Abstract
Substance P (SP), a neuroprotective peptidergic neurotransmitter, is known to have immunoreactivity (IR) localized to amacrine and/or ganglion cells in a variety of species’ retinas, but it has not yet been studied in the mouse retina. Thus, we investigated the distribution and synaptic organization of SP-IR by confocal and electron microscopy immunocytochemistry in the mouse retina. SP-IR was distributed in the inner nuclear layer (INL), inner plexiform layer (IPL), and ganglion cell layer (GCL). Most of the SP-IR somas belonged to amacrine cells (2.5% of all) in the INL and their processes stratified into the S1, S3, and S5 layers of the IPL, with the most intense band in the S5 layer. Some SP-IR somas can also be observed in the GCL, which were identified as displaced amacrine cells (82%, 1269/1550) and ganglion cells (18%, 281/1550) by antibodies against AP2α and RBPMS, respectively. Such SP-IR ganglion cells (1.2% of all RGCs) can be further divided into 3 subgroups expressing SP/α-Synuclein (α-Syn), SP/GAD67, and/or SP/GAD67/α-Syn. Possible physiological and pathological roles of these ganglion cells are discussed. Further, electron microscopy evidence demonstrates that SP-IR amacrine cells receive major inputs from other SP-IR amacrine cell processes (146/242 inputs) and output mostly to SP-negative amacrine cell processes (291/673 outputs), suggesting series inhibition among amacrine cells. These results reveal for the first time an explicit distribution, novel ganglion cell features, and synaptic organization of SP-IR in the mouse retina, which is important for the future use of mouse models to study the roles of SP in healthy and diseased (including Parkinson’s disease) retinal states.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
Data availability
The data used to support the findings of this study are available from the corresponding author upon request but not publicly available due to ethical or privacy reasons.
References
Abeliovich A, Schmitz Y, Fariñas I, Choi-Lundberg D, Ho WH, Castillo PE, Shinsky N, Verdugo JM, Armanini M, Ryan A, Hynes M, Phillips H, Sulzer D, Rosenthal A (2000) Mice lacking alpha-synuclein display functional deficits in the nigrostriatal dopamine system. Neuron 25(1):239–252. https://doi.org/10.1016/s0896-6273(00)80886-7
Alireza M, Anna M, Mohsen T, Grace PM, Charalabos P, Reza D (2016) Neuropeptide substance P and the immune response. J Cell Mol Life Sci CMLS 73(22):4249
Almeida TA, Rojo J, Nieto PM, Pinto FM, Hernandez M, Martín JD, Candenas ML (2004) Tachykinins and tachykinin receptors: structure and activity relationships. Curr Med Chem 11(15):2045–2081. https://doi.org/10.2174/0929867043364748
Atik A, Stewart T, Zhang J (2016) Alpha-synuclein as a biomarker for Parkinson’s disease. Brain Pathol 26(3):410–418. https://doi.org/10.1111/bpa.12370
Baek SM, Kim K, Kim S, Son Y, Hong HS, Yu SY (2020) SP prevents T2DM complications by immunomodulation. Sci Rep 10(1):16753. https://doi.org/10.1038/s41598-020-73994-1
Berson DM, Castrucci AM, Provencio I (2010) Morphology and mosaics of melanopsin-expressing retinal ganglion cell types in mice. J Comp Neurol 518(13):2405–2422. https://doi.org/10.1002/cne.22381
Bodis-Wollner I, Kozlowski PB, Glazman S, Miri S (2014) α-synuclein in the inner retina in Parkinson disease. Ann Neurol 75(6):964–966. https://doi.org/10.1002/ana.24182
Bolam JP, Smith Y (1990) The GABA and substance P input to dopaminergic neurones in the substantia nigra of the rat. Brain Res 529(1–2):57–78. https://doi.org/10.1016/0006-8993(90)90811-o
