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bioRxiv · 10.1101/2024.09.17.613513

Overabundant endocannabinoids in neurons are detrimental to cognitive function

Zhu, D.·Zhang, J.·Ma, X.·Hu, M.·Gao, F.·Hashem, J.·Lyu, J.·Wei, J.·Cui, Y.·Qiu, S.·Chen, C.
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Abstract

2-Arachidonoylglycerol (2-AG) is the most prevalent endocannabinoid involved in maintaining brain homeostasis. Previous studies have demonstrated that inactivating monoacylglycerol lipase (MAGL), the primary enzyme responsible for degrading 2-AG in the brain, alleviates neuropathology and prevents synaptic and cognitive decline in animal models of neurodegenerative diseases. However, we show that selectively inhibiting 2-AG metabolism in neurons impairs cognitive function in mice. This cognitive impairment appears to result from decreased expression of synaptic proteins and synapse numbers, impaired long-term synaptic plasticity and cortical circuit functional connectivity, and diminished neurogenesis. Interestingly, the synaptic and cognitive deficits induced by neuronal MAGL inactivation can be counterbalanced by inhibiting astrocytic 2-AG metabolism. Transcriptomic analyses reveal that inhibiting neuronal 2-AG degradation leads to widespread changes in expression of genes associated with synaptic function. These findings suggest that crosstalk in 2-AG signaling between astrocytes and neurons is crucial for maintaining synaptic and cognitive functions and that excessive 2-AG in neurons alone is detrimental to cognitive function.

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Zhu, D., Zhang, J., Ma, X., Hu, M., Gao, F., Hashem, J., Lyu, J., Wei, J., Cui, Y., Qiu, S., Chen, C.. 2024-09-17. Overabundant endocannabinoids in neurons are detrimental to cognitive function. https://doi.org/10.1101/2024.09.17.613513

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