The manuscript describes the role of a novel protein, termed stargazin, in the trafficking of the AMPA subtype of glutamate receptor in the brain. The paper shows the critical role of stargazin in delivering AMPA receptors to the membrane surface and then, by a separate mechanism, targeting these surface receptors to the synapse. It is generally accepted that the trafficking of AMPA receptors underlies certain forms of synaptic plasticity involved in learning and memory, and thus our findings have generated a great deal of excitement regarding the molecular mechanisms of memory.

As a result of our discovery, many laboratories, including my own, have pursued numerous leads. For instance, my colleague, David Bredt, and I have found that stargazin is a member of a family of proteins that have similar, but not identical, functions throughout the brain. Furthermore, in addition to their role in trafficking, we, and others, have recently discovered that these proteins control the biophysical properties of AMPA receptors. Thus the discovery of stargazin has opened a new chapter in the molecular regulation of AMPA receptors and by implication, learning and memory.

Brain function depends upon neurons communicating with one another via specialized contacts termed synapses. Most synapses release glutamate that activates AMPA receptors on the postsynaptic neuron. It is well accepted that learning and memory involves long lasting increases in the strength of synaptic transmission and this increase is due, in large part, to the recruitment of AMPA receptors to the synapse. Our paper demonstrated that a novel protein, stargazin, plays a critical role in this trafficking of AMPA receptors. Thus the paper provides a modest, but important, step toward understanding the molecular basis of learning and memory.

I have long been fascinated by the cellular and molecular basis of learning and memory. Prior to this paper, work in my lab, as well as in others, had established that synaptic plasticity, which underlies certain forms of learning and memory, involves the rapid trafficking of the AMPA-type glutamate receptor at synapses. This realization stimulated great interest in determining the molecular basis for AMPA receptor trafficking. Most studies involved isolating synaptic proteins and determining how these proteins interact with AMPA receptors. For our studies we took advantage of a spontaneous mutant mouse with ataxia and epilepsy. This mouse has a mutation in a small membrane protein termed stargazin and as a result lacks functional AMPA receptors in cerebellar granule cells. Our paper showed how stargazin regulates AMPA receptors in the cerebellum and elsewhere in the brain.

With an aging society, cognitive impairment from diseases, such as Alzheimer’s, is fast becoming a leading health problem. It is hoped that by elucidating the cellular and molecular basis of learning and memory a rational pharmacology will emerge for the treatment of cognitive decline.