NMDA receptor activation potentiates inhibitory transmission through GABA receptor-associated protein-dependent exocytosis of GABA(A) receptors.
The trafficking of postsynaptic AMPA receptors (AMPARs) is a powerful mechanism for regulating the strength of excitatory synapses. It has become clear that the surface levels of inhibitory GABA(A) receptors (GABA(A)Rs) are also subject to regulation and that GABA(A)R trafficking may contribute to inhibitory plasticity, although the underlying mechanisms are not fully understood. Here, we report that NMDA receptor activation, which has been shown to drive excitatory long-term depression through AMPAR endocytosis, simultaneously increases expression of GABA(A)Rs at the dendritic surface of hippocampal neurons. This NMDA stimulus increases miniature IPSC amplitudes and requires the activity of Ca2+ calmodulin-dependent kinase II and the trafficking proteins N-ethylmaleimide-sensitive factor, GABA receptor-associated protein (GABARAP), and glutamate receptor interacting protein (GRIP). These data demonstrate for the first time that endogenous GABARAP and GRIP contribute to the regulated trafficking of GABA(A)Rs. In addition, they reveal that the bidirectional trafficking of AMPA and GABA(A) receptors can be driven by a single glutamatergic stimulus, providing a potent postsynaptic mechanism for modulating neuronal excitability.
Marsden
Kurt C
KC
Dominick P. Purpura Department of Neuroscience, Rose Kennedy Center for Mental Retardation, Albert Einstein College of Medicine of Yeshiva University, Bronx, New York 10461, USA.
Beattie
Jennifer B
JB
Friedenthal
Jenna
J
Carroll
Reed C
RC
D000818:Animals; D000831:Animals, Newborn; D019921:Biotinylation / Q000379:methods; D002478:Cells, Cultured; D004791:Enzyme Inhibitors / Q000494:pharmacology; D018683:Excitatory Amino Acid Agents / Q000494:pharmacology; D005089:Exocytosis / Q000187:drug effects / Q000502:physiology*; D005968:Glutamate Decarboxylase / Q000378:metabolism*; D006624:Hippocampus / Q000166:cytology; D066298:In Vitro Techniques; D053444:Inhibitory Postsynaptic Potentials / Q000187:drug effects / Q000502:physiology* / Q000528:radiation effects; D008869:Microtubule-Associated Proteins / Q000378:metabolism*; D016202:N-Methylaspartate / Q000494:pharmacology; D009474:Neurons / Q000187:drug effects / Q000502:physiology*; D018408:Patch-Clamp Techniques / Q000379:methods; D021381:Protein Transport / Q000187:drug effects / Q000502:physiology; D034741:RNA, Small Interfering / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D018079:Receptors, GABA / Q000502:physiology*; D016194:Receptors, N-Methyl-D-Aspartate / Q000502:physiology*; D013997:Time Factors
D004791:Enzyme Inhibitors; D018683:Excitatory Amino Acid Agents; C502186:GABARAP protein, rat; D008869:Microtubule-Associated Proteins; D034741:RNA, Small Interfering; D018079:Receptors, GABA; D016194:Receptors, N-Methyl-D-Aspartate; D016202:N-Methylaspartate; D005968:Glutamate Decarboxylase; C402565:glutamate decarboxylase 1