Abstract
Regulation of calcium-permeable AMPA receptors (CP-AMPARs) is crucial in normal synaptic function and neurological disease states. Although transmembrane AMPAR regulatory proteins (TARPs) such as stargazin (γ-2) modulate the properties of calcium-impermeable AMPARs (CI-AMPARs) and promote their synaptic targeting, the TARP-specific rules governing CP-AMPAR synaptic trafficking remain unclear. We used RNA interference to manipulate AMPAR-subunit and TARP expression in γ-2-lacking stargazer cerebellar granule cells--the classic model of TARP deficiency. We found that TARP γ-7 selectively enhanced the synaptic expression of CP-AMPARs and suppressed CI-AMPARs, identifying a pivotal role of γ-7 in regulating the prevalence of CP-AMPARs. In the absence of associated TARPs, both CP-AMPARs and CI-AMPARs were able to localize to synapses and mediate transmission, although their properties were altered. Our results also establish that TARPed synaptic receptors in granule cells require both γ-2 and γ-7 and reveal an unexpected basis for the loss of AMPAR-mediated transmission in stargazer mice.
Publication types
-
Research Support, Non-U.S. Gov't
MeSH terms
-
Animals
-
Animals, Newborn
-
Calcium / metabolism*
-
Cells, Cultured
-
Cerebellum / cytology
-
Chlorides / metabolism
-
Excitatory Amino Acid Agents / pharmacology
-
Excitatory Postsynaptic Potentials / drug effects
-
Excitatory Postsynaptic Potentials / genetics
-
Female
-
Gene Expression Regulation / genetics*
-
Male
-
Membrane Proteins / genetics
-
Membrane Proteins / metabolism*
-
Mice
-
Mice, Inbred C57BL
-
Mice, Transgenic
-
Mutation / genetics
-
Neurons / drug effects
-
Neurons / physiology*
-
RNA, Small Interfering / genetics
-
RNA, Small Interfering / metabolism
-
Receptors, AMPA / genetics
-
Receptors, AMPA / metabolism*
-
Spermine / pharmacology
-
Synaptic Transmission / drug effects
-
Synaptic Transmission / genetics
-
Synaptic Transmission / physiology*
-
alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid / pharmacology
Substances
-
Chlorides
-
Excitatory Amino Acid Agents
-
Membrane Proteins
-
RNA, Small Interfering
-
Receptors, AMPA
-
TARP gamma-7 protein, mouse
-
Spermine
-
alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid
-
glutamate receptor ionotropic, AMPA 2
-
Calcium