Brecha N, Hendrickson A, Florén I, Karten HJ (1982) Localization of substance P-like immunoreactivity within the monkey retina. Invest Ophthalmol vis Sci 23(2):147–153
Brecha N, Johnson D, Bolz J, Sharma S, Parnavelas JG, Lieberman AR (1987) Substance P-immunoreactive retinal ganglion cells and their central axon terminals in the rabbit. Nature 327(6118):155–158. https://doi.org/10.1038/327155a0
Britto LR, Hamassaki DE (1991) A subpopulation of displaced ganglion cells of the pigeon retina exhibits substance P-like immunoreactivity. Brain Res 546(1):61–68. https://doi.org/10.1016/0006-8993(91)91159-x
Butz E, Peichl L, Müller B (2015) Cone bipolar cells in the retina of the microbat Carollia perspicillata. J Comp Neurol 523(6):963–981. https://doi.org/10.1002/cne.23726
Cai D, Luo X, Shen K, Shen Y (2021) GABAergic retinal ganglion cells regulate innate defensive responses. NeuroReport 32(7):643–649. https://doi.org/10.1097/wnr.0000000000001652
Carter-Dawson LD, LaVail MM (1979) Rods and cones in the mouse retina. I. Structural analysis using light and electron microscopy. J Comp Neurol 188(2):245–262. https://doi.org/10.1002/cne.901880204
Caruso DM, Owczarzak MT, Pourcho RG (1990) Colocalization of substance P and GABA in retinal ganglion cells: a computer-assisted visualization. Vis Neurosci 5(4):389–394. https://doi.org/10.1017/s095252380000047x
Casini G, Rickman DW, Sternini C, Brecha NC (1997) Neurokinin 1 receptor expression in the rat retina. J Comp Neurol 389(3):496–507
Casini G, Dal Monte M, Fornai F, Bosco L, Willems D, Yang Q, Zhou ZJ, Bagnoli P (2004) Neurokinin 1 receptor expression and substance P physiological actions are developmentally regulated in the rabbit retina. Neuroscience 124(1):147–160. https://doi.org/10.1016/j.neuroscience.2003.10.049
Chan K, Hoon M, Pattnaik BR, Ver Hoeve JN, Wahlgren B, Gloe S, Williams J, Wetherbee B, Kiland JA, Vogel KR, Jansen E, Salomons G, Walters D, Roullet JB, Gibson KM, McLellan GJ (2020) Vigabatrin-induced retinal functional alterations and second-order neuron plasticity in C57BL/6J Mice. Invest Ophthalmol Vis Sci 61(2):17. https://doi.org/10.1167/iovs.61.2.17
Chan-Palay V, Palay SL (1977) Ultrastructural identification of substance P cells and their processes in rat sensory ganglia and their terminals in the spinal cord by immunocytochemistry. Proc Natl Acad Sci USA 74(9):4050–4054. https://doi.org/10.1073/pnas.74.9.4050
Chávez AE, Grimes WN, Diamond JS (2010) Mechanisms underlying lateral GABAergic feedback onto rod bipolar cells in rat retina. J Neurosci 30(6):2330–2339. https://doi.org/10.1523/jneurosci.5574-09.2010
Clayton DF, George JM (1999) Synucleins in synaptic plasticity and neurodegenerative disorders. J Neurosci Res 58(1):120–129
Cuenca N, Kolb H (1989) Morphology and distribution of neurons immunoreactive for substance P in the turtle retina. J Comp Neurol 290(3):391–411. https://doi.org/10.1002/cne.902900308
Cuenca N, Kolb H (1998) Circuitry and role of substance P-immunoreactive neurons in the primate retina. J Comp Neurol 393(4):439–456
Cuenca N, De Juan J, Kolb H (1995) Substance P-immunoreactive neurons in the human retina. J Comp Neurol 356(4):491–504. https://doi.org/10.1002/cne.903560402
De Sevilla P, Müller L, Shelley J, Weiler R (2007) Displaced amacrine cells of the mouse retina. J Comp Neurol 505:177–189
de Sevilla P, Müller L, Solomon A, Sheets K, Hapukino H, Rodriguez AR, Brecha NC (2019) Multiple cell types form the VIP amacrine cell population. J Comp Neurol 527(1):133–158. https://doi.org/10.1002/cne.24234
