Social interactions are the pillars of human activity, with institutions such as marriage, family, and friendships immortalized in all manners of art and literature, and thus upheld as being the pinnacles of a good life. We all feel these interactions through the warmth of a mother’s love, the strength of the friend’s support, or the passion in a lover’s embrace. When a person lacks the ability to show such emotions, society finds it hard to accept them. However, such is the fate of children who, by no fault of their own, are born with autism spectrum disorders (ASDs). ASDs, commonly referred to as autism, is defined by two core symptoms: (a) deficits in social communication and (b) restricted, repetitive patterns of behavior. The Center for Disease Control (CDC, USA) reported that the prevalence of autism was 1 in 68 children, or about 1.5%. You can rest assured that 1 in 68 families whole are also affected deeply by this disorder. The need to understand and overcome this disorder increases with each child diagnosed and with each family struck to its core by this debilitating condition.
Sadly enough, decades of research have revealed that autism is not caused by a single mutation in the genome or a single environmental factor. However, increasing evidence points to an important mechanism in the causation of autism: an imbalance in synaptic activity. This means that there is either an excess or lack of excitation in the synapse (basic communication unit between neurons in the brain). Understanding how autism changes the brain requires a much more detailed analysis of animal models that display relevant phenotypes.
To expand the current knowledge regarding the mechanism of autism, the IBS Center for Synaptic Brain Dysfunctions experimented on mice lacking a key brain molecule, the insulin receptor substrate protein of 53 kDa (IRSp53), present throughout the brain structures and disrupted in human individuals with autism. These mice displayed one of the two core symptoms of autism: social impairment.
When tested for their ability to socialize, the mice continued to avoid other mice and, when presented with a choice, preferred to be with inanimate objects.

It turns out that these mice displayed NMDAR hyper-function at the synapse. A NMDA receptor (NMDAR) is a type of ion channel, present in the synapse and heavily influences the efficiency of synaptic transmission during neuronal activity. When the research group treated the mice with a drug called memantine, which reduces the activity of NMDAR, the same mice reverted to normal levels of social interaction, comparable to that of wildtype mice. As memantine directly lodges into the channel of NMDAR, the research group tried to elicit the same rescue effect by targeting NMDAR indirectly via the mGluR5 pathway with a drug called MPEP, in order to confirm the hypothesis in a secondary manner. The rescuing effect of the drugs were confirmed at the synapse level as well, where electrophysiological recordings of synapse activity showed a normalization of NMDAR activity once applied with either drugs.
It seems that the reason for the hyper-function of NMDAR in the KO mice (mice lacking IRSp53) was not due to any malfunction of the NMDAR per se, but rather that NMDAR was not able to loosen itself from the synaptic cytoskeletal infrastructure at the appropriate time, leading to an overall accumulation of the ion channels in the synapse. Since the IRSp53 protein has no direct interaction with the NMDAR, this explanation made sense. The role of IRSp53 in the synapse is to manage the said infrastructure via regulatory proteins such as Cofilin and Eps8. When IRSp53 is lacking in the synapse, there seems to be a “hardening” of the local cytoskeleton, resulting in a lack of NMDAR mobility, which is critical for normal synaptic function. Thus, this study shows that synaptic imbalance can malfunction in unexpected ways, and be a possible cause for the development of neuropsychiatry Although it is still far from comprehensively understanding and overcoming the devastating effects of autism, the pieces of the puzzle are starting to come together. The results in the paper seem to not only confirm the theme of synaptic activity imbalance, but also go handin- hand with the paper the Center has already published (Won et. al., Nature 2012), in which mice lacking the synaptic protein Shank2 display not only both core symptoms of autism but also a reduced NMDAR function. Together, these results seem to suggest that a “normal” range of NMDAR activity (a range that corresponds with that of healthy people) in relevant parts of the brain is crucial for social behavior and that deviations from that range invoke aberrant social behaviors.
Understanding autism is definitely a collaborative effort that requires the participation of the collective scientific community. The effort is great, but the rewards will be even greater when the children who are now lost within their own minds can at last partake in the social constructs around them.

Published paper
Eunjoon Kim et al., “Social deficits in IRSp53 mutant mice improved by NMDAR and mGluR5 suppression”, Nature Neuroscience, Vol. 18, pp. 435-443, (2015)