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Convergence and Divergence of CRH Amacrine Cells in Mouse Retinal Circuitry

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Convergence and Divergence of CRH Amacrine Cells in Mouse Retinal Circuitry This Accepted Manuscript has not been copyedited and formatted. The final version may differ from this version. Research Articles: Systems/Circuits Convergence and divergence of CRH amacrine cells in mouse retinal circuitry Silvia J.H. Park1, Joseph Pottackal2, Jiang-Bin Ke3, Na Young Jun1, Pouyan Rahmani1, In-Jung Kim1,2,4, Joshua H. Singer3 and Jonathan B. Demb1,2,5 1Department of Ophthalmology & Visual Science 2Interdepartmental Neuroscience Program 4Department of Neuroscience 5Department of Cellular & Molecular Physiology Yale University, New Haven, CT 06511 3Department of Biology University of Maryland,. College Park, MD 20742 DOI: 10.1523/JNEUROSCI.2518-17.2018 Received: 1 September 2017 Revised: 1 March 2018 Accepted: 7 March 2018 Published: 23 March 2018 Author contributions: S.J.H.P., J.P., I.-J.K., J.H.S., and J.B.D. designed research; S.J.H.P., J.P., J.-B.K., N.Y.J., and P.R. performed research; J.B.D. contributed unpublished reagents/analytic tools; S.J.H.P., J.P., J.- B.K., N.Y.J., P.R., I.-J.K., J.H.S., and J.B.D. analyzed data; S.J.H.P., J.P., J.H.S., and J.B.D. wrote the paper. Conflict of Interest: The authors declare no competing financial interests. This research was funded by NIH grants EY014454, EY021372, EY017836, EY026878, the Whitehall Foundation, and an unrestricted grant from Research to Prevent Blindness to the Department of Ophthalmology & Visual Science at Yale University. Correspondence: [email protected] Cite as: J. Neurosci ; 10.1523/JNEUROSCI.2518-17.2018 Alerts: Sign up at www.jneurosci.org/cgi/alerts to receive customized email alerts when the fully formatted version of this article is published. Accepted manuscripts are peer-reviewed but have not been through the copyediting, formatting, or proofreading process. Copyright © 2018 the authors ͳ Convergence and divergence of CRH amacrine cells in mouse retinal circuitry ʹ ͵ Abbreviated title: Circuit function of CRH amacrine cells Ͷ ͷ Silvia J.H. Park1, Joseph Pottackal2, Jiang-Bin Ke3, Na Young Jun1, Pouyan Rahmani1, ͸ In-Jung Kim1,2,4, Joshua H. Singer3, Jonathan B. Demb1,2,5 ͹ ͺ Department of Ophthalmology & Visual Science1 ͻ Interdepartmental Neuroscience Program2 ͳͲ Department of Neuroscience4 ͳͳ Department of Cellular & Molecular Physiology5 ͳʹ Yale University ͳ͵ New Haven, CT 06511 ͳͶ ͳͷ Department of Biology3 ͳ͸ University of Maryland ͳ͹ College Park, MD 20742 ͳͺ ͳͻ Correspondence: [email protected] ʹͲ ʹͳ Number of pages: 35 ʹʹ Number of figures: 9 ʹ͵ Number of words in Abstract: 250 ʹͶ Introduction: 501 ʹͷ Discussion: 1180 ʹ͸ Conflict of Interest: None ʹ͹ Acknowledgements: This research was funded by NIH grants EY014454, EY021372, ʹͺ EY017836, EY026878, the Whitehall Foundation, and an unrestricted grant from ʹͻ Research to Prevent Blindness to the Department of Ophthalmology & Visual Science ͵Ͳ at Yale University. The authors declare no competing financial interests. ͵ͳ ͵ʹ Abstract ͵͵ Inhibitory interneurons sculpt the outputs of excitatory circuits to expand the dynamic ͵Ͷ range of information processing. In mammalian retina, more than 30 types of amacrine ͵ͷ cells provide lateral inhibition to