Ebner K, Singewald N (2006) The role of substance P in stress and anxiety responses. Amino Acids 31(3):251–272. https://doi.org/10.1007/s00726-006-0335-9
Ehrlich D, Keyser KT, Karten HJ (1987) Distribution of substance P-like immunoreactive retinal ganglion cells and their pattern of termination in the optic tectum of chick (Gallus gallus). J Comp Neurol 266(2):220–233. https://doi.org/10.1002/cne.902660208
Euler USV, Gaddum JH (1931) An unidentified depressor substance in certain tissue extracts. J Physiol 72:74–87
Fouke KE, Wegman ME, Weber SA, Brady EB, Román-Vendrell C, Morgan JR (2021) Synuclein regulates synaptic vesicle clustering and docking at a vertebrate synapse. Front Cell Dev Biol 9:774650. https://doi.org/10.3389/fcell.2021.774650
Fritsch HA, Van Noorden S, Pearse AG (1980) Substance P-, neurotensin- and bombesin-like immunoreactivities in the gill epithelium of Ciona intestinalis L. Cell Tissue Res 208(3):467–473. https://doi.org/10.1007/bf00233878
Fukuda M, Kuwayama Y, Shiosaka S, Ishimoto I, Shimizu Y, Takagi H, Inagaki S, Sakanaka M, Semba E, Takatsuki K, Tohyama M (1981) Demonstration of a substance P-like immunoreactivity in retinal cells of the rat. Neurosci Lett 23(3):239–242. https://doi.org/10.1016/0304-3940(81)90004-5
Glickman RD, Adolph AR, Dowling JE (1982) Inner plexiform circuits in the carp retina: effects of cholinergic agonists, GABA, and substance P on the ganglion cells. Brain Res 234(1):81–99. https://doi.org/10.1016/0006-8993(82)90474-7
Gong X, Ren Y, Fang X, Cai J, Song E (2020) Substance P induces sympathetic immune response in the contralateral eye after the first eye cataract surgery in type 2 diabetic patients. BMC Ophthalmol 20(1):339. https://doi.org/10.1186/s12886-020-01598-4
Halliday GM, Blumbergs PC, Cotton RG, Blessing WW, Geffen LB (1990) Loss of brainstem serotonin- and substance P-containing neurons in Parkinson’s disease. Brain Res 510(1):104–107. https://doi.org/10.1016/0006-8993(90)90733-r
Haverkamp S, Wässle H (2000) Immunocytochemical analysis of the mouse retina. J Comp Neurol 424(1):1–23
Haverkamp S, Ghosh KK, Hirano AA, Wässle H (2003) Immunocytochemical description of five bipolar cell types of the mouse retina. J Comp Neurol 455(4):463–476. https://doi.org/10.1002/cne.10491
Haverkamp S, Inta D, Monyer H, Wässle H (2009) Expression analysis of green fluorescent protein in retinal neurons of four transgenic mouse lines. Neuroscience 160(1):126–139. https://doi.org/10.1016/j.neuroscience.2009.01.081
Haycock JW, Waymire JC (1982) Activating antibodies to tyrosine hydroxylase. J Biol Chem 257(16):9416–9423
He ZX, Liu TY, Yin YY, Song HF, Zhu XJ (2019) Substance P plays a critical role in synaptic transmission in striatal neurons. Biochem Biophys Res Commun 511(2):369–373. https://doi.org/10.1016/j.bbrc.2019.02.055
Herpfer I, Lieb K (2003) Substance P and Substance P receptor antagonists in the pathogenesis and treatment of affective disorders. World J Biol Psychiatry 4(2):56–63. https://doi.org/10.3109/15622970309167952
Hirasawa H, Betensky RA, Raviola E (2012) Corelease of dopamine and GABA by a retinal dopaminergic neuron. J Neurosci 32(38):13281–13291. https://doi.org/10.1523/jneurosci.2213-12.2012
Hökfelt T, Vincent S, Dalsgaard CJ, Skirboll L, Johansson O, Schultzberg M, Lundberg JM, Rosell S, Pernow B, Jancsó G (1982) Distribution of substance P in brain and periphery and its possible role as a co-transmitter. Ciba Found Symp 91:84–106. https://doi.org/10.1002/9780470720738.ch6
