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Dear Readers, Welcome to the latest issue of The Magazine
Every second our brains are exposed to a variety of signals, from the barking of a puppy to raindrops hitting the windows, and everything in between. Most of the time we ignore insignificant cues like the buzzing of a fly or the gentle rustle of leaves in a tree. We pay attention to the more important ones, such as the sound of the car horn and the bang on the doors. This allows us navigate and function in the world around.
Brain’s incredible ability to filter through the endless flow of information is possible because of an intricate neural network composed of billions and trillions of synapses. These junctions regulate signal transmission between and within cells. Some of these junctions block signal transmission, while others accelerate it–a minute-by-minute balancing act which allows our brains to function at their maximum potential.
New research by Harvard Medical School researchers and the Broad Institute of MIT/Harvard has shown that this delicate balance between inhibitions and excitation is maintained at minimum in part by a highly specialized set of microglia–the brain’s resident immune cells. These cells are known for their ability to fight infection and clean up cellular debris.
This research was performed in mice and published in Cell June 6, 2006. It revealed for the first time that the cadre of specialized immuno cells is highly attuned to detecting inhibitory synapses. These are junctions that slow down information flow.
We found that specialized immune and neuronal cells engage in important communication during early brain development and form interactions critical to the establishment of balanced brain wiring.”
Emilia Favuzzi, Study First Author and Research Fellow in Neurobiology in Blavatnik Institute at Harvaed Medical Sschool
Favuzzi works at the Broad as a postdoctoral researcher.
“Our observations suggest microglia engages an act in intricate interplay with certain types of synapses. This enables them to hone in on them and sculpt the nervous system in a synapse -by synapse” said Gordon Fishell, senior investigator and professor at HMS Blavatnik, and group leader at HMS Stanley Center for Psychiatric Research. “This is the very first time that we have demonstrated that certain types are recruited to certain kinds of synapses in order to engage with them in an extremely specific manner.
This research demonstrated that the cells interact with inhibitory synapses through direct physical contact. It was an unprecedented observation possible thanks to advanced imaging techniques. The researchers were able observe in realtime how cells of the brains of mice interact with one another.
The experiments showed that the contact happens via a GABA signaling receptor, which is located on the surface and makes microglia extremely responsive to GABA-emitting inhibitory signals. GABA acts as a brake against cell-to–cell signaling and is the brain’s primary inhibitory neurotransmitter. GABA seems to act as a signal of come-hither to a certain subset, inviting these cells into the GABA-releasing synapses.
Additionally, experiments showed that this process takes place via three steps: movement recognition, ingestion, and recognition. GABA-sensitive Microglia are able to engulf inhibitory synapses in a similar way that cells consume pathogens and cellular waste.
The researchers believe that these insights may provide valuable clues for the development of new therapeutic strategies for patients with brain damage. Such defects can disturb the delicate balance between excitation and inhibitor and cause serious functional aberrations to sensory perceptions, from sensory overstimulation to sensor blunting. Such sensory disruptions are common in conditions such autism-spectrum disorders (ADHD), schizophrenia, and other mental illnesses.
Favuzzi explained that it is possible to selectively toggle or alter the balance between excitatory-inhibitory connections in the brain by recruiting specialized microglia, which are responsible for remodeling and pruning certain synapses.
Specialists and jacks – of all trades Similar Stories Microglia are well-known for their ability recognize and destroy microbes and clean up cellular waste in the central nervous. Recent research suggests that these trash-collecting cells might also function as modulators of brain wires. They are responsible for organizing the brain’s neural network by helping to build connections and then pruning them out to eliminate synapses which are not needed. This research suggests that immune cells can play multiple roles in wiring brains.
But, it remains a mystery as to how microglia manage their synapse modulating function. The new study findings have begun to reveal the answer. The findings show that microglia are capable of selectively attaching and engaging with either inhibitory nor excitatory synapses. This is a striking molecular affinity.
A set of initial experiments demonstrated that the removal of all microglia from mice’s cells caused disruptions in both inhibitory as well as excitatory neural connections. This surprising finding was not surprising since microglia have been shown to affect both types. Researchers were able to focus on the microglia that have GABA receptors on the surface and observed that these cells preferred to interact with GABA-emitting inhibity synapses.
In another important experiment, researchers removed GABA-receptors from these specialized microglial neurons. They found that these cells had lost their desire for inhibitory connections after doing so. These cells, unlike microglia with intact GABA receptors, formed fewer connections with inhibitory synapses than the modified ones. Also, removal of GABA from microglial-cells did not result in the loss of excitatory synapses. These results again highlight their affinity for particular types synapses.
Mice that did not have GABA receptors found on their microglial neurons had a high number of inhibitory synapses, and their neurons showed high levels inhibitive signaling. The activity of their excitatory cells remained unaffected.
Next, researchers used a brand new imaging technology called MERFISH in order to distinguish microglial subtypes within animals. The researchers measured the variation in gene expression between microglia and GABA receptors with granular precision.
The final step was to test whether the elimination of GABA receptors from microglia cells could lead to behavioral change in animals. It did.
Young animals that lack GABA receptors on the microglia of their microglia showed signs of an overabundant inhibitory stimulus. They were disinterested, disengaged, ran and leapt less often than their peers, ventured far less outside their immediate environment, and had no interest in exploring the space surrounding them.
It was an interesting time when these animals became adults.
These mice also became hyperactive once they were fully grown. They were more active and ran and jumped, exploring their surroundings. When the researchers looked at the synapses type and number, they found that in adulthood, the animals suffered from a lack of inhibitory neurons. The researchers stated that this observation is somewhat contradictory and points to an over-compensatory mechanism.
Fishell stated that all of these insights can be used to help correct synaptic wire deficiencies.
“With a better understanding and treatment of microglias, we can design therapies to correct nervous system dysfunction.”
Harvard Medical School