vertical, excitatory bipolar cell circuits, but functional ͵͸ roles for only a few amacrine cells are well established. Here, we elucidate the function ͵͹ of corticotropin-releasing hormone (CRH)-expressing amacrine cells labeled in Cre ͵ͺ transgenic mice of either sex. CRH cells co-stratify with the ON Alpha ganglion cell, a ͵ͻ neuron highly sensitive to positive contrast. Electrophysiological and optogenetic ͶͲ analyses demonstrate that two CRH types (CRH-1, CRH-3) make GABAergic synapses Ͷͳ with ON Alpha cells. CRH-1 cells signal via graded membrane potential changes Ͷʹ whereas CRH-3 cells fire action potentials. Both types show sustained ON-type Ͷ͵ responses to positive contrast over a range of stimulus conditions. Optogenetic control ͶͶ of transmission at CRH-1 synapses demonstrates that these synapses are tuned to low Ͷͷ temporal frequencies, maintaining GABA release during fast hyperpolarizations during Ͷ͸ brief periods of negative contrast. CRH amacrine cell output is suppressed by prolonged Ͷ͹ negative contrast, when ON Alpha ganglion cells continue to receive inhibitory input Ͷͺ from converging OFF-pathway amacrine cells; the converging ON- and OFF-pathway Ͷͻ inhibition balances tonic excitatory drive to ON Alpha cells. Previously, it was ͷͲ demonstrated that CRH-1 cells inhibit firing by Suppressed-by-Contrast ganglion cells ͷͳ during positive contrast. Thus, divergent outputs of CRH-1 cells inhibit two ganglion cell ͷʹ types with opposite responses to positive contrast. The opposing responses of ON ͷ͵ Alpha and Suppressed-by-Contrast ganglion cells are explained by differing ͷͶ excitation/inhibition balance in the two circuits. ͷͷ ͷ͸ Significance Statement ͷ͹ A goal of neuroscience research is to explain the function of neural circuits at the level ͷͺ of specific cell types. Here, we studied the function of specific types of inhibitory ͷͻ interneurons, called CRH amacrine cells, in the mouse retina. Genetic tools were used ͸Ͳ to identify and manipulate CRH cells, which make GABAergic synapses with a well- ͸ͳ studied ganglion cell type, the ON Alpha cell. CRH cells converge with other types of ͸ʹ amacrine cells to tonically inhibit ON Alpha cells and balance their high level of 2 ͸͵ excitation. CRH cells diverge to different types of ganglion cell, whose unique properties ͸Ͷ depend on their balance of excitation and inhibition. ͸ͷ ͸͸ ͸͹ Introduction ͸ͺ ͸ͻ The mammalian retina implements the first stage of visual processing via ~35 parallel ͹Ͳ circuits that drive the same number of ganglion cell types, each of which encodes a ͹ͳ different feature of the visual scene (Demb and Singer, 2015; Baden et al., 2016). At its ͹ʹ core, each parallel circuit comprises one or more of the ~15 types of excitatory bipolar ͹͵ cell converging on the ganglion cell (Helmstaedter et al., 2013; Sanes and Masland, ͹Ͷ 2015; Baden et al., 2016). Bipolar cells are glutamatergic interneurons depolarized by ͹ͷ either light increments (ON bipolar cells) or decrements (OFF bipolar cells) (Wässle et ͹͸ al., 2009; Euler et al., 2014; Shekhar et al., 2016; Franke et al., 2017). Bipolar cell ͹͹ outputs are shaped by more than 30 types of amacrine cells, which make synapses with ͹ͺ bipolar cell axon terminals and ganglion cell dendrites (MacNeil and Masland, 1998; ͹ͻ Demb and Singer, 2015; Diamond, 2017). Amacrine cells are primarily inhibitory, ͺͲ releasing either