When people feel as if a favorite song has worn grooves into their brain, they're not far off. Repeated stimulation of the synapse, the site of communication between two neurons, induces chemical and structural changes that strengthen connections between those cells.

As a result, nerve signals flow more easily across the synapses, connecting neurons involved in learning and memory, so that hearing the first notes of “A Hard Day's Night” instantly recalls the entire Beatles song.

Alteration of synaptic signal strength underlies “neural plasticity,” the brain's ability to be changed by a person's experience—in other words, learning and memory—without manufacturing new brain cells.

Recent discoveries led by HHMI investigators Michael Ehlers at Duke University Medical Center and Pietro De Camilli at Yale School of Medicine have clarified some of the mechanisms that dial signal strength up and down. Their findings may also expand understanding of Alzheimer's disease and suggest new avenues for prevention or treatment.

The discoveries, reported separately in the fall of 2008, involve the “postsynaptic” side of the junction, where signals that have jumped the gap stimulate antenna-like receptors in the dendrites—the branching projections of the receiving nerve terminal. Much more is known about the transmitting, or “presynaptic,” mechanisms: “We're at very early days in the postsynapse,” says Ehlers. Both teams' experiments were designed to explore trafficking of neurotransmitters and receptors to and from neuronal membranes on either side of the synapse.

Most neurons involved in learning and memory secrete glutamate neurotransmitters into the synaptic gap, where they stimulate specific receptors (termed AMPA and NMDA receptors) anchored in the postsynaptic membrane. The number of these receptors determines the neuron's sensitivity—and as a result, the power of the signal. The receptors are located in nub-like “spines” that protrude from dendrites—neuronal branches that carry the signal from the synapse to the main nerve cell body. explains Eisenberg.

Tiny sac-like vesicles deliver neurotransmitters and their receptors to the synaptic space by fusing with the surface membranes of the pre- and postsynaptic cells, respectively, through a process called exocytosis. After offloading their cargo, the empty vesicles merge with the cell surface membrane and new carrier vesicles form by recycling and pinching off part of this surface membrane, a process called endocytosis.

De Camilli has spent nearly three decades investigating vesicle recycling. In 1996, he discovered an enzyme, synaptojanin1, or SJ1, that degrades a lipid compound called PIP2 in cell membranes, including vesicle membranes. In the absence of SJ1, PIP2 prevents vesicles from shedding their cage-like coating, which they need to do to recycle the membrane for another shipment. The result: a logjam of accumulated vesicles and a shortage of membrane to create new ones.

Until recently, “we thought that SJ1 affected endocytosis just on the presynaptic side,” De Camilli says. “But then we began to realize that there is a little synaptojanin everywhere in the neuron, and that it could be involved in postsynaptic vesicle recycling as well.”

Illustration: Emmanuel Polanco, colagene.com

	PAGE 1 OF 2	Continue