Breakthrough in the Treatment of Cognitive and Developmental Disorders

2020-12-14 Academic

Professor Insop Shim of the School of Medicine and his research team have discovered a causative gene of the guanine nucleotide binding protein (G protein) gamma 8 (Gng8) and a brain neural circuit related to cognitive and developmental disorders and brain diseases. The research outcome has been published in the latest issue of Molecular Psychiatry, an international authority in neuroscience and psychiatry

A joint research team led by Professor Shim and Professor Chulhee Kim of Chungnam National University has discovered a new causative gene, Gng8, and a brain neural circuit related to cognitive/developmental disorders and brain diseases. Their findings of a gene and a brain circuit dedicated to learning and memory are expected to set off extensive therapeutic research on memory loss, cognitive disorders, and neurodegenerative diseases.

Their previous research already revealed that the failure of a chemokine-like gene family, samdori, to be expressed in a habenular nucleus may lead to autism. To identify the mechanism in action, they looked for a samdori-like gene that is specifically expressed in habenular nuclei and then discovered Gng8, a gene related to cognitive impairment. Habenular nuclei are suspected to be involved in nociception, mood, aversion, and sleep, but its relation to cognitive function has yet been addressed.

Inactivation of Gng8, which is expressed only in habenular nuclei, and ensuing cognitive impairment in mice
The joint research team generated Gng8 knockout mice through the CRISPR/Cas9 system and observed cognitive impairment. The mice exhibited deficiency in learning and memory in passive avoidance and Morris water maze tests. The researchers found that this decline in cognitive function was the result of a decrease in acetylcholine production in habenular nuclei.

The novel causative gene of Gng8, which was discovered through the whole genome sequencing of patients with developmental disorders characterized by cognitive decline, is specifically expressed in the medial habenula (MHb) in the brain. In this study, Professor Shim's team revealed that Gng8 is expressed in cholinergic neurons in the MHb. They also observed that levels of acetylcholine and choline acetyltransferase in the MHb of Gng8 knockout mice significantly decreased, compared to wild-type (WT) mice. Also, the mouse models showed a significant reduction in long-term potentiation in the hippocampus compared to that of WT mice.

Interestingly, the administration of an agonist of α4β2 nicotinic acetylcholine receptor significantly improved cognitive behaviors in the Gng8 knockout mouse models.

“Contributing to the development of molecular diagnosis and treatments for neuropsychiatric disorders, such as autism and Alzheimer's disease”
This study is expected to make a breakthrough in research on intellectual, developmental, and emotional disabilities. In the short term, it can be used as a direct biomarker for early molecular diagnosis, and over the mid- to long-term, it will serve as basic data for the development of therapeutic agents through disease modeling.

Professor Shim said, “Memory/cognitive disorders are major symptoms most commonly observed in degenerative brain diseases as well as developmental disorders. My team identified that the medial habenula and interpeduncular nucleus circuitry regulates cognitive function, which can be applied to studies of Alzheimer's disease and other degenerative cognitive disorders."

In addition to the Gng8-related cognitive deficit, Professor Shim plans to study the causes of cognitive impairment, abnormal behaviors, and related new neuro-molecular mechanisms, and discover sam2-like new genes, which are expressed only in the MHb, to further investigate associated functions.

This research was carried out with the support of the Original Technology Research Program for Brain Science and the Research Resources Support Program under the Biomedical Technology Development Research (Zebrafish Center for Disease Modeling) managed by the Ministry of Science and ICT and the National Research Foundation of Korea. The findings were published in the latest issue of Molecular Psychiatry, the top international journal in neuroscience and psychiatry.

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