Neuro-Diversity, microglia, Synapses & Energy

Val's Take/Conjecture

• BIO-ENERGETICS is expressed in many DIVERSE ways in Neuro-Diverse people.
• Further, a common strategy for Neuro-Diverse folks is "HYPER-FOCUS."
• That can look like ENORMOUS MENTAL ENERGY ---
  
  • ​which in some ways it is.
    
  • BUT it is also a strategy to CONSERVE ENERGY and REDUCE TRANSITIONS.
    

​Synapses: The Brain's Energy-Demanding Sites (2022)

Abstract

The brain is one of the most energy-consuming organs in the mammalian body, and synaptic transmission is one of the major contributors.

To meet these energetic requirements, the brain primarily uses glucose, which can be metabolized through glycolysis and/or mitochondrial oxidative phosphorylation.

The relevance of these two energy production pathways in fulfilling energy at presynaptic terminals has been the subject of recent studies.

In this review, we dissect the balance of glycolysis and oxidative phosphorylation to meet synaptic energy demands in both resting and stimulation conditions.

Besides ATP output needs, mitochondria at synapse are also important for calcium buffering and regulation of reactive oxygen species.

These two mitochondrial-associated pathways, once hampered, impact negatively on neuronal homeostasis and synaptic activity.

Therefore, as mitochondria assume a critical role in synaptic homeostasis, it is becoming evident that the synaptic mitochondria population possesses a distinct functional fingerprint compared to other brain mitochondria.

Ultimately, dysregulation of synaptic bioenergetics through glycolytic and mitochondrial dysfunctions is increasingly implicated in neurodegenerative disorders, as one of the first hallmarks in several of these diseases are synaptic energy deficits, followed by synapse degeneration.

​Metabolome subtyping reveals multi-omics characteristics and biological heterogeneity in major psychiatric disorders (2023)

Abstract
Growing evidence suggests that major psychiatric disorders (MPDs) share common etiologies and pathological processes. However, the diagnosis is currently based on descriptive symptoms, which ignores the underlying pathogenesis and hinders the development of clinical treatments.

This highlights the urgency of characterizing molecular biomarkers and establishing objective diagnoses of MPDs.

​Here, we collected untargeted metabolomics, proteomics and DNA methylation data of 327 patients with MPDs, 131 individuals with genetic high risk and 146 healthy controls to explore the multi-omics characteristics of MPDs.

First, differential metabolites (DMs) were identified and we classified MPD patients into 3 subtypes based on DMs.

The subtypes showed distinct metabolomics, proteomics and DNA methylation signatures.

Specifically, one subtype showed dysregulation of complement and coagulation proteins, while the DNA methylation showed abnormalities in chemical synapses and autophagy.

Integrative analysis in metabolic pathways identified the important roles of the citrate cycle, sphingolipid metabolism and amino acid metabolism.

Finally, we constructed prediction models based on the metabolites and proteomics that successfully captured the risks of MPD patients.

Our study established molecular subtypes of MPDs and elucidated their biological heterogeneity through a multi-omics investigation.

These results facilitate the understanding of pathological mechanisms and promote the diagnosis and prevention of MPDs [Major Psychiatric Disorders].

The Underlying Neurobiological Mechanisms of Psychosis (2024):

Focus on

• Neurotransmission Dysregulation,
• Neuroinflammation,
• Oxidative Stress, and
• Mitochondrial Dysfunction 

Synaptic elimination by microglia and disturbed higher brain functions (2021)

Highlights

Microglia engage in synaptic elimination by phagocytosis in mature brains.

Selective synaptic elimination changes excitatory/inhibitory (E/I) balance.

Microglia modulate neuropsychiatric disorders by synaptic elimination.

This review discusses Parkinson's and Alzheimer's diseases, ASD [Autism Spectrum Disorder], ADHD, and schizophrenia.

Errant gardeners: glial-cell-dependent synaptic pruning and neurodevelopmental disorders (2017)

​Key Points

Brain development is associated with the formation of excessive synapses that have to be removed in a controlled and timely manner to achieve refined mature circuitry.

Glial cells, including microglia and astrocytes, are the effectors of synaptic pruning, identifying and eliminating superfluous synapses.

Synaptic pruning depends on various molecules, including those controlling glial chemotaxis, target recognition and phagocytosis.

Autism spectrum disorders are associated with excessive synapses, autophagy and dysregulated microglial function.

Schizophrenia is linked to exaggerated synaptic pruning owing to elevated levels of complement proteins and microglial activation.

Epilepsy is thought to arise owing to immature circuitry that was not refined via synaptic pruning.

This initial epileptiform activity is followed by microglial activation and upregulation of complement components.

Synapses & Neuro-Developmental & Psychiatric Disorders

Synaptic changes in psychiatric and neurological disorders: state-of-the art of in vivo imaging (2024)

The stressed synapse 2.0: pathophysiological mechanisms in stress-related neuropsychiatric disorders (2022)

Immune synaptopathies: how maternal immune activation impacts synaptic function during development (2023)

​"In the present review, we highlight this concept, which we define by the term “immune‐synaptopathy,” and we discuss recent evidence suggesting a bi‐directional link between the genetic architecture of individuals and maternal activation of the immune system in modulating brain developmental trajectories in health and disease."