Michael Ehlers, left; Pietro De Camilli, right.

To measure the effect of knocking out SJ1 on synaptic signaling, De Camilli focused on the hippocampal region of the brain, a major memory center that is rich in glutamate synapses. In the November 11, 2008, Proceedings of the National Academy of Sciences, he reported that cultured postsynaptic hippocampal nerve cells lacking SJ1 responded more strongly to stimulation than unmodified neurons. The absence of SJ1 on the postsynaptic side hampered the endocytosis and recycling of receptor-carrying vesicles, so receptors accumulated in the membrane, increasing its sensitivity to nerve signaling. In other words, SJ1's normal task in postsynaptic structures is to dampen signal strength.

“A major point is that while pre- and postsynaptic compartments play different and complementary functions, they adapt for those functions some of the same fundamental molecular mechanisms,” says De Camilli. “SJ1, a protein thought to be only presynaptic is also postsynaptic.”

De Camilli is also investigating a possible link between SJ1 and Alzheimer's disease. The same PIP2 lipid degraded by SJ1 has recently been found by his former postdoctoral fellow, Gilbert DiPaolo, now an independent scientist at Columbia University, to protect brain cells from the toxicity of amyloid-beta, a peptide implicated in Alzheimer's disease. Thus, lowering SJ1 levels could increase the amount of PIP2 in brain neurons, potentially slowing amyloid-beta poisoning.

Ehlers' discovery also involved the exocytosis and endocytosis of receptors in the postsynaptic neuron—specifically, within dendritic spines.

To move receptors from the interior of the dendritic spine to the synaptic membrane, the cell deploys endosomes, containers akin to vesicles but larger. Exactly how endosomes move was a puzzle until Ehlers identified a “molecular motor” that tows them toward the membrane when the synapse is active. The motor is a specific form of myosin—a contractile protein found in muscle—called myosin Vb. He reported the finding October 31, 2008, in Cell.

Because this transport mechanism can be triggered in a single dendritic spine of a brain neuron, Ehlers says, it helps explain the fine-tuning that enables a nerve signal to stimulate a single synapse without exciting nearby synapses—a prerequisite for neuronal plasticity.

As much as scientists are discovering about synaptic transmission and plasticity, Ehlers says, the “fundamental mystery” remains to be solved—how the changes that occur in the synaptic membrane within “tens of seconds” are maintained in the much longer term, and why we can call up those Beatles classics years after the songs became hits.

Photos: Ehlers: Duke Photography: De Camilli: Paul Fetters

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