Protein accumulation affects the social behavior of mice by altering brain signals

Autophagy was proposed by Keith R. Porter and Thomas Ashford in 1962 when they discovered that the cells themselves "eat themselves".  Autophagy refers to the cells degrade the excess or missing components. It allows for the orderly degradation and recycling of cellular components to achieve the metabolic needs of the cells themselves and the renewal of certain organelles. If the autophagy process is out of tune, some cells will enter a crisis of uncontrollable growth, causing irritating DNA damage that usually causes cancer or other neurological diseases.

Scientists at the American Institute of Brain Science (CBS) found that when the normal cell cleanup process was disrupted, the mice began to behave similarly to human autism spectrum disorders (ASD) and schizophrenia. When autophagy is out of control, the process of recovering damaged cellular components (such as proteins), affects brain cells' response to each other's inhibition signals and leads to behavioral changes. The complex signaling pathway may be a new therapeutic target for neurodevelopmental and neuropsychiatric disorders.

The autophagy process is controlled by mTOR signaling pathway. Abnormal activation of mTOR is associated with a variety of neurological disorders, such as mutations in certain components found in patients with autism (ASD). CBS researchers have come to the conclusion that abnormal protein clearance affects how neurons work and may cause downstream manifestations of neurological symptoms. Their study, published in the open-access journal Science Progress, confirmed that the social behavioral deficits in mice may be the result of autophagy collapse and excess protein accumulation.

Cells need a protein encoded by the Atg7 gene to initiate autophagy. Therefore, the researchers created knockout mice by selectively deleting the genes from the two cell populations of excitatory and inhibitory interneurons. It is well known that excitatory and inhibitory interneurons are the chief culprits of dysfunction in many neurodevelopmental and neuropsychiatric disorders.

The team observed that the two groups of mice exhibited overlapping behavioral abnormalities such as increased anxiety, reduced social interaction, and nesting. They believed that the loss of autophagy function has the same behavioral effects in different types of neurons, suggesting a common mechanism at work.

When analyzing the "garbage" of cells accumulated in the affected cells, the researchers discovered protein aggregates composed of GABARAPs. GABARAPs are a group of proteins that help bring receptors of the major inhibitory neurotransmitter, GABA, to the cell surface. These proteins not only build up but are also dumped into p62+ aggregates, forming p62+ aggregates when autophagy is disrupted.

Kelvin Hui, the first author of the article, thinks that autophagy is like a garbage collection station, while the p62 works as a garbage truck. It travels back and forth in the cells and picks up the garbage with the recycling label. When the recycle bin is shut down or the capacity is reduced, p62 has nowhere to carry the rubbish, and they begin to accumulate in the cells, causing serious problems.

Neurons do not communicate properly in this situation. After GABARAP is captured, GABA receptors cannot be transported to the cell surface and neurons become abnormally active. The team also studied postmortem human brain samples from some ASD patients and observed the same protein aggregation and p62 increase. This finding, along with previous studies of gene deletions in patients with ASD and mental retardation, further suggests that autophagy and protein aggregation disorders occur in the pathogenesis of these diseases.

This is the first demonstration of the link between mTOR autophagy and GABA signaling. Since these processes can also be seen in cancer and diabetes, it is of great clinical significance to study whether this identified molecular mechanism is also associated with these diseases. Given the role of protein aggregation in neurological and behavioral abnormalities, the team believes that small molecules capable of disrupting the accumulation of harmful proteins may be a new factor in the treatment of neurodevelopmental and neuropsychiatric disorders.