This proper brain function. Glutamatergic AMPAR subunits form tetrameric

This
project will study the interactions between AMPAR complexes and their auxiliary
subunits in vitro, ex vivo slice preparations and in vivo as well. AMPARs are the dominant
excitatory neurotransmitter receptor in the adult CNS and their function is
critical for proper brain function. Glutamatergic AMPAR subunits form tetrameric
protein complexes with the 4 subunits creating a central pore which passes ions
5. In the CNS there is a large variety in
post-synaptic response to glutamate at different synapses 10. This in part is explained by different
expression patterns of AMPAR subunits (GluA1-4), alternative splicing of these subunits,
and RNA editing each confer some degree of the variety of synapses found in the
CNS 10. Nevertheless there remained a
previously unexplained difference between the properties of native AMPARs
compared to those expressed recombinantly. Specifically it was noticed that
recombinantly expressed AMPARs had faster gating currents 11 compared to native AMPARs 12 which suggested that there may be
additional protein interactions at play in native synapses.

Recent
advances have highlighted the importance of auxiliary subunits for both
modulation of AMPAR biophysical properties and facilitating trafficking 6. The initial work in this field has
largely been restricted to knockout experiments of auxiliary proteins as in the
case of the initial observation of the AMPAR auxiliary protein stargazin, also
known as TARP ?2 7, 13. The dominant cellular phenotype from
these experiments was a severe defect in AMPAR trafficking. Indeed the ?2 KO
animal results in an almost complete loss of excitatory glutamatergic currents
in cerebellar granule cells 13 which can be rescued by transfection of
?2 back into the slice 7 (Figure 1). Further work on AMPAR
auxiliary proteins identified a family of proteins which have closely conserved
structures to stargazin and are now grouped into the so called “type I TARPs” (stargazin,
?3, 4, and 8) 14. This family have been described to
have similar effects on AMPAR biophysical properties including slowing
deactivation and desensitization kinetics, shifting ligand affinity, and altering
polyamine block 6, 15, 16 (Figure 2). The modulatory effects of “TARPed” AMPARs have
generally reconciled the differences shown between native and recombinantly
expressed experiments on AMPARs 17.

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