Northwestern Medicine scientists identified the mechanism that transports a class of important neuroreceptors from outside the synapse to sites within, publishing their findings in Cell Reports.
Too many receptors outside the synapse can contribute to neuron death in a variety of conditions, so identifying this mechanism is the first step towards a drug that could protect neurons by shuttling receptors inside where they are safe, according to Antonio Sanz Clemente, PhD, assistant professor of Pharmacology and lead author of the study.
“The receptors expressed here at the synaptic sites control many synaptic functions, so if we are able to modify the number of receptors that are expressed by recruiting those that are outside the synapse, we could modulate important neuronal processes,” Sanz-Clemente said.
Neurons communicate with one another through synapses, the junctions between neighboring neurons which don’t physically contact each other. Synapses transmit information across that gap using chemical messengers, released by neurotransmitters and received by neuroreceptors. Each transmitter has a corresponding receptor, like a key in a lock, which causes a variety of changes in the receiving neuron.
The type of receptors in the current study, postsynaptic N-methyl-D-aspartate (NMDA) receptors, are a particularly important group: they receive glutamate, a small ion that modulates the strength of neurotransmissions and is used in over 80 percent of the synaptic connections in the human brain.
While most NMDA receptors are present within the receiving end of the synapse, a small population of these receptors reside just outside the synapse, on the surface. The function of these extrasynaptic receptors is murky — some scientists believe they provide further fine-tuning of glutamate signaling — but more definitively known is what happens when extrasynaptic receptors are overloaded with too much glutamate.
“When they are over-activated, there is too much activity and it can kill the neuron,” Sanz-Clemente said.
When neurons die, they release more glutamate, meaning neuron death can spread throughout the brain like mouse-traps loaded with ping-pong balls. Scientists have seen this over-activation and neuron death in a variety of conditions, including Alzheimer’s disease, Huntington’s disease, stroke and traumatic brain injury.
Receptors move from inside the synapse to outside and vice-versa with relative frequency, but the actual mechanism by which this occurs was unknown until now, according to Sanz-Clemente.
“We know that it happens, but we had no idea how,” he said.
To investigate, Sanz-Clemente and his collaborators searched for modifications in the receptors that cause movement inside or outside the synapse. When they created a mutant receptor that was always phosphorylated, — that is, activated — all of the NMDA receptors were found at the external sites, showing that phosphorylation was the trigger. On the other hand, de-phosphorylation sends the receptors back inside the synapse. The authors found a common reaction catalyst called PP1 was the mediator for this de-phosphorylation reaction.
“There is actually a sub-population of PP1 that is already making a complex with the NMDA receptor, just waiting to be activated,” Sanz-Clemente said.
In the future, Sanz-Clemente says he wants to explore the possibility of forcing most of the extra synaptic neurons inside the synapse by striking a balance in de-phosphorylation.
“Now we know that it’s PP1, we can modify this balance in vivo and see what happens,” Sanz-Clemente said.
Andrew Chiu, student in the Medical Scientist Training Program, was the lead author of the study. Jiejie Wang, PhD, postdoctoral fellow and Levi Barse, research staff, both members of the Sanz-Clemente laboratory, were co-authors of the study.
This research was supported by National Institute of General Medical Sciences grant T32GM008061, National Institutes of Mental Health grant K08MH100562, National Institute on Aging grant K99AG041225, and a NARSAD Young Investigator Grant from the Brain & Behavior Research Foundation.