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Retinal Waves in Mice Lacking the 2 Subunit of the Nicotinic Retinal waves in mice lacking the ␤2 subunit of the nicotinic acetylcholine receptor Chao Sun*, David K. Warland*, Jose M. Ballesteros*, Deborah van der List*, and Leo M. Chalupa*†‡ Departments of *Neurobiology, Physiology, and Behavior, and †Ophthalmology and Vision Science, University of California, Davis, CA 95616 Communicated by Edward G. Jones, University of California, Davis, CA, July 24, 2008 (received for review June 9, 2008) The structural and functional properties of the visual system are disrupted in mutant animals lacking the ␤2 subunit of the nicotinic acetylcholine receptor. In particular, eye-specific retinogeniculate projections do not develop normally in these mutants. It is widely thought that the developing retinas of ␤2؊/؊ mutants do not manifest correlated activity, leading to the notion that retinal waves play an instructional role in the formation of eye-specific retinogeniculate projections. By multielectrode array recordings, we show here that the ␤2؊/؊ mutants have robust retinal waves during the formation of eye-specific projections. Unlike in WT animals, however, the mutant retinal waves are propagated by gap junctions rather than cholinergic circuitry. These results indi- cate that lack of retinal waves cannot account for the abnormalities that have been documented in the retinogeniculate pathway of the ␤2؊/؊ mutants and suggest that other factors must contribute Fig. 1. Confocal images of retina and LGN using antibodies against Chrnb2 (M270). WT retina (A) stains (red) in the inner plexiform layer (IPL) with two to the deficits in the visual system that have been noted in these distinguishable bands. In contrast, the sections from the Picciotto (B) and Xu animals. (C) mutant mice show no M270 binding. INL, inner nuclear layer; GCL, gan- glion cell layer. (D–F) Confocal images showing M270 staining (red) in the lateral geniculate nucleus ͉ multielectrode array ͉ retinal ganglion cells ͉ dLGN (outlined) of the P4 WT mouse (D) and a lack of staining with this retinogeniculate segregation ͉ gap junction antibody for the Picciotto (E) and Xu (F) mutant mice at comparable ages. D, dorsal; V, ventral; M, medial; L, lateral. DAPI-stained nuclei are pseudocolored green. (Scale bars: A–C,50␮m 50; D–F, 200 ␮m.) he precise connections that characterize the mature nervous Tsystem often arise from an early exuberant pattern that becomes refined through a combination of molecular and and ␤2Ϫ/Ϫ mutants have been reported to lack retinal waves during activity-dependent cues. In the case of the visual system, the this developmental period (15, 17, 19). Other visual system defects projections of the two eyes to the dorsal lateral geniculate have been reported including: (i) the projections of the two eyes nucleus (dLGN) are initially intermingled before gradually remain intermingled within both the dLGN and the superior becoming segregated into separate layers in animals with a colliculus at an age when they are fully segregated in WT mice laminated dLGN such as ferret, cat, and monkey or to different (15–17), (ii) retinotopic organization is less precise than in WT regions of the geniculate as in the mouse and rat (1–3). During animals (19, 21, 26), and (iii) receptive field properties of dLGN and the developmental period when eye-specific retinogeniculate visual cortical neurons are abnormal (18, 20, 26). projections are being established the retina manifests a remark- To probe further into the relationship between neuronal able pattern of activity. Immature retinal ganglion cells (RGCs) activity and developing retinal projections, we sought to docu- discharge periodic bursts of action potentials, with adjacent cells ment in greater detail the spontaneous discharge patterns of Ϫ Ϫ firing in a temporally correlated manner, resulting in waves of RGCs in the ␤2 / mutant retinas during the developmental activity sweeping across the retinal surface (4–7). These retinal period when the projections of the two eyes become segregated. ␤ Ϫ/Ϫ waves have been considered to be essential for the formation of Multielectrode array (MEA) recordings from 2 mutants eye-specific retinogeniculate projections through a Hebbian- unexpectedly revealed retinal waves and correlated discharges in type mechanism where the connections stemming from one eye all cases. These surprising results contradict previous lack-of- are strengthened and maintained, whereas those of the other eye waves reports (15, 17, 19). We conclude that the segregation defects and other structural and functional abnormalities that become eliminated based on which set of inputs is more capable ␤ Ϫ/Ϫ of activating dLGN neurons (8, 9). Evidence in support of this have been documented in the 2 mutants are not caused by the absence of retinal waves. prevalent notion has been provided by studies that have relied on pharmacological agents to alter the normal activity patterns of Results