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In the brain fast
excitatory neurotransmission is mediated by ionotropic glutamate receptors
(iGluRs).  Dysfunction of glutamatergic
neurotransmission has been implicated with many diseases including epilepsy,
autism, ischemic brain damage, and neurodevelopmental diseases such as
Alzheimer’s and Parkinson’s disease 1. Since the first indications that
glutamate is a neurotransmitter in the brain 2, the study of excitatory
neurotransmission has undergone many major breakthroughs including cloning and
identifying the 18 major subunits of glutamate receptors found in the human CNS
3. These receptors are organized into 4 different
families called AMPA (GluA1-4), kainate (GluK1-5), NMDA (GluN1, GluN2A-D, and
GluN3A,B) and delta-type (GluD1,2) receptors 3. Under basal synaptic transmission AMPA
receptors (AMPAR) are the predominant iGluR at most excitatory synapses, with
smaller contributions coming from kainate (KAR) and NMDA receptors (NMDAR) 4. AMPARs, like other iGluRs are composed
of tetramers of subunits consisting of a dimer of dimers 5. They can form both heteromeric or
homomeric complexes and their stoichiometry is important for determining AMPAR function
3.

 

Recent breakthroughs have
shown that AMPARs have additional auxiliary subunits including the
transmembrane AMPAR receptor regulatory protein (TARP) and cornichon (CNIH)
families 6. 
These auxiliary proteins have been demonstrated to important for
appropriate receptor trafficking in neurons and for modifying the ion channel
responses to agonists 6. 
Absence of auxiliary proteins results in dramatically reduced AMPAR
currents due to a lack of surface trafficking 7. Recent advances have revealed that the
different characteristics that TARPs confer on AMPARs, specifically the
trafficking and biophysical properties, are mediated by distinct structural
elements 8. This raises an intriguing question about
the properties of AMPAR-auxiliary complexes in the CNS which we plan to address
with the following three aims. As the synaptic properties is in part determined
by the specific AMPAR subunits and their auxiliary proteins expressed the
results from these aims will be of great interest to the neuroscience field 3.

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