Developmental changes in NMDA receptor subunit composition at ON and OFF bipolar cell synapses onto direction-selective retinal ganglion cells.
In the developing mouse retina, spontaneous and light-driven activity shapes bipolar→ganglion cell glutamatergic synapse formation, beginning around the time of eye-opening (P12-P14) and extending through the first postnatal month. During this time, glutamate release can spill outside the synaptic cleft and possibly stimulate extrasynaptic NMDA-type glutamate receptors (NMDARs) on ganglion cells. Furthermore, the role of NMDARs during development may differ between ON and OFF bipolar synapses as in mature retina, where ON synapses reportedly include extrasynaptic NMDARs with GluN2B subunits. To better understand the function of glutamatergic synapses during development, we made whole-cell recordings of NMDAR-mediated responses, in vitro, from two types of genetically identified direction-selective ganglion cells (dsGCs): TRHR (thyrotropin-releasing hormone receptor) and Drd4 (dopamine receptor 4). Both dsGC types responded to puffed NMDA between P7 and P28; and both types exhibited robust light-evoked NMDAR-mediated responses at P14 and P28 that were quantified by conductance analysis during nicotinic and GABA(A) receptor blockade. For a given cell type and at a given age, ON and OFF bipolar cell inputs evoked similar NMDAR-mediated responses, suggesting that ON-versus-OFF differences in mature retina do not apply to the cell types or ages studied here. At P14, puff- and light-evoked NMDAR-mediated responses in both dsGCs were partially blocked by the GluN2B antagonist ifenprodil, whereas at P28 only TRHR cells remained ifenprodil-sensitive. NMDARs contribute at both ON and OFF bipolar cell synapses during a period of robust activity-dependent synaptic development, with declining GluN2B involvement over time in specific ganglion cell types.
Departments of Ophthalmology and Visual Sciences, and Molecular, Cellular, and Developmental Biology, University of Michigan, Ann Arbor, Michigan 48105, Departments of Ophthalmology and Visual Science, and Cellular and Molecular Physiology, Yale University, New Haven, Connecticut 06511.
Benjamin K
BK
Stafford
Silvia J H
SJ
Park
Kwoon Y
KY
Wong
Jonathan B
JB
Demb
D000367:Age Factors; D000818:Animals; D000831:Animals, Newborn; D018690:Excitatory Amino Acid Agonists / Q000494:pharmacology; D005260:Female; D018507:Gene Expression Regulation, Developmental / Q000187:drug effects / Q000502:physiology*; D018698:Glutamic Acid / Q000378:metabolism; D049452:Green Fluorescent Proteins / Q000235:genetics; D066298:In Vitro Techniques; D008027:Light; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D016202:N-Methylaspartate / Q000494:pharmacology; D018377:Neurotransmitter Agents / Q000494:pharmacology; D018408:Patch-Clamp Techniques; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism*; D012160:Retina / Q000166:cytology; D051245:Retinal Bipolar Cells / Q000378:metabolism*; D012165:Retinal Ganglion Cells / Q000166:cytology / Q000502:physiology*; D013569:Synapses / Q000502:physiology*; D014795:Visual Pathways / Q000187:drug effects / Q000502:physiology
D018690:Excitatory Amino Acid Agonists; C121001:NR2B NMDA receptor; D018377:Neurotransmitter Agents; D016194:Receptors, N-Methyl-D-Aspartate; D049452:Green Fluorescent Proteins; D018698:Glutamic Acid; D016202:N-Methylaspartate
GluN2B subunit; NMDA receptors; activity-dependent; bipolar cell; circuit development; ganglion cell