Eye-Specific Retinogeniculate Segregation Independent of Normal Neuronal Activity

Huberman, Andrew D.; Wang, Guoyong; Liets, Lauren C.; Collins, O. A.; Chapman, Barbara; Chalupa, Leo M.

doi:10.1126/science.1080694

Cited by 113 publications

(106 citation statements)

References 28 publications

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“…Image acquisition and quantification of the extent of ipsilateral eye axons and overlap were identical to previous reports 12, 15,20 . For details of quantification of long and short axis length, aspect ratio and extent of ipsilateral eye terminations, see Supplementary Methods online.…”

Section: Imaging and Quantification Of Eye-specific Retinogeniculate mentioning

confidence: 76%

Ephrin-As mediate targeting of eye-specific projections to the lateral geniculate nucleus

et al. 2005

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Axon guidance cues contributing to the development of eye-specific visual projections to the lateral geniculate nucleus (LGN) have not previously been identified. Here we show that gradients of ephrinAs and their receptors (EphAs) direct retinal ganglion cell (RGC) axons from the two eyes into their stereotyped pattern of layers in the LGN. Overexpression of EphAs in ferret RGCs using in vivo electroporation induced axons from both eyes to misproject within the LGN. The effects of EphA overexpression were competition-dependent and restricted to the early postnatal period. These findings represent the first demonstration of eye-specific pathfinding mediated by axon guidance cues and, taken with other reports, indicate that ephrin-As can mediate several mapping functions within individual target structures.In mammals, retinal ganglion cell (RGC) axons are segregated into eye-specific layers in the lateral geniculate nucleus (LGN). Early in development, however, retinogeniculate axons from the two eyes are intermingled 1-3 . The segregation of eye-specific projections into layers is an established model system for studying axon targeting during development 4 . Technically, the term "layers" refers to discrete cellular groupings. However, "eye-specific LGN layers" is also used to refer to the regions of stereotyped size, shape and position formed by RGC axons arising from each eye. (Hereafter we use the term "layers" only in this latter sense.) The regularity of eye-specific layers is a distinguishing feature of mammalian brains; their spatial arrangement is different between, but invariant within, species 5 . In carnivores such as cats and ferrets, layer A contains axons from the contralateral eye and always resides in the inner portion of the LGN, whereas layer A1 contains axons from the ipsilateral eye and always resides in the outer LGN 5 . This invariance is in bold contrast to eye-specific projections found elsewhere along the visual pathway, such as eye-specific patches in the superior colliculus (SC) 6 or ocular dominance columns in visual cortex 7 , which vary tremendously across individuals of a given species in terms of their size, shape and position.Correspondence should be addressed to B.C. (bxchapman@ucdavis.edu). 4 Present address: Department of Neurobiology, Fairchild Building, Stanford University School of Medicine, Palo Alto, California 94305, USA.Note: Supplementary information is available on the Nature Neuroscience website. COMPETING INTERESTS STATEMENTThe authors declare that they have no competing financial interests. NIH Public Access NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author ManuscriptNumerous studies have shown that altering neural activity perturbs eye-specific retinogeniculate segregation 8-12 . However, the invariant positioning of eye-specific LGN layers cannot be explained by purely activity-dependent mechanisms 13,14 and recent data have challenged the idea that neural activity plays a direct, instructive role in segregation of eyespecific projections to ...

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Section: Imaging and Quantification Of Eye-specific Retinogeniculate mentioning

confidence: 76%

Ephrin-As mediate targeting of eye-specific projections to the lateral geniculate nucleus

et al. 2005

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“…Second, AChR KOs analyzed to date lack only some receptors, leaving other pathways for cholinergic transmission intact (Bansal et al, 2000;Rossi et al, 2001). Third, attempts to ablate retinal cholinergic neurons (i.e., starburst amacrine cells) were unable to completely eliminate these cells before synapse formation in the inner retina Reese et al, 2001;Yoshida et al, 2001;Huberman et al, 2003). Here, we used an alternate method that circumvents these limitations.…”

Section: Discussionmentioning

confidence: 99%

“…How network activity is affected when specific forms of neurotransmission are blocked in vivo is more difficult to address because it requires selective and complete blockade throughout development, an approach that has not been possible in the past (Bansal et al, 2000;Reese et al, 2001;Rossi et al, 2001;Huberman et al, 2003). Here, we asked whether patterned retinal activity emerges when cholinergic neurotransmission never occurs.…”

