Microglia and lipids: how metabolism controls brain innate immunity (2021)

In the last years, single-cell analyses have revealed that microglia exhibit diverse phenotypes during development, growth and disease. Emerging evidence suggests that such phenotype transitions are mediated by reprogramming of cell metabolism. Indeed, metabolic …

Cytokine Imbalance in Schizophrenia. From Research to Clinic: Potential Implications for Treatment (2021)

• Gene polymorphisms of several cytokines are associated with the development of the schizophrenia syndrome. In patients with schizophrenia, presence of gene polymorphisms of proinflammatory cytokines, such as IL-1β and IL-6, have been linked to high serum levels of these cytokines. 

Inflammation in Bipolar Disorder (2018)

Elevated levels of pro-inflammatory cytokines

• Bipolar disorder (BD) is a severe and persistent mental illness associated with increased rates of several inflammatory medical comorbidities. Replicated evidence has demonstrated a strong association between BD and elevated levels of pro-inflammatory cytokines.

Inflammatory Cytokine: An Attractive Target for Cancer Treatment (2022)

"The pro-inflammatory cytokines are associated with advanced cancer stages, resistance to immunotherapy, and poor prognoses, such as in objective response and disease control rates, and progression-free and overall survival.

"In this review, we selected colorectal, pancreatic, breast, gastric, lung, and prostate cancers, which are well-reported for an association between cancer and inflammatory cytokines."

"The related cytokines and their effects on each cancer’s development and prognosis were summarized.

In addition, the treatment strategies targeting inflammatory cytokines in each carcinoma were also described here. By understanding the biological roles of cancer-related inflammatory cytokines, we may modulate the inflammatory tumor microenvironment for potential cancer treatment.

The causal relationship between 41 inflammatory cytokines and hypothyroidism: bidirectional two-sample Mendelian randomization study (2023)

"The high rate of comorbidity between hypothyroidism and psychiatric disorders deserves special attention, indicating the importance of consistent monitoring and timely identification of psychiatric symptoms to prevent disease exacerbation and facilitate therapeutic management."

Role of pro-inflammatory cytokines released from microglia in neurodegenerative diseases  (2011)

• Microglia are activated in response to a number of different pathological states within the CNS including injury, ischemia, and infection.
• Microglial activation results in their production of pro-inflammatory cytokines such as IL-1, IL-6, and TNF-α
  

Maternal immune activation alters fetal and neonatal microglia phenotype and disrupts neurogenesis in mice

Maternal immune activation (MIA) alters microglial phenotypes in the brain of fetal and neonatal mouse offspring. MIA leads to excessive proliferation and overproduction of neural progenitors in the subventricular zone (SVZ). MIA reduces parvalbumin+ while increases Reelin+ interneurons in the prefrontal cortex.

Maternal immune activation and neuroinflammation in human neurodevelopmental disorders (2021)

Abstract

"Maternal health during pregnancy plays a major role in shaping health and disease risks in the offspring.

"The maternal immune activation hypothesis proposes that inflammatory perturbations in utero can affect fetal neurodevelopment, and evidence from human epidemiological studies supports an association between maternal inflammation during pregnancy and offspring neurodevelopmental disorders (NDDs).

"Diverse maternal inflammatory factors, including obesity, asthma, autoimmune disease, infection and psychosocial stress, are associated with an increased risk of NDDs in the offspring.

"In addition to inflammation, epigenetic factors are increasingly recognized to operate at the gene-environment interface during NDD pathogenesis.

"For example, integrated brain transcriptome and epigenetic analyses of individuals with NDDs demonstrate convergent dysregulated immune pathways.

"In this Review, we focus on the emerging human evidence for an association between maternal immune activation and childhood NDDs, including autism spectrum disorder, attention-deficit/hyperactivity disorder and Tourette syndrome.

"We refer to established pathophysiological concepts in animal models, including immune signalling across the placenta, epigenetic 'priming' of offspring microglia and postnatal immune-brain crosstalk.

"The increasing incidence of NDDs has created an urgent need to mitigate the risk and severity of these conditions through both preventive strategies in pregnancy and novel postnatal therapies targeting disease mechanisms."

