Latest Study on Neuronal Gene Expression May Shed Light on the Memory Formation Process

Researchers from the University of California, Davis (UC Davis) School of Medicine have recently identified an intricate molecular process involving gene expression in the neurons of a mouse brain. This process appears to play a crucial role in how the brain forms memories.

Published in the March 28 issue of Science Signaling, the findings from this study show that an enzyme called phosphodiesterase 4D5 (PDE4D5) is essential for controlling gene expression necessary for memory consolidation.

Related article: Human “Mini-Brains” Transplantation Shows a Way to Cure Blindness 

Importance of the Adrenergic System on Memory

This recent mouse study focuses on the central adrenergic system of the brain. The system is a neural and endocrine circuit that uses epinephrine (adrenaline) and/or norepinephrine (noradrenaline) as neurotransmitters. It controls an individual’s ability to pay attention, which is essential in learning and memory. Prior research has shown the association between alterations in the central adrenergic system and depression and memory loss, including those suffered by patients with senile dementia.

In particular, the team investigated beta-2 adrenergic receptors (β₂AR), which are present in various cell types throughout the body. They are also present in nerve cells in the hippocampal region of the brain. Researchers demonstrate that activation of these receptors can stimulate the hippocampal neuron nucleus to export the enzyme PDE4D5, a member of the PDE4 (phosphodiesterase-4) enzyme family which degrades the second messenger cyclic AMP (cAMP), thereby supporting nuclear cAMP signaling and memory consolidation. In fact, previous studies have identified PDE4D5 as having a role in promoting learning and memory.

Gene Expression May Hold the Key to Memory Consolidation

According to Dr. Yang K. Xiang, Associate Professor of the Department of Pharmacology at UC Davis School of Medicine and the senior author of the paper, gene expression lays the material foundation for the brain to form and consolidate memory. In this study, Prof. Xiang’s team found that the phosphorylation of β₂AR, which is done by an enzyme called G-protein receptor kinase (GRK), appears to be a key step in stimulating the memory-related gene expression which results in the nuclear export of PDE4D5. 

The researchers used genetically engineered mice to test whether phosphorylation of the β₂AR by GRK would be necessary for gene expression, hence the export of the PDE4D5 enzyme. These mice expressed a form of the β₂AR that could not be phosphorylated by GRK, meaning that their neurons were unable to follow the normal cAMP signaling pathway when the receptors were activated. Research findings revealed that these genetically modified mice suffered from deficits of memory related to space and location. 

Then the researchers administered roflumilast to these mice. The drug is a long-acting PDE4 inhibitor which works similarly to the PDE4D5 enzyme in the original cAMP signaling pathway. Then they found that direct PDE4 inhibition rescued β₂AR-induced nuclear cAMP signaling and ameliorated memory deficits in mice.

Can PDE Inhibitor Save Alzheimer’s Patients From Memory Loss?

In fact, the disruption of the memory-related cell signaling pathway mentioned in this study also occurs during the early stages of Alzheimer’s disease. Besides, apart from mitigating memory deficiency in mice, the use of PDE inhibitors for patients with Alzheimer’s disease is currently under investigation. 

One example is Sildenafil (Viagra), a PDE5 inhibitor. An NIH-funded study in 2021 revealed that Viagra was associated with a reduced risk of Alzheimer’s disease. However, another study published in the journal Brain Communications in October 2022 showed the exact opposite, stating that Viagra and Cialis (Tadalafil, another PDE5 inhibitor) had no association with reduced risk of Alzheimer’s disease.

According to Prof. Xiang, this study highlights the possibility that PDE inhibitors may be useful for saving Alzheimer’s patients from memory loss. “We need to understand what is causing impairment in diseases like Alzheimer’s so we can find interventions that allow patients to regain ability or slow down the disease progression,” said Prof. Xiang.

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Author

Richard Chau