the developing retina. Several studies have shown that blocking ؊ ؊ Characterization of the Two Independent ␤2 / Mouse Lines. Based or perturbing retinal activity prevents the formation of segre- on published information, the Picciotto mutant allele deletes only gated retinogeniculate projections (9–11). These observations have led to the conclusion that retinal waves instruct the formation of eye-specific domains (8, 12–14). Author contributions: C.S., D.K.W., D.v.d.L., and L.M.C. designed research; C.S., J.M.B., and Studies that have used mutant mice have also supported a linkage D.v.d.L. performed research; C.S., D.K.W., J.M.B., and D.v.d.L. analyzed data; and C.S., between retinal waves and development of segregated retino- D.K.W., J.M.B., D.v.d.L., and L.M.C. wrote the paper. geniculate projections. In particular, animals in which the ␤2 The authors declare no conflict of interest. subunit of the nicotinic acetylcholine receptor gene (Chrnb2) has Freely available online through the PNAS open access option. been deleted (throughout the text, these mice are designated as ‡To whom correspondence should be addressed. E-mail: [email protected]. Ϫ/Ϫ ␤2 mutants) have served as a popular model in this arena This article contains supporting information online at www.pnas.org/cgi/content/full/ (15–22). When eye-specific projections are being formed, the 0807178105/DCSupplemental. correlated discharges of RGCs reflect cholinergic activity (23–25), © 2008 by The National Academy of Sciences of the USA 13638–13643 ͉ PNAS ͉ September 9, 2008 ͉ vol. 105 ͉ no. 36 www.pnas.org͞cgi͞doi͞10.1073͞pnas.0807178105 Downloaded by guest on October 2, 2021 NEUROSCIENCE Fig. 2. Retinal waves in WT and ␤2Ϫ/Ϫ mutants by MEA recording. (A) Raster plots of individual RGC spike activity obtained from 18 P4–5 WT and mutant retinas via MEA recording. Each row is the spike train from a single RGC. Within each row, vertical lines represent spikes from the corresponding cell. (Scale bar ϭ 2 min.) (B) The retinal wave frequency (waves/min) in P4–5 WT and mutant mice. The WT mice showed significantly lower retinal wave frequencies than the two mutants. There was no difference between Picciotto and Xu mice. Numbers reflect retinas recorded. Data are given as mean Ϯ SEM. *,P Ͻ 0.05; Student’s t test. (C) The mean firing frequency (spikes/s) of RGCs in P4–5 WT and mutant mice were significantly different from each other. The WT mice had the lowest firing frequency, and the Picciotto mice had the highest firing frequency. Numbers reflect RGCs recorded. Data are given as mean Ϯ SEM. *, P Ͻ 0.05; Kruskal-Wallis test. part of the exon 1, which results in an mRNA abnormally truncated through adulthood [supporting information (SI) Fig. S1A]. At at the 5Ј end. Although a truncated peptide might exist, Picciotto P1, there was considerable overlap of the contralateral and ipsilat- et al. (27) have shown that the Chrnb2 protein is undetectable in the eral input in the WT mouse and the two ␤2Ϫ/Ϫ mutants. In WT homozygous mutant mice. In contrast, the Xu mutant allele deletes animals, the ipsilateral projection decreased with age, becoming five exons. The entire coding region for the Chrnb2 mRNA is confined to the gap within the contralateral input, a pattern clearly essentially deleted in the Xu allele. This allele should be a null allele evident at P5. By contrast, in the two mutants, the ipsilateral because no Chrnb2 protein can be generated. Both the Picciotto projection remained relatively widespread at P5. At P12 as in the and Xu mutant alleles were generated by inserting a neo (neomycin- adult, the ipsilateral projection became patchy, with distinct clumps resistant) cassette into the genomic sequence. We also examined of label interspersed within the contralateral projections (Fig. S2). the presence of Chrnb2 proteins in the two mutant mice by using Quantitative analysis revealed that in the WT mouse the segrega- antibodies against Chrnb2 (Fig. 1). As may be seen, there is clear tion of the retinogeniculate projections was essentially complete by staining in the retina and dLGN of the WT mice, with no detectable P8, whereas significant binocular overlap was still present in the two staining in either the Picciotto or Xu mutants. These analyses mutants at P12 (Fig. S1B) the retinogeniculate projection remains indicate that we can unequivocally identify the homozygous mu- abnormal in the adult ␤2Ϫ/Ϫ mutants. tants for both mutant lines and that these two mutant lines are essentially null. Retinal Waves Are Present in Both ␤2؊/؊ Mutant Lines. We next assessed retinal activity by MEA recordings. Such recordings Retinogeniculate Projections Are Abnormally Segregated in Both from developing WT retinas at P4 and P5 revealed typical retinal ;2؊/؊ Mutant Lines. To assess the retinogeniculate pathway, waves with periodic correlated discharges (Fig. 2A; n ϭ 3 for P4␤ intraocular injections of different tracers were made into each n ϭ 4 for P5).
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