GABA or glycine (Zhang and McCall, 2012). Additionally, many types ͺͳ co-release a neuromodulator, peptide, or fast excitatory neurotransmitter (Bagnoli et al., ͺʹ 2003; Lee et al., 2014; Zhu et al., 2014; Hirasawa et al., 2015). ͺ͵ ͺͶ The functional roles of only a few types of amacrine cells are well established. These ͺͷ types include the starburst amacrine cell, which mediates a direction-selective ͺ͸ computation (Vaney et al., 2012), and the AII and A17 amacrine cells, which play ͺ͹ important roles in night vision (Grimes et al., 2010; Demb and Singer, 2012; Diamond, ͺͺ 2017). Additional amacrine cell types now can be studied functionally using Cre ͺͻ transgenic mouse lines (Taniguchi et al., 2011; Lee et al., 2014; Zhu et al., 2014; ͻͲ Krishnaswamy et al., 2015; Akrouh et al., 2015; Park et al., 2015; Tien et al., 2016). ͻͳ ͻʹ Two types of amacrine cell were identified in the corticotropin-releasing hormone ͻ͵ (CRH)-ires-Cre transgenic mouse (Zhu et al., 2014). One of these, CRH-1, makes 3 ͻͶ synapses with a Suppressed-by-Contrast (SbC) ganglion cell that exhibits suppressed ͻͷ firing in response to either positive or negative contrast (Sivyer et al., 2010; Jacoby et ͻ͸ al., 2015; Tien et al., 2015; Lee et al., 2016). CRH-1 provides GABAergic inhibition to ͻ͹ suppress SbC firing during positive contrast (Jacoby et al., 2015). Another well-studied ͻͺ ganglion cell type, the ON Alpha cell, co-stratifies with CRH cells, suggesting that it also ͻͻ receives synaptic input from them. But, unlike the SbC cell, the ON Alpha cell responds ͳͲͲ to positive contrast with increased firing. Here, we identify a third type of CRH cell and ͳͲͳ show that two CRH types (CRH-1, CRH-3) make synapses with ON Alpha cells. ͳͲʹ Outputs from CRH cells and OFF-pathway amacrine cells converge at ON Alpha cells to ͳͲ͵ control the gain of responses to tonic excitation from continuously active bipolar cell ͳͲͶ synapses. CRH-1 output diverges to two circuits, SbC and ON Alpha ganglion cells, ͳͲͷ with opposite responses to positive contrast, demonstrating that a single inhibitory ͳͲ͸ interneuron can contribute to diverse retinal outputs. The distinct contrast responses of ͳͲ͹ SbC and ON Alpha ganglion cells are explained by differences in the balance of ͳͲͺ excitation and inhibition in the two circuits. ͳͲͻ ͳͳͲ Materials and Methods ͳͳͳ ͳͳʹ Animals ͳͳ͵ All animal procedures were approved by the Institutional Animal Care and Use ͳͳͶ Committees at Yale University or the University of Maryland and were in compliance ͳͳͷ with National Institutes of Health guidelines. Mice of either sex, maintained on C57BL/6J ͳͳ͸ backgrounds, were studied at ages between two weeks and six months. ͳͳ͹ In CRH-ires-Cre mice (B6(Cg)-CRHtm1(cre)Zjh/J; Jackson Laboratory #012704, ͳͳͺ RRID:IMSR_JAX:012704), expression of Cre recombinase is driven by endogenous ͳͳͻ CRH regulatory elements (Taniguchi et. al., 2011). In nNOS-CreER mice (B6; 129S- ͳʹͲ Nos1tm1.1(cre/ERT2)/Zjh/J; Jackson Laboratory #014541, RRID:IMSR_JAX:014541), ͳʹͳ expression of Cre recombinase is driven by endogenous Nos1 regulatory elements ͳʹʹ (Taniguchi et. al., 2011). For nNOS-CreER mice, Cre expression was induced by ͳʹ͵ tamoxifen (2 mg delivered on two consecutive days) administered by either IP injection ͳʹͶ or gavage at ~P30, and at least two weeks before the experiment.
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