Ion channels are often modulated by auxiliary subunits. Transmembrane AMPA receptor regulatory proteins (TARPs) are auxiliary subunits for AMPA-type glutamate receptors. These receptors are responsible for much of the fast excitatory synaptic transmission in the brain, and their mobility is thought to contribute to memory storage mechanisms. Although TARPs are known to modify AMPA receptor trafficking and gating in vitro, their contribution to in vivo AMPA receptor function is less clear.

By generating mice lacking multiple TARP family members, we found that TARPs are functionally redundant. Single TARP knockout mice are viable, while those lacking multiple isoforms are often lethal. Consistent with molecular redundancy, AMPA receptor transmission in cerebellar Golgi cells is unaffected in single TARP knockout mice, but nearly eliminated in double knockouts. Unexpectedly, the remaining AMPA receptors have a different subunit composition, suggesting that TARPs may preferentially traffic GluR2 containing receptors.

Our studies also highlight a role for TARPs in inhibitory neurons because AMPA receptor function in cerebellar Purkinje cells and Golgi cells is reduced in TARP knockout mice. Additionally, the loss of TARPs reduces the decay time of interneuron EPSCs. This indicates that AMPA receptor biophysical properties make a significant contribution to the time course of synaptic events, even at fast-decaying interneuron synapses.

Our studies investigating TARP function in vivo also led to the discovery that TARPs profoundly change AMPA receptor pharmacology. Whereas CNQX is a competitive antagonist on AMPA receptors alone, it is a partial agonist on receptors containing any member of the TARP family and elicits depolarizing currents in neurons throughout the brain. By obtaining the crystal structure of CNQX bound to the AMPA receptor ligand-binding domain, we determined that CNQX induces a small amount of domain closure. Based on our findings, we propose an expanded model of AMPA receptor gating such that TARPs increase the likelihood that domain closure leads to channel opening, i.e. they increase the coupling efficiency. Together our studies demonstrate that TARPs are an integral component of AMPA receptors in the central nervous system.