title: Spontaneous activity promotes synapse formation in a cell-type-dependent manner in the developing retina.
abstract: Spontaneous activity is thought to regulate synaptogenesis in many parts of the developing nervous system. In vivo evidence for this regulation, however, is scarce and comes almost exclusively from experiments in which normal activity was reduced or blocked completely. Thus, whether spontaneous activity itself promotes synaptogenesis or plays a purely permissive role remains uncertain. In addition, how activity influences synapse dynamics to shape connectivity and whether its effects among neurons are uniform or cell-type-dependent is unclear. In mice lacking the cone-rod homeobox gene (Crx), photoreceptors fail to establish normal connections with bipolar cells (BCs). Here, we find that retinal ganglion cells (RGCs) in Crx⁻/⁻ mice become rhythmically hyperactive around the time of eye opening as a result of increased spontaneous glutamate release from BCs. This elevated neurotransmission enhances synaptogenesis between BCs and RGCs, without altering the overall circuit architecture. Using live imaging, we discover that spontaneous activity selectively regulates the rate of synapse formation, not elimination, in this circuit. Reconstructions of the connectivity patterns of three BC types with a shared RGC target further revealed that neurotransmission specifically promotes the formation of multisynaptic appositions from one BC type without affecting the maintenance or elimination of connections from the other two. Although hyperactivity in Crx⁻/⁻ mice persists, synapse numbers do not increase beyond 4 weeks of age, suggesting closure of a critical period for synaptic refinement in the inner retina. Interestingly, despite their hyperactivity, RGC axons maintain normal eye-specific territories and cell-type-specific layers in the dorsal lateral geniculate nucleus.
authors.affiliation: Departments of Ophthalmology and Visual Sciences and Anatomy and Neurobiology, Washington University School of Medicine, St. Louis, Missouri 63110, USA.
authors.forename: Florentina
authors.initials: F
authors.lastname: Soto
authors.forename: Xiaofeng
authors.initials: X
authors.lastname: Ma
authors.forename: Jacob L
authors.initials: JL
authors.lastname: Cecil
authors.forename: Bradly Q
authors.initials: BQ
authors.lastname: Vo
authors.forename: Susan M
authors.initials: SM
authors.lastname: Culican
authors.forename: Daniel
authors.initials: D
authors.lastname: Kerschensteiner
mesh_terms: D000200:Action Potentials / Q000235:genetics / Q000502:physiology*; D000367:Age Factors; D000818:Animals; D000831:Animals, Newborn; D001703:Biophysics; D064026:Calbindins; D015220:Calcium Channels / Q000378:metabolism; D020746:Calcium Channels, L-Type; D002772:Cholera Toxin / Q000008:administration & dosage / Q000378:metabolism; D002795:Choline O-Acetyltransferase / Q000378:metabolism; D000076122:Disks Large Homolog 4 Protein; D004558:Electric Stimulation / Q000379:methods; D019706:Excitatory Postsynaptic Potentials / Q000235:genetics; D005123:Eye / Q000033:anatomy & histology; D005260:Female; D018507:Gene Expression Regulation, Developmental / Q000235:genetics; D005829:Geniculate Bodies / Q000166:cytology / Q000502:physiology; D051528:Guanylate Kinases / Q000235:genetics / Q000378:metabolism; D018398:Homeodomain Proteins; D056965:Injections, Intraocular / Q000379:methods; D008164:Luminescent Proteins / Q000235:genetics / Q000378:metabolism; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D055495:Neurogenesis / Q000235:genetics; D009474:Neurons / Q000145:classification* / Q000166:cytology*; D018377:Neurotransmitter Agents / Q000378:metabolism; D018408:Patch-Clamp Techniques; D019887:Peanut Agglutinin / Q000378:metabolism; D010507:Periodicity; D017729:Presynaptic Terminals / Q000502:physiology; D050638:Receptors, Dopamine D4 / Q000235:genetics; D012160:Retina / Q000166:cytology* / Q000254:growth & development*; D012165:Retinal Ganglion Cells / Q000166:cytology / Q000502:physiology; D012243:Rhodopsin / Q000378:metabolism; D064030:S100 Calcium Binding Protein G / Q000378:metabolism; D013569:Synapses / Q000502:physiology*; D015534:Trans-Activators / Q000172:deficiency; D014162:Transfection; D050598:Vesicular Glutamate Transport Protein 1 / Q000378:metabolism; D014795:Visual Pathways / Q000166:cytology / Q000502:physiology
chemical_list: C529218:CACNA1S protein, mouse; D064026:Calbindins; D015220:Calcium Channels; D020746:Calcium Channels, L-Type; D000076122:Disks Large Homolog 4 Protein; C501447:Dlg4 protein, mouse; C493600:Drd4 protein, mouse; D018398:Homeodomain Proteins; D008164:Luminescent Proteins; D008565:Membrane Proteins; D018377:Neurotransmitter Agents; D019887:Peanut Agglutinin; D064030:S100 Calcium Binding Protein G; C493465:Slc17a7 protein, mouse; D015534:Trans-Activators; D050598:Vesicular Glutamate Transport Protein 1; C109288:cone rod homeobox protein; D050638:Receptors, Dopamine D4; D012243:Rhodopsin; D002772:Cholera Toxin; D002795:Choline O-Acetyltransferase; D051528:Guanylate Kinases