It’s an experience most of us have encountered at one time or another. We turn on the radio, stereo, television, or YouTube video and the volume is just too loud. Our reactions are almost immediate combining a mixture of frustration, helplessness, and a need to turn down the sound. Thankfully, we quickly can adjust the dial, slider, or remote to achieve a more comfortable level.
Now imagine that volume control cannot be adjusted and is fixed in one spot. If the levels are too high, you have to find other ways to deal with the auditory intrusion. It can lead to pain, frustration, and possibly an alteration in normal behaviour. In essence, when the sound is too loud, you suffer.
This scenario may be occurring in some individuals with autism. However, rather than sound, the culprit is the movement of chemical ions, which like a battery produce small amounts of electrical charge. These act as signals in the brain, and are known as excitatory transmissions. When there are too many of these excitations occurring at once, the smooth harmony of brain function turns into a cacophony leading to an inability to process properly. This in turn may lead to a variety of outward symptoms such as impaired memory, lack of social skills and repetition of certain actions, known as stereotypy.
Figuring out how the brain develops this fixed electrical volume control has been a challenge. Yet there may be a breakthrough thanks to a team of researchers led by Drs. Steven Connor and Ann Marie Craig at the University of British Columbia. The group has discovered a possible volume control switch during development. Based on their research, which is published in the journal, Neuron, the answer may lie in a single protein known quite simply as MDGA2.
In the brain, there are two specific types of synapses responsible for electrical transmission, excitatory and inhibitory. As the names imply, these structures control the levels of signal going through the brain. In healthy individuals, there is equilibrium between the two types of signals. Yet in several cases of autism spectrum disorders, there appears to be a mismatch in which there is more excitation. For Dr. Craig’s group, this imbalance provided a basis for their search.
Their efforts paid off in 2013 when they discovered a group of proteins officially called MAM domain–containing glycosylphosphatidylinositol anchors (thus the MDGA). They used lab cultures to show that one of these proteins, MDGA1 suppressed the inhibitory side of volume control, suggesting deletion or at least reduction of these proteins might somehow cause an imbalance. But to show this concretely, they needed to move from the lab to mice. When the shift was made, there were quite a few surprises in store.
The first was the absolute necessity of the other form of MDGA, MDGA2. When they knocked out the gene making the protein, the mice died. Another means to test their theory was through using a model known as a haploinsufficiency. The mice carried one copy of the gene but not both. This meant less protein was made as opposed to no protein at all. Yet, the animals lived.
Once the testing on these haploinsufficient mice began, the second surprise became evident. From those 2013 results, the team expected a reduction in MDGA2 would lead to an increase in the inhibitory transmissions. This was not the case. Instead, the balance shifted even more heavily to excitatory. When the team examined the hippocampus more closely, they found the actual density of excitatory synapses was increased.
To be sure the results were occurring in real-time the team used fluorescent dyes that become brighter when cells are active. Not surprisingly, they are called voltage-sensitive dyes. The use of voltage imaging allows the investigation of network brain activity in a manner similar to use of functional magnetic resonance (fMRI) in humans. As previous results suggested, the amount of activity – the volume – in the brain was strikingly higher. Cortical activity also appeared more synchronous. This indicated a higher degree of functional connectivity, which has been seen in autism patients assessed using fMRI . Moreover, these effects were seen throughout the cortical surface of the brain. This was enough to show this genetic change was leading to a dramatic, widespread shift, not only in the hippocampus.
The only unsurprising result was in the nature of the haploinsufficient mice. They demonstrated numerous symptoms associated with autism spectrum disorders. They had impaired cognitive performance, they could not properly interact socially, and stereotypy was present.
At the most basic level, this study unveiled how one particular protein, MDGA2, may be involved in the development of autism. For this reason, the authors suggested this mouse model may serve well for future studies on autism. This may help to understand a variety of questions related to neurodevelopment and autism.
From a larger perspective, this study also revealed how a genetic change such as haploinsufficiency can have such a drastic effect on an individual. The concept of a single protein having such control over the volume of electrical transmissions suggests every molecule matters in the developing brain. It’s also indicative of the general fragility of brain development and how even a minor alteration, whether genetic or environmental, can have lasting impacts.
Read the original research article in Neuron:
Connor SA, Ammendrup-Johnsen I, Chan AW, Kishimoto Y, Murayama C, Kurihara N, Tada A, Ge Y, Lu H, Yan R, LeDue JM, Matsumoto H, Kiyonari H, Kirino Y, Matsuzaki F, Suzuki T, Murphy TH, Wang YT, Yamamoto T, Craig AM. Altered Cortical Dynamics and Cognitive Function upon Haploinsufficiency of the Autism-Linked Excitatory Synaptic Suppressor MDGA2. Neuron. 2016 Sep 7;91(5):1052-68. doi: