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Marci Smith, Fred Souza, Christianne Strang, Barbara Morley, Kent Keyser; Compensation for the loss of the alpha7 nAChR in the retina of the alpha7 nAChR knockout mouse. Invest. Ophthalmol. Vis. Sci. 2013;54(15):2476.
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© ARVO (1962-2015); The Authors (2016-present)
Nicotinic acetylcholine receptors (nAChRs) are pentameric ligand-gated cation channels expressed throughout the central nervous system, including in the retina. The alpha7 nAChR subtype is expressed by bipolar, amacrine, and ganglion cells in the rabbit retina (Dmitrieva et al., 2007). These receptors may play both a direct and modulatory role in visual signaling. Alzheimer’s disease (AD) and schizophrenia are disease states which have visual dysfunction and decreased alpha7 nAChR expression. In contrast, the alpha7 nAChR knockout (KO) mouse has a relatively mild phenotype, with only mild visual dysfunction (Morley & Rodriguez-Sierra, 2004; Origlia et al., 2012). Consequently, we predict that there is compensatory up-regulation of other genes, including muscarinic and nicotinic AChRs, during development that is not present in AD and schizophrenia.
We employed quantitative real-time polymerase chain reaction (qPCR), using RNA extracted from whole retina as well as RNA extracted from specific retinal layers obtained by laser capture microdissection, to quantify expression of AChR transcripts.
In whole retina alpha2, alpha9, alpha10, beta4, m1, and m4 AChR transcripts were up-regulated. In the ganglion cell layer beta3 and beta4 nAChR transcripts were significantly down-regulated while m2 and m4 mAChR transcripts were significantly up-regulated. In the inner portion of the inner nuclear layer (INL) alpha2, alpha9, beta4, m3 and m4 AChR subunits were all significantly down-regulated. Finally, in the outer portion of the INL beta2, beta4 and m4 AChR transcripts were all significantly up-regulated.
Thus, rather than a simple up-regulation of a single AChR subtype, compensation for the loss of the alpha7 nAChR in the KO mouse was differentially mediated by changes in mRNA levels of a number of different AChR transcripts in different retinal layers. Compensatory changes in subunit transcription may provide insight into potential receptor based pharmaceutical targets for treatment of AD and schizophrenia symptoms, success of which may be testable through assessment of visual dysfunction.
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