Huang AY, Wu SY (2018) Substance P as a putative efferent transmitter mediates GABAergic inhibition in mouse taste buds. Br J Pharmacol 175(7):1039–1053. https://doi.org/10.1111/bph.14142
Huang L, Yuan T, Tan M, Xi Y, Hu Y, Tao Q, Zhao Z, Zheng J, Han Y, Xu F, Luo M, Sollars PJ, Pu M, Pickard GE, So KF, Ren C (2017) A retinoraphe projection regulates serotonergic activity and looming-evoked defensive behaviour. Nat Commun 8:14908. https://doi.org/10.1038/ncomms14908
Jin K, Jiang H, Xiao D, Zou M, Zhu J, Xiang M (2015) Tfap2a and 2b act downstream of Ptf1a to promote amacrine cell differentiation during retinogenesis. Mol Brain 8:28. https://doi.org/10.1186/s13041-015-0118-x
Johnson J, Tian N, Caywood MS, Reimer RJ, Edwards RH, Copenhagen DR (2003) Vesicular neurotransmitter transporter expression in developing postnatal rodent retina: GABA and glycine precede glutamate. J Neurosci 23(2):518–529. https://doi.org/10.1523/jneurosci.23-02-00518.2003
Keeley PW, Reese BE (2010) Morphology of dopaminergic amacrine cells in the mouse retina: independence from homotypic interactions. J Comp Neurol 518(8):1220–1231. https://doi.org/10.1002/cne.22270
Kondoh A, Houtani T, Ueyama T, Baba K, Ikeda M, Yamagishi K, Miki H, Uyama M, Nakanishi S, Sugimoto T (1996) In situ hybridization analysis of substance P receptor in the rat retina. Exp Brain Res 112(2):181–186. https://doi.org/10.1007/bf00227636
Lai JP, Douglas SD, Ho WZ (1998) Human lymphocytes express substance P and its receptor. J Neuroimmunol 86(1):80–86. https://doi.org/10.1016/s0165-5728(98)00025-3
Lai JP, Zhan GX, Campbell DE, Douglas SD, Ho WZ (2000) Detection of substance P and its receptor in human fetal microglia. Neuroscience 101(4):1137–1144. https://doi.org/10.1016/s0306-4522(00)00398-5
Lazzerini Ospri L, Prusky G, Hattar S (2017) Mood, the circadian system, and melanopsin retinal ganglion cells. Annu Rev Neurosci 40:539–556. https://doi.org/10.1146/annurev-neuro-072116-031324
Lee MY, Chun MH, Han SH, Oh SJ, Chung JW (1995) Light- and electron-microscopic study of substance P-immunoreactive neurons in the guinea pig retina. Cell Tissue Res 281(2):261–271. https://doi.org/10.1007/bf00583395
Li S, Jakobs TC (2022) Secreted phosphoprotein 1 slows neurodegeneration and rescues visual function in mouse models of aging and glaucoma. Cell Rep 41(13):111880. https://doi.org/10.1016/j.celrep.2022.111880
Li HB, So KF, Cheuk W (1999) Substance P-immunoreactive neurons in hamster retinas. Vis Neurosci 16(3):475–481. https://doi.org/10.1017/s0952523899163089
Mammadova N, Summers CM, Kokemuller RD, He Q, Ding S, Baron T, Yu C, Valentine RJ, Sakaguchi DS, Kanthasamy AG, Greenlee JJ, Heather West Greenlee M (2019) Accelerated accumulation of retinal α-synuclein (pSer129) and tau, neuroinflammation, and autophagic dysregulation in a seeded mouse model of Parkinson’s disease. Neurobiol Dis 121:1–16. https://doi.org/10.1016/j.nbd.2018.09.013
Mammadova N, Baron T, Verchère J, Greenlee JJ, Greenlee MHW (2021) Retina as a model to study in vivo transmission of α-synuclein in the A53T mouse model of Parkinson’s disease. Methods Mol Biol 2224:75–85. https://doi.org/10.1007/978-1-0716-1008-4_5
Maroteaux L, Campanelli JT, Scheller RH (1988) Synuclein: a neuron-specific protein localized to the nucleus and presynaptic nerve terminal. J Neurosci 8(8):2804–2815. https://doi.org/10.1523/jneurosci.08-08-02804.1988
