Nature Sub-journal: Professor Feng Guoping reveals the key mechanisms for autism perception abnormalities.

Autism (ASD) is a highly inherited neurodevelopmental disorder whose core symptoms are social disorder, repetitive stereotyped behavior and language communication disorder.in May 2013, the American Psychiatric Association launched the latest version of the American Classification and diagnostic criteria for mental disorders, which included typical sensory abnormalities as one of the diagnostic criteria for autism.MRI data suggest that abnormal cortical neural circuits may cause sensory changes.at present, some studies have shown that GABAergic neuron defects are associated with multiple sensory information integration defects in ASD mouse models. However, there is no direct evidence to show the relationship between the dysfunction of GABAergic neurons in cortex and sensory abnormalities of ASD.on March 5, 2020, Professor Feng Guoping, Department of brain and cognitive science, Massachusetts Institute of technology, found that cortical inhibitory intermediate neurons play a key role in the tactile abnormalities of ASD model mice through two-photon microscopy.the researchers designed an interesting experiment to test the tactile sensitivity of mice: the mice were fixed on a device, the water supply was limited, and the whisker stimulation with fixed frequency but different intensity was applied. When the mice could respond to the stimulation correctly, the mice were rewarded with drinking water.through this experiment, it was found that there was no difference in tactile sensitivity index between wild-type mice and shank3b knockout mice under strong stimulation, but shank3b knockout mice showed stronger tactile sensitivity index under lower stimulation.this indicates that there are tactile abnormalities in autism.in order to further explore the neuronal mechanism of this tactile abnormality, researchers injected gcamp6, a calcium indicator of excitatory neuron promoter, into the primary somatosensory cortex to observe the spontaneous calcium activity in wild-type mice and shank3b knockout mice. It was found that the calcium signal intensity of shank3b knockout mice was significantly increased under normal conditions.then under the stimulation of tentacles, does the change of calcium activity in this brain area also increase? Using two-photon microscopy, the researchers found that 26% of the neurons in wild-type mice responded to whisker stimulation, compared with 52% in shank3b knockout mice.these results indicate that the excitatory neurons in the primary somatosensory cortex of shank3b knockout mice are more sensitive to external stimuli.based on previous research results, it is possible that the disturbance of inhibitory neural circuits in somatosensory cortex may cause hyperactivity of excitatory neurons.therefore, after injecting gcamp6, a calcium indicator of inhibitory neuron promoter, into the primary somatosensory cortex, the researchers found that the activity of inhibitory neurons in shank3b knockout mice decreased.the proportion of inhibitory neurons in the brain region to the response of the tentacle stimulation was also significantly reduced.these results indicate that the activity of inhibitory neurons in the primary somatosensory cortex of shank3b knockout mice is decreased.further, the researchers injected AAV CRE virus with inhibitory neuron promoter into shank3b FLX mice to specifically knock out shank3b of inhibitory neurons in primary somatosensory cortex, resulting in decreased neuronal activity induced by spontaneous and tactile stimulation.in addition, surprisingly, shank3b, which specifically knocks out inhibitory neurons, promotes the firing frequency of excitatory neurons, and the proportion of excitatory neurons responding to the stimulation of tentacles is also significantly increased. at the same time, both strong and weak stimulation showed stronger sensitivity index after specific knockout of shank3b of inhibitory neurons. after chronic inhibition of inhibitory neurons in the primary somatosensory cortex of wild-type mice, the spontaneous neuronal activity of excitatory neurons in the brain region increased, and the activity of neurons after the stimulation of tentacles increased. in addition, both strong and weak stimuli showed stronger sensitivity index, which was similar to shank3b knockout mice and specific knockout inhibitory neuron shank3b, which further confirmed the role of cortical inhibitory loop in tactile abnormalities. however, it should be noted that there is leakage of this CRE dependent specific knock-out. In this study, we found that when we knock out shank3b on inhibitory neurons, we also knocked out shank3b in 23% excitatory neurons. will this kind of leakage have an impact? Therefore, by using a similar strategy, they further specifically knocked out shank3b of the excitatory neurons, and the spontaneous activity of the excitatory neurons decreased, even under the stimulation of the tentacles. in addition, under strong and weak stimulation, the tactile sensitivity index of knockout mice was similar to that of normal mice. These data indicate that knockout of shank3b in only a part of excitatory neurons does not increase the sensitivity to stimulation. in conclusion, in this study, we specifically knock out shank3b in the inhibitory neurons of the primary somatosensory cortex, resulting in decreased activity of inhibitory neurons, hyperactivity of the excitatory neural network, and finally caused tactile hypersensitivity, which explained part of the causes of sensory abnormalities in autism. original link: