title: The Down syndrome critical region regulates retinogeniculate refinement.
abstract: Down syndrome (DS) is a developmental disorder caused by a third chromosome 21 in humans (Trisomy 21), leading to neurological deficits and cognitive impairment. Studies in mouse models of DS suggest that cognitive deficits in the adult are associated with deficits in synaptic learning and memory mechanisms, but it is unclear whether alterations in the early wiring and refinement of neuronal circuits contribute to these deficits. Here, we show that early developmental refinement of visual circuits is perturbed in mouse models of Down syndrome. Specifically, we find excessive eye-specific segregation of retinal axons in the dorsal lateral geniculate nucleus. Indeed, the degree of refinement scales with defects in the "Down syndrome critical region" (DSCR) in a dose-dependent manner. We further identify Dscam (Down syndrome cell adhesion molecule), a gene within the DSCR, as a regulator of eye-specific segregation of retinogeniculate projections. Although Dscam is not the sole gene in the DSCR contributing to enhanced refinement in trisomy, Dscam dosage clearly regulates cell spacing and dendritic fasciculation in a specific class of retinal ganglion cells. Thus, altered developmental refinement of visual circuits that occurs before sensory experience is likely to contribute to visual impairment in individuals with Down syndrome.
authors.affiliation: Department of Psychiatry, Stanford University School of Medicine, Stanford, California, 94305, USA.
authors.forename: Martina
authors.initials: M
authors.lastname: Blank
authors.forename: Peter G
authors.initials: PG
authors.lastname: Fuerst
authors.forename: Beth
authors.initials: B
authors.lastname: Stevens
authors.forename: Navid
authors.initials: N
authors.lastname: Nouri
authors.forename: Lowry
authors.initials: L
authors.lastname: Kirkby
authors.forename: Deepti
authors.initials: D
authors.lastname: Warrier
authors.forename: Ben A
authors.initials: BA
authors.lastname: Barres
authors.forename: Marla B
authors.initials: MB
authors.lastname: Feller
authors.forename: Andrew D
authors.initials: AD
authors.lastname: Huberman
authors.forename: Robert W
authors.initials: RW
authors.lastname: Burgess
authors.forename: Craig C
authors.initials: CC
authors.lastname: Garner
mesh_terms: D000465:Algorithms; D000818:Animals; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000008:administration & dosage / Q000494:pharmacology; D015815:Cell Adhesion Molecules / Q000235:genetics / Q000502:physiology; D002452:Cell Count; D003712:Dendrites / Q000502:physiology; D004305:Dose-Response Relationship, Drug; D004314:Down Syndrome / Q000503:physiopathology*; D005207:Fasciculation / Q000503:physiopathology; D018628:Gene Dosage; D005829:Geniculate Bodies / Q000503:physiopathology*; D007150:Immunohistochemistry; D008297:Male; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008839:Microelectrodes; D009475:Neurons, Afferent / Q000502:physiology; D018722:Nicotinic Agonists / Q000008:administration & dosage / Q000494:pharmacology; D011725:Pyridines / Q000008:administration & dosage / Q000494:pharmacology; D012160:Retina / Q000503:physiopathology*; D012165:Retinal Ganglion Cells / Q000502:physiology; D014314:Trisomy / Q000473:pathology; D014795:Visual Pathways / Q000502:physiology
chemical_list: D019086:Bridged Bicyclo Compounds, Heterocyclic; D015815:Cell Adhesion Molecules; C110833:DSCAM protein, human; D018722:Nicotinic Agonists; D011725:Pyridines; C082748:epibatidine