Val's Take/Conjecture

• Ignorance is one of the most anxiety producing states, especially when the stakes are high.
• In 2013, the National Institute of Mental Health found that ADHD, Autism, Bipolar Disorder, Depression and Schizopheria were not distinct, and were blurred --- sharing common genes and mechanisms such as calcium channels.
  

National Institute of Mental Health
Five Mental Disorders Share Some of the Same Genes

See also:

Even back in 2013, the National Institute of Mental Health was recognizing the importance of the IMMUNE SYSTEM in Neuro-Developmental and Psychiatric Disorders --- it wasn't necessarily the dominant theme in the research.

Now over a decade later, the research is exploding all over the world, and we're talking about the importance of Maternal Immune Activation and the Microglia (immune cells in the Brain -- Central Nervous System) and the Mitochondria in those cells.

In 2024, we're seeing overlaps not only between Neuro-Developmental and Psychiatric Disorders, but also Endocrine Disorders, Autoimmune Disorders, Metabolic Dysregulation, Cancer, and Neuro-Degenerative Disorders.

Transcriptional and epigenetic decoding of the microglial aging process (2023)

The role of microglia in early neurodevelopment and the effects of maternal immune activation (2024)

Emerging epigenetic dynamics in gut-microglia brain axis: experimental and clinical implications for accelerated brain aging in schizophrenia (2023)

Microglia promote autoimmune inflammation via the noncanonical NF-κB pathway (2021)

Microglial Metabolic Reprogramming: Emerging Insights and Therapeutic Strategies in Neurodegenerative Diseases (2023)

Microglia, neurodegeneration and loss of neuroendocrine control (2020)

The Role of Microglia in Brain Metastases: Mechanisms and Strategies (2024)

Ensheathing glia promote increased lifespan and healthy brain aging (2023)

Deletion of TRPC6, an Autism Risk Gene, Induces Hyperexcitability in Cortical Neurons Derived from Human Pluripotent Stem Cells. (2023)

"ASD often co-occurs with attention-deficit hyperactivity disorder and epilepsy, which are associated with hyperexcitability of neurons.

"...Our data provide evidence that reduction of SOCE by TRPC6 KO results in neuronal hyperexc …"

Bright, but allergic and neurotic? A critical investigation of the "overexcitable genius" hypothesis. (2022)

"Individuals at the upmost end of the intelligence distribution are reported to be disproportionately afflicted by a set of stress-related physical and mental health conditions: so-called overexcitabilities.

"Few accounts have investigated this issue and no studies are avail …"

Potential of GABA-ergic cell therapy for schizophrenia, neuropathic pain, and Alzheimer's and Parkinson's diseases. (2016)

"Several neurological and psychiatric disorders present hyperexcitability of neurons in specific regions of the brain or spinal cord, partly because of some loss and/or dysfunction of gamma-amino butyric acid positive (GABA-ergic) inhibitory interneurons."

Intergenerational Metabolic Syndrome and Neuronal Network Hyperexcitability in Autism.  (2019)

"Maternal insulin resistance, obesity, and diabetes may predispose offspring to ASD by mechanisms involving chronic activation of anabolic cellular pathways and a lack of metabolic switching to ketosis resulting in a deficit in GABAergic signaling and neuronal network hy …"

Disruption of the Na(+)/K(+)-ATPase-purinergic P2X7 receptor complex in microglia promotes stress-induced anxiety.  (2024)

"Accordingly, global deletion or conditional deletion of NKAalpha1 in microglia under chronic stress-induced aggravated anxiety-like behavior and neuronal hyperexcitability.

"DR5-12D, a monoclonal antibody that stabilizes membrane NKAalpha1, improved stress-ind …"

Rod-shaped microglia interact with neuronal dendrites to regulate cortical excitability in TDP-43 related neurodegeneration. (Preprint, July 2024)

"Notably, rod-shaped microglia predominantly interact with neuronal dendrites and excitatory synaptic inputs to attenuate motor cortical hyperactivity.

"The elimination of rod-shaped microglia through TREM2 deficiency increased neuronal hyperactivity, ex …"