Strokes, seizures, traumatic brain injury and schizophrenia: these conditions can cause persistent, widespread acidity around neurons in the brain. But exactly how that acidity affects brain function isn't well understood.
In a paper published in Scientific Reports researchers found that an elusive brain receptor may play an important role in the death of neurons from neurological diseases.
The University at Buffalo researchers study a family of brain receptors that are critical to learning and memory, called NMDA (N-methyl-D-aspartate) receptors. They found that one of these receptors called N3A functions through a different mechanism than all other NMDA receptors.
"We found that in contrast to all other NMDA receptors, acidity can reactivate dormant N3A receptors," said, senior author. "This insight led us to hypothesize that N3A receptors are silent in normal conditions, which may explain why other researchers have failed to observe them previously."
Authors found that when the N3A receptors were exposed to acidic conditions, as occurs in brain disorders such as stroke or epilepsy, they reactivate, causing neurons to become more sensitive to the neurotransmitter glutamate, which can, under certain circumstances, kill them.
"So finding ways to prevent acidification or the reactivation of N3A receptors may prevent brain damage from strokes or seizures, for example," said the senior author. N3A proteins appear to be more abundant in brains of people with schizophrenia. "This is in line with our findings, since schizophrenia, a disease associated with high acidity in the brain, causes brains to shrink," senior author said.
The finding also sheds much needed light on the N3A receptors. "Since their discovery more than 20 years ago, attempts to understand the roles of N3A receptors in the brain have been unsuccessful," senior author said. "Because many labs have failed to record N3A activity from neurons, some researchers even began to doubt their relevance to brain activity."
The researchers have identified the site on the receptor where acidity acts to reactivate these receptors, a different location from the site where acidity acts to inhibit all other NMDA receptors.
"This site is new and unique and thus can be used to make drugs that are very specific to the N3A receptor," said the senior author.