A new study from the University of Pittsburgh Brain Institute and the Pittsburgh Hearing Research Center challenges a decades-old dogma on how the metal zinc functions in the brain’s synapses.
The study, published last week in Science Advances, shows that zinc, a metal that’s released in vast areas of the human brain, takes an unexpected, possibly circuitous route to affect one of its main targets, the NMDA receptor. These receptors are involved in a large number of important brain functions, including learning and memory.
Synapses are the tiny gaps between adjacent neurons. When a presynaptic neuron releases chemicals into the gaps, those so-called neurotransmitters incite activity in surrounding postsynaptic neurons.
“Zinc has always been assumed to simply diffuse across the synaptic cleft to directly bind and inhibit postsynaptic NMDA receptor function,” said first author Rebecca Krall, a doctoral student in Pitt’s Center for Neuroscience. “We found, however, that during synaptic activity and presynaptic zinc release, zinc inside the postsynaptic cell must come out into the cleft exactly to block the NMDA receptors.”
The study, which was co-led by professor of neurobiology Elias Aizenman, Ph.D., and endowed professor of otolaryngology Thanos Tzounopoulos, Ph.D., was made possible by the development of a novel drug peptide called TAT-N2AZ, which mimics a small portion of the NMDA receptor called GluN2A. It takes over the spot at which the receptor usually binds to the zinc transporter protein ZnT1, pulling the complex apart.
“ZnT1 is one of 24 zinc transporters in cells and is primarily responsible for pumping zinc out of cells,” Tzounopoulos explained. “But when we separated GluN2A from ZnT1 with the peptide, the release of zinc in the synapse could no longer block NMDA receptor activity. That was an exciting discovery.”
“The simplest explanation for this finding,” Aizenman added, “is that synaptically released zinc somehow enters the target cell by a yet unidentified mechanism, and then comes out again via ZnT1 in the immediate vicinity of GluN2A.”
NMDA receptor dysfunction has been implicated in many brain disruptions, from stroke damage to schizophrenia. In schizophrenia, a decrease in NMDA receptor function has been hypothesized.
“It would be interesting to evaluate whether TAT-N2AZ, or a similar drug that decreases the zinc block on NMDA receptors, could alleviate some of the symptoms associated with schizophrenia,” Aizenman said.
Other authors of the paper were Mathew Phillips, B.S., and Jon Johnson, Ph.D., from the University of Pittsburgh; Aubin Moutal, Ph.D., and Rajesh Khanna, Ph.D., from the University of Arizona; and Hila Asraf, Ph.D., and Michal Hershfinkel, Ph.D., of Ben Gurion University in Israel.
--Anita Srikameswaran, MD