Modulating AMPA receptors makes memories special

In current models of learning and memory, the brain stores information by remodeling synapses, specifically by changing the numbers of AMPA glutamate receptors at postsynaptic densities. Different brain regions lay down memories differently, though, and AMPA receptors are distributed throughout the brain, so there must be another component of the system providing specificity. On page 805, Tomita et al. address this long-standing problem by defining a family of four differentially expressed transmembrane proteins that regulate AMPA receptors in all types of neurons.

Previously, the authors showed that AMPA receptors in the cerebellum are regulated by a transmembrane protein called stargazin, which is mutated in a strain of epileptic mice, but it was unclear whether this was a general mechanism or restricted to the cerebellum. The new study shows that stargazin and three related proteins comprise a family of transmembrane AMPA receptor regulatory proteins (TARPs). TARPs promote the surface expression of functional AMPA receptors, and each TARP shows a specific pattern of expression in the brain. In areas that express multiple isoforms, TARP complexes are strictly segregated.

The expression patterns and properties of the four TARP isoforms could explain how AMPA receptors are differentially regulated in different parts of the brain. TARPs appear to stabilize AMPA receptors, either during biogenesis or at the cell surface, so the TARP isoforms expressed in a particular neuron could determine whether AMPA receptor concentrations are increased, decreased, or maintained at a synapse in response to a given stimulus.

All four isoforms contain a conserved cytoplasmic protein binding domain that appears to drive synaptic clustering, and phosphorylation of this domain might initiate synaptic remodeling. The authors are now studying the prototypic TARP, stargazin, to see whether calcium influxes can induce changes in the phosphorylation status and activity of the protein. ▪