Microglia Dysfunction in Brain Pathology

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Abnormal microglia synapse elimination can cause imbalances in excitatory and inhibitory synapses and give way to brain disease.

Written by Brett Weiss


As cells that engulf and consume dead or dying neurons, microglia constitute the immune system of the brain and spinal cord– the central nervous system. Scientists have long considered them to be resting until neuron injury or disease take place. More recently, though, research indicates they consume– phagocytose– connections between neurons called synapses and in doing so maintain neural circuits.

Recently, Tanaka and colleagues from Ehime University in Japan published a review in Neurochemistry International where they described current research on microglia and how their dysfunction can lead to memory and attention impairments which culminates in disease. They described three proposed cellular models whereby abnormal microglial function leads to the diseases autism spectrum disorder (ASD), attention deficit hyperactivity disorder (ADHD), and schizophrenia.

Research has demonstrated that microglia eliminate neuronal synapses. For instance, evidence suggests microglia eliminate synapses during sleep as a mechanism to forget more or less irrelevant memories acquired throughout a day.

Through synaptic elimination, microglia can affect the balance between excitatory and inhibitory synapses. An excitatory synapse means that activation of the synapse makes the activation of the neuron receiving the neural signal more likely. Activation of an inhibitory neuronal connection makes the excitement of the neuron receiving the signal less likely.

Tanaka and colleagues reported that a suppressed microglial elimination of synapses occurs in ASD. Deficits in social communication and limited interest with repetitive behaviors are hallmarks of ASD. Animal models like mice and rats that have genetic alterations that diminish microglial activity display these characteristics of ASD. Not only that but males have four times the incidence of ASD compared to females, and female microglia have greater ability to eliminate synapses and injured neurons. Studies also indicate an imbalance between excitatory and inhibitory neuronal connections with synapses tending toward overexcitation in ASD.

Research indicates an overactivation of microglia in ADHD with excessive elimination of inhibitory synapses. Symptoms of hyperactivity, inattention, and impulsivity go along with diagnoses of ADHD. Hyperactivation of neurons in regions of the brain involved in self-regulation, planning, and focusing attention can result in behavioral symptoms of ADHD possibly owing to excessive microglial elimination of inhibitory neural connections.

Studies indicate overactivation of microglia in schizophrenia patients with reductions in excitatory and inhibitory neural connections alike. Symptoms of schizophrenia include hallucinations, delusions, disordered thinking, and behavioral problems. These complications could come in part from overactivation of microglia which can reduce the thickness of brain regions containing neuron cell bodies called gray matter and lead to abnormal neural connections.

(Miyanishi | Neurochemistry International) Dysfunctional microglia activation occurs in autism spectrum disorder (ASD), attention deficit hyperactivity disorder (ADHD), and schizophrenia (SCZ). In ASD, less elimination of synapses occurs along with a propensity toward the presence of more excitatory synapses than inhibitory synapses. In ADHD, more elimination of synapses occurs which tends to target inhibitory synapses, leading to the presence of more excitatory than inhibitory synapses. In SCZ, an overactivation of microglia exists that decreases the total number of excitatory and inhibitory synapses and which may also lead to brain volume reductions.

“Elucidation of the mechanisms and regulatory systems underlying the microglial synaptic elimination, as well as its physiological significance in the normal mature brain, will lead to development of novel therapeutic interventions in mental, developmental, and degenerating neurological disorders,” stated Tanaka and colleagues in their review. Most importantly, the review points to microglial function and dysfunction as a cellular mechanism that can lead to multiple diseases and disorders of the brain. Previous studies had only addressed microglia as cells that respond to injury or disease as a means to heal the brain. From the perspective that Tanaka and colleagues presented, microglial dysfunction in itself can be source of brain dysfunction and disease and could thus be a therapeutic target.

Story Source

Miyanishi K, Sato A, Kihara N, Utsunomiya R, Tanaka J. Synaptic elimination by microglia and disturbed higher brain functions. Neurochem Int. 2020 Nov 9;142:104901. doi: 10.1016/j.neuint.2020.104901. Epub ahead of print. PMID: 33181238.

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