The process by which memories are formed in the hippocampus region of the brain is complex. It relies on a precise choreography of interactions between neurons, neurotransmitters, receptors and enzymes.
A new mouse study led by researchers at the has identified an intricate molecular process involving gene expression in the neurons that appears to play a critical role in memory consolidation. The research was .
鈥淭his is an exciting mechanism. It shows that an enzyme like phosphodiesterase is key in controlling gene expression necessary for memory consolidation,鈥 said , a professor in the and senior author of the paper.
Xiang鈥檚 research focuses on understanding how dysregulation or impairment of cellular and molecular mechanisms in the heart and brain can lead to diseases like heart failure and Alzheimer鈥檚.
Multiple steps in neuron appear critical
The new study focuses on the . The ability to pay attention, which is essential in learning and memory, is controlled by the central adrenergic system in the brain.
To understand the components critical for memory, the researchers looked at . The receptors are present in different cell types throughout the body. They are also found on nerve cells in the hippocampal region of the brain.
The researchers show that when beta-2 adrenergic receptors are activated 鈥 through a series of molecular steps known as a signaling pathway 鈥 they stimulate the nucleus of the neuron to export an enzyme, phosphodiesterase 4D5 (PDE4D5).
Previous studies have identified PDE4D5 as having a role in promoting learning and memory.
Lack of phosphorylation leads to poor memory
A crucial step to stimulating this memory-related gene expression 鈥 the export of PDE4D5 鈥 appears to be the attachment of a phosphate group (known as phosphorylation) to the receptor. This is accomplished by an enzyme known as a kinase.
The kinase involved in this case is a .
The researchers used genetically altered mice to test whether phosphorylation of the beta-2 adrenergic receptors by G-protein receptor kinase was necessary for gene expression 鈥 the export of the PDE4D5 enzyme.
The mice lacked a phosphorylation site on their beta-2 adrenergic receptors, meaning their neurons could not follow the normal signaling pathway when the receptors were activated.
The researchers found that, as expected, these genetically altered mice exhibited poor memory related to space and location. This is the same memory pathway that is disrupted during the early stages of Alzheimer鈥檚 disease.
However, when they provided the memory-impaired mice with a drug known as a PDE4 inhibitor (comparable to the PDE4D5 enzyme that would normally be exported), the mice鈥檚 ability to learn and retain memories was increased.
鈥淭he gene expression forms the material foundation of the memory in your brain. If you don't have gene expression, you won't have memory,鈥 Xiang explained.
PDE inhibitors in Alzheimer鈥檚 have had mixed results
The use of PDE inhibitors is being explored for Alzheimer鈥檚 disease. Studies of the PDE5 inhibitor sildenafil, known as Viagra, have had mixed results. A found Viagra was associated with a reduced risk of Alzheimer鈥檚 disease, but found Viagra was not associated with lower Alzheimer鈥檚 risk.
鈥淲e need to understand what is causing impairment in diseases like Alzheimer鈥檚 so we can find interventions that allow patients to regain ability or slow down the disease progression,鈥 said Xiang. 鈥淭his study highlights the potential of PDE inhibitors in rescuing memory in Alzheimer鈥檚 patients.鈥
Additional authors on the paper are Joseph M. Martinez, Aleksandra Jovanovic and Josephine de Chabot from 新澳门六合彩内幕信息 Davis; Ao Shen from 新澳门六合彩内幕信息 Davis and Guangzhou Medical University; Bing Xu from 新澳门六合彩内幕信息 Davis and VA Northern California Health Care System; and Jin Zhang from 新澳门六合彩内幕信息 San Diego.
Funding for this research came from the National Institutes of Health.
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(Science Signaling)