Discovery of Causative Gene for Cognitive Impairment... New Chapter for Therapeutics

Gene GNG8 Expressed Exclusively in the Brain Globus Pallidus
Cognitive Impairment Observed in Knockout Mice

Identification of Brain Neurons Expressing the Cognitive Impairment Causative Gene GNG8

[Asia Economy Reporter Junho Hwang] Domestic researchers have discovered a new brain neural circuit responsible for functions such as learning, memory, and cognition in our brain, as well as a gene that causes disorders of these functions. This discovery is expected to contribute to the development of treatments for degenerative diseases related to cognition, memory, and nerves.

The National Research Foundation of Korea announced on the 8th that a joint research team led by Professor Inseop Shim of Kyung Hee University College of Medicine and Professor Cheolhee Kim of Chungnam National University identified a new causative gene (GNG8) and neural circuit (goppi nucleus) related to cognitive and developmental disabilities and brain diseases. The results of this study were recently published in Molecular Psychiatry, an international journal in the fields of neuroscience and psychiatry.

Discovery of Causative Gene GNG8 Related to Cognitive Impairment

Cognitive Function Behavioral Analysis Using Disease Model Animals with the Cognitive Impairment Causative Gene GNG8 Removed

The research team previously revealed that if the 'Samdori' gene is not expressed in the brain's goppi nucleus, it can lead to autism. Samdori is a cytokine gene (a signaling molecule that regulates the body's defense system) expressed in the nervous system and is known as a key factor related to mental disorders, especially autism. Subsequently, the team searched for a new gene specifically expressed in the brain's goppi nucleus like Samdori to find the detailed mechanism causing autism and discovered the gene GNG8 related to cognitive impairment. The goppi nucleus is a part of the brain involved in emotional regulation such as emotions, disgust, and sleep, but its relationship with cognitive function had not been clarified.

To verify the function of the discovered gene, the research team examined mice with the GNG8 gene knocked out using gene-editing technology. The results confirmed the appearance of cognitive impairment. Passive avoidance tests and water maze tests showed impairments in long-term memory and spatial learning.

Reduction of Acetylcholine and Its Synthesizing Enzyme

Professor Shim Inseop of Kyung Hee University College of Medicine (from the left), Professor Kim Cheolhee of Chungnam National University Department of Biological Sciences, Researcher Lee Hyunju of Korea Brain Research Institute Degenerative Brain Disease Research Group

The research team also revealed that this decline in cognitive function was due to decreased acetylcholine production in the brain's goppi nucleus. GNG8-deficient mice showed significantly reduced production of acetylcholine, a representative neurotransmitter that regulates memory and learning, and its synthesizing enzyme. Long-term potentiation (LTP) in the hippocampus, an indicator of synaptic plasticity related to learning and memory, was also markedly decreased. When the team administered a compound that enhances acetylcholine signaling, the mice's long-term memory and spatial learning impairments were restored.

When acetylcholine, which helps connections between nerve cells, is produced less or the number of cholinergic neurons in the brain decreases, cognitive function declines. In fact, acetylcholinesterase inhibitors are used to alleviate memory loss caused by Alzheimer's dementia.

The research team expressed expectations that "with the discovery of a new brain neural circuit and gene responsible for learning and memory through this study, it will serve as a starting point for research on developing treatments targeting cognitive, memory, and neurodegenerative diseases."

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