted in patients affected by schizophrenia.
Their findings could thus help to identify pre-natal neural processes that may interact with a person’s genetic propensity for developing schizophrenia, increasing his/her risk of the developing the disorder later in life.
“We now plan to pursue further studies investigating the detailed mechanisms and pathways that are affected by inflammatory environments surrounding cortical interneurons,” Chung said.
There is increasing evidence indicating that maternal immune activation (MIA) during pregnancy is an important risk factor for the progeny to develop neuropsychiatric disorders including autism spectrum disorders (ASD). Infections during pregnancy activate the mother’s immune system leading to various alterations in the fetal environment that may have negative impact on offspring development [1].
In particular, activation of MIA during critical time points of fetal neurogenesis may negatively affect brain structure and function of progeny.
The relevance of inflammation in these disorders suggests the correlation between brain dysfunction and alterations in pro-inflammatory cytokines and the number and/or morphology of microglial cells [2]. During brain development, the autocrine and paracrine signaling via cytokines regulates neuronal migration, growth, function and survival.
Therefore, the MIA-evoked cytokine imbalance significantly affects developmental processes [3,4,5]. Throughout prenatal exposure to inflammation, there are apparent links between ASD and penetration of pro-inflammatory agents into the developing brain [6,7,8,9].
In vivo experimental data indicated that male offspring of rat dams treated with lipopolysaccharide (LPS), which mimics bacterial infection, displayed impaired communication and repetitive behavior, suggestive of autism-like behavior [10,11,12]. Moreover, preclinical studies on prenatal infection as well as on animal models of MIA demonstrated observable abnormalities in neuronal development of offspring along with an increase in microglia, which is linked to schizophrenia-like behavior [13,14,15].
Notably, microglial activation and an increase in the density of microglial cells have been also demonstrated post-mortem in the cerebral cortex of patients with autism [16] and schizophrenia [17]. However, the cellular and molecular links between MIA-mediated disturbances in fetal brain development, impaired brain function, and occurrence of neuropsychiatric disorders are still unclear.
Current knowledge suggests a combination of genetic, epigenetic, and environmental factors, and their involvement in dysregulation of neurotransmission [6,18].
Despite multiple hypotheses concerning the etiology of ASD or schizophrenia, it is believed that the common pathological features for these disorders are associated with dysfunction in synaptic transmission, including trans-synaptic recognition and signaling processes, mediated by specific cell adhesion molecules.
The main piece of evidence supporting this concept came from genetic studies showing that gene mutations in neuroligins (Nlgn), the cell adhesion molecules that mediate formation and maintenance of synapses, especially Nlgn3 and Nlgn4x, are key determinants of ASD [19,20,21,22,23].
Currently, almost 100 gene mutations associated with this system have been identified in patients with ASD [24,25,26,27]. A significant proportion of these genes encode proteins that are localized in the post-synaptic terminals or those regulating synaptic function.
The best characterized are the intracellular binding partners: SHANK (SH3 and multiple ankyrin repeat domains protein) and PSD-95 (post-synaptic density protein 95). Also neurexins, the adhesive partners for neuroligins, were previously demonstrated to be affected in individuals with ASD [22,28,29].
These synaptic scaffolding proteins are necessary for the proper organization of various receptors on post-synaptic densities (PSD), by linking them to their signaling effectors and to the cytoskeleton [30,31,32]. Despite the numerous links between MIA and the pathology of ASD and schizophrenia, data demonstrating the impact of MIA on synaptic structure are relatively scarce.
Most recently, a study demonstrated that MIA deregulates the expression of genes associated with synaptogenesis, axonal guidance, synaptic contact and neurogenesis in rat fetal brain within 4 h post-LPS injection [33]. However, it is not known how those changes affect the structure and function of nerve terminals in offspring.
Therefore, the aim of the present study was to characterize the effects of MIA on postnatal behavioral deficits, extent of inflammatory changes, and the most important, abnormalities in synaptic structure, and on the levels of synaptic proteins in adolescent rat offspring.
reference link : https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7312084/
More information: Activated microglia cause metabolic disruptions in developmental cortical interneurons that persist in interneurons from individuals with schizophrenia. Nature Neuroscience(2020). DOI: 10.1038/s41593-020-00724-1
