GABA(A) receptor membrane trafficking regulates spine maturity.
GABA(A) receptors (GABA(A)Rs), the principal sites of synaptic inhibition in the brain, are dynamic entities on the neuronal cell surface, but the role their membrane trafficking plays in shaping neuronal activity remains obscure. Here, we examined this by using mutant receptor beta3 subunits (beta3S408/9A), which have reduced binding to the clathrin adaptor protein-2, a critical regulator of GABA(A)R endocytosis. Neurons expressing beta3S408/9A subunits exhibited increases in the number and size of inhibitory synapses, together with enhanced inhibitory synaptic transmission due to reduced GABA(A)R endocytosis. Furthermore, neurons expressing beta3S408/9A subunits had deficits in the number of mature spines and reduced accumulation of postsynaptic density protein-95 at excitatory synapses. This deficit in spine maturity was reversed by pharmacological blockade of GABA(A)Rs. Therefore, regulating the efficacy of synaptic inhibition by modulating GABA(A)R membrane trafficking may play a critical role in regulating spine maturity with significant implications for synaptic plasticity together with behavior.
Jacob
Tija C
TC
Department of Neuroscience, Tufts University School of Medicine, Boston, MA 02030, USA.
Wan
Qin
Q
Vithlani
Mansi
M
Saliba
Richard S
RS
Succol
Francesca
F
Pangalos
Menelas N
MN
Moss
Stephen J
SJ
D000818:Animals; D001692:Biological Transport / Q000187:drug effects; D002460:Cell Line; D002462:Cell Membrane / Q000378:metabolism*; D002478:Cells, Cultured; D049229:Dendritic Spines / Q000187:drug effects / Q000502:physiology*; D004705:Endocytosis; D018756:GABA Antagonists / Q000494:pharmacology; D058787:GABA-A Receptor Antagonists; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D006624:Hippocampus / Q000166:cytology; D006801:Humans; D053444:Inhibitory Postsynaptic Potentials / Q000502:physiology; D018613:Microscopy, Confocal; D009154:Mutation; D009433:Neural Inhibition / Q000502:physiology; D009474:Neurons / Q000166:cytology / Q000378:metabolism / Q000502:physiology*; D018408:Patch-Clamp Techniques; D010852:Picrotoxin / Q000494:pharmacology; D021122:Protein Subunits / Q000235:genetics / Q000378:metabolism; D051381:Rats; D011963:Receptors, GABA-A / Q000235:genetics / Q000378:metabolism*
D018756:GABA Antagonists; D058787:GABA-A Receptor Antagonists; D049452:Green Fluorescent Proteins; D010852:Picrotoxin; D021122:Protein Subunits; D011963:Receptors, GABA-A