How microglia function in healthy brain
Microglia regulation of neuron activity was missed until very recently. Microglia are better known as the resident immune cells, or macrophages, of the central nervous system (CNS), the brain and the spinal cord. It is only since 2009 that the multifaceted nature of microglial cell involvement in neuron signaling and plasticity became recognized.
Traditional view of microglia function
Unlike peripheral immune system macrophages that are short lived, microglia are long-lived cells and subject to the influences of normal aging. Central nervous system resident times for microglia extend across much of an animal’s lifespan. This is in contrast to the few hours to few days that peripheral macrophages survive.
Microglia are of embryonic mesodermal origin. They appear very early in embryological development during primitive blood cell formation in the yolk sac long before bone marrow blood cell development. Thus microglia and bone marrow originated macrophages represent two genetically distinct populations.
Microglia, prior to pathogen exposure, possess a very small cell body with many long branched processes extending into the surrounding area. The processes continuously contact and elongated to scan their tissue environment.
One aspect of microglia function is to act as a pathogen sensor. They become ‘activated’ upon infection with bacteria and viruses. In their activated state microglia can engulf and digest infectious particles and damaged cellular material. Activated microglia also release many immune system effector molecules that recruit T cells and macrophages across the blood-brain barrier to limit infections in the central nervous system.
In the adult, microglia represent about 10% of the cells in the brain and spinal cord and they are very evenly distributed in all regions. Processes of neighboring microglia do not overlap, and each microgllial cell acts as a scavenger for its immediate area.
It is sensors – proteins also known as receptors – in the membrane of these processes that detect signals (chemicals called ligands) requiring a response from microglia.
If it is a pathogen signal that is detected, microglia processes retract and the cell body becomes mobile – activated – and advances toward the signal to carry out its role as the brain’s innate immune defense. Activated microglia also migrate to sites of tissue injury where they proliferate and engulf and digest dying cells. Damaged tissue they restore by secretion of growth factors.
Microglia as partners in neuronal signaling
There are a multitude of receptor proteins on microglia cells membranes. Ligands that bind those receptors, and thereby initiate response of microglia, may originate from pathogens, dying tissue, or they may originate from healthy neurons, oligodendrocytes, and astrocytes.
Only subsets of ligands for microglia receptors mobilize microglia and turn them into immune responders. Some signals in the normal environment have the opposite effect of maintaining the characteristics of non-mobile microglia.
Surveying processes of non-mobile microglia make brief, about 5 minute, direct contact with neuronal synapses at a frequency of about once per hour. Such contact increases with increasing neural activity at synapses and decreases when there is less activity at synapses.
Active synapses release ATP into the extracellular environment and it is the level of ATP that is being monitored by microglia surveying processes. ATP is a chemo-attractant that induces microglia to polarize their processes toward an active synapses.
The frequency of contact at nerve synapses by microglia processes has been interpreted to suggest that microglia diligently monitor and respond to the functional status of synapses. Data obtained with live imaging studies are consistent with the theory that microglia contact is directly related to which synapses are pruned in the process of neuron remodeling.
Those dendritic spines where the duration of contact by microglia was extended were more often eliminated than those where the contact was of short duration. The capacity for microglia to phagocytose synapses is currently being evaluated.
But, the dynamic behavior of microglial processes at neuron synapses seems to be non-random. Unnecessary synapses appear to be tagged for pruning by deposition of complement proteins. It is likely that several steps are involved in the pruning process.
First, the level of synaptic activity is determined, then alterations in nerve synapse protein glycosylation is monitored, then tagging of selected synapses with complement proteins is accomplished, and finally dendritic spines are removed by microglia processes in a phagocytic manner.
Role of microglia in diseases of aging
Microglia are thought to play a variety of roles in most neurodegenerative diseases including Alzheimer’s, Parkinson, and Huntington’s. One common factor in these diseases is the lack of physiologic regulation of the brain’s major excitation neurotransmitter, glutamate. Excess extracellular glutamate is toxic to neurons.
It is recognized that microglia activated by pathogen or brain damage secrete glutamate using a membrane exchange transporter. Under conditions of mild activation other glial cells, astrocytes, are able to scavenge the excess glutamate. In diseased states such as Alzheimer’s microglia activation is so extensive that astrocytes are unable to maintain tissue glutamate at normal physiologic levels. More about the role of microglia in the neurodegenation observed in Alzheimer’s disease can be found in my latest book “Inside the Closed World of the Brain, How brain cells connect, share and disengage–and why this holds the key to Alzheimer’s disease.”
Considering central nervous system microglia as regulatory partners in neuron activity in healthy brain in addition to their role in innate immunity, paves the way for creating more effective methods of preventing neurodegenerative diseases of aging. It is expected that ongoing research will continue to expand our knowledge of microglial cell function within the next few years.
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Margaret Thompson Reece PhD, physiologist, former Senior Scientist and Laboratory Director at academic medical centers in California, New York and Massachusetts and CSO at Serometrix LLC is now CEO at Reece Biomedical Consulting LLC.
Dr. Reece is passionate about helping students, online and in person, pursue careers in life sciences. Her books “Physiology: Custom-Designed Chemistry” (2012), “Inside the Closed World of the Brain” (2015) and upcoming “Step-by-step Guide for Study of Physiology” (2016) are written for those new to life science.
Dr. Reece offers a free 30 minute “how-to-get-started” phone conference to students struggling with human anatomy and physiology. Appointments are scheduled by email at DrReece@MedicalScienceNavigator.com.by