Section: Introductionmentioning

confidence: 99%

Disruption and Recovery of Patterned Retinal Activity in the Absence of Acetylcholine

et al. 2005

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Many developing neural circuits generate synchronized bursting activity among neighboring neurons, a pattern thought to be important for sculpting precise neural connectivity. Network output remains relatively constant as the cellular and synaptic components of these immature circuits change during development, suggesting the presence of homeostatic mechanisms. In the retina, spontaneous waves of activity are present even before chemical synapse formation, needing gap junctions to propagate. However, as synaptogenesis proceeds, retinal waves become dependent on cholinergic neurotransmission, no longer requiring gap junctions. Later still in development, waves are driven by glutamatergic rather than cholinergic synapses. Here, we asked how retinal activity evolves in the absence of cholinergic transmission by using a conditional mutant in which the gene encoding choline acetyltransferase (ChAT), the sole synthetic enzyme for acetylcholine (ACh), was deleted from large retinal regions. ChAT-negative regions lacked retinal waves for the first few days after birth, but by postnatal day 5 (P5), ACh-independent waves propagated across these regions. Pharmacological analysis of the waves in ChAT knock-out regions revealed a requirement for gap junctions but not glutamate, suggesting that patterned activity may have emerged via restoration of previous gap-junctional networks. Similarly, in P5 wild-type retinas, spontaneous activity recovered after a few hours in nicotinic receptor antagonists, often as local patches of coactive cells but not waves. The rapid recovery of rhythmic spontaneous activity in the presence of cholinergic antagonists and the eventual emergence of waves in ChAT knock-out regions suggest that homeostatic mechanisms regulate retinal output during development.

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“…Images were pseudocolored using the Wasabi software (Hamamatsu) and loaded to Adobe Photoshop and Illustrator for construction of montage. Parameters of >30% threshold for white and <30% threshold for black (Huberman et al 2003) were used to analyze the tissue with the Image J program (NIH). Multiplying the threshold images of both projections and determining the number of pixels common to both projections provided a measure of binocular overlap.…”

Section: Imaging and Analysismentioning

confidence: 99%

“…It was demonstrated first by Rakic in the fetal monkey (Rakic, 1976) and, subsequently, in many other species that early in development the projections from the two eyes overlap in the dlgn before segregating into eye-specific domains, and several lines of evidence indicate that neuronal activity has a key role in this process (Chapman, 2000;Huberman et al, 2003). In particular, several recent papers have relied on β2-/-mice, which lack the β2 subunit of the nicotinic acetylcholine receptor, to assess the role of retinal activity on the state of retinogeniculate projections (Rossi et al, 2001;Grubb et al, 2003;Grubb and Thompson, 2004a;Grubb and Thompson, 2004b;Torborg et al, 2004;Torborg et al, 2005).…”

Section: Introductionmentioning

confidence: 99%

Formation of eye-specific retinogeniculate projections occurs prior to the innervation of the dorsal lateral geniculate nucleus by cholinergic fibers

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Chalupa

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We compared the developmental periods in the mouse when projections from the two eyes become segregated in the dorsal lateral geniculate nucleus with the time when this nucleus becomes innervated by cholinergic fibers from the brainstem. Changes in labeling patterns of different tracers injected into each eye revealed that segregation of retinogeniculate inputs commences at postnatal day five (P5) and is largely complete by P8. Immunocytochemical staining showed that cholinergic neurons are present in the parabrachial region of the brain stem on the day of birth. However, cholinergic fibers are not evident in the geniculate until P5, and these are sparse at this age, increasing in density to form well-defined clusters by P12. These results indicate that segregation of eye-specific projections during normal development is unlikely to be regulated by cholinergic inputs from the brainstem.

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Eye-Specific Retinogeniculate Segregation Independent of Normal Neuronal Activity

Cited by 113 publications

References 28 publications

Ephrin-As mediate targeting of eye-specific projections to the lateral geniculate nucleus

Ephrin-As mediate targeting of eye-specific projections to the lateral geniculate nucleus

Disruption and Recovery of Patterned Retinal Activity in the Absence of Acetylcholine

Formation of eye-specific retinogeniculate projections occurs prior to the innervation of the dorsal lateral geniculate nucleus by cholinergic fibers

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