Martínez-Navarrete GC, Martín-Nieto J, Esteve-Rudd J, Angulo A, Cuenca N (2007) Alpha synuclein gene expression profile in the retina of vertebrates. Mol Vis 13:949–961
Masliah E, Rockenstein E, Veinbergs I, Mallory M, Hashimoto M, Takeda A, Sagara Y, Sisk A, Mucke L (2000) Dopaminergic loss and inclusion body formation in alpha-synuclein mice: implications for neurodegenerative disorders. Science 287(5456):1265–1269. https://doi.org/10.1126/science.287.5456.1265
Mataruga A, Kremmer E, Müller F (2007) Type 3a and type 3b OFF cone bipolar cells provide for the alternative rod pathway in the mouse retina. J Comp Neurol 502(6):1123–1137. https://doi.org/10.1002/cne.21367
Michel JP, Sakamoto N, Bouvier R, Tommasi M, Pearson J (1986) Substance P-immunoreactive astrocytes related to deep white matter and striatal blood vessels in human brain. Brain Res 377(2):383–387. https://doi.org/10.1016/0006-8993(86)90886-3
Murphy DD, Rueter SM, Trojanowski JQ, Lee VM (2000) Synucleins are developmentally expressed, and alpha-synuclein regulates the size of the presynaptic vesicular pool in primary hippocampal neurons. J Neurosci 20(9):3214–3220. https://doi.org/10.1523/jneurosci.20-09-03214.2000
Murueta-Goyena A, Del Pino R, Reyero P, Galdós M, Arana B, Lucas-Jiménez O, Acera M, Tijero B, Ibarretxe-Bilbao N, Ojeda N, Peña J, Cortés J, Gómez-Esteban JC, Gabilondo I (2019) Parafoveal thinning of inner retina is associated with visual dysfunction in Lewy body diseases. Mov Disord 34(9):1315–1324. https://doi.org/10.1002/mds.27728
Noro T, Shah SH, Yin Y, Kawaguchi R, Yokota S, Chang KC, Madaan A, Sun C, Coppola G, Geschwind D, Benowitz LI, Goldberg JL (2022) Elk-1 regulates retinal ganglion cell axon regeneration after injury. Sci Rep 12(1):17446. https://doi.org/10.1038/s41598-022-21767-3
Ortuño-Lizarán I, Beach TG, Serrano GE, Walker DG, Adler CH, Cuenca N (2018a) Phosphorylated α-synuclein in the retina is a biomarker of Parkinson’s disease pathology severity. Mov Disord 33(8):1315–1324. https://doi.org/10.1002/mds.27392
Ortuño-Lizarán I, Esquiva G, Beach TG, Serrano GE, Adler CH, Lax P, Cuenca N (2018b) Degeneration of human photosensitive retinal ganglion cells may explain sleep and circadian rhythms disorders in Parkinson’s disease. Acta Neuropathol Commun 6(1):90. https://doi.org/10.1186/s40478-018-0596-z
Ortuño-Lizarán I, Sánchez-Sáez X, Lax P, Serrano GE, Beach TG, Adler CH, Cuenca N (2020) Dopaminergic retinal cell loss and visual dysfunction in parkinson disease. Ann Neurol 88(5):893–906. https://doi.org/10.1002/ana.25897
Ou K, Mertsch S, Theodoropoulou S, Wu J, Liu J, Copland DA, Schrader S, Liu L, Dick AD (2019) Restoring retinal neurovascular health via substance P. Exp Cell Res 380(2):115–123. https://doi.org/10.1016/j.yexcr.2019.04.008
Panda S, Sato TK, Castrucci AM, Rollag MD, DeGrip WJ, Hogenesch JB, Provencio I, Kay SA (2002) Melanopsin (Opn4) requirement for normal light-induced circadian phase shifting. Science 298(5601):2213–2216. https://doi.org/10.1126/science.1076848
Perez RG, Waymire JC, Lin E, Liu JJ, Guo F, Zigmond MJ (2002) A role for alpha-synuclein in the regulation of dopamine biosynthesis. J Neurosci 22(8):3090–3099. https://doi.org/10.1523/jneurosci.22-08-03090.2002
Pernow B (1953) Distribution of substance P in the central and peripheral nervous system. Nature 171(4356):746. https://doi.org/10.1038/171746a0
Petersen K, Olesen OF, Mikkelsen JD (1999) Developmental expression of alpha-synuclein in rat hippocampus and cerebral cortex. Neuroscience 91(2):651–659. https://doi.org/10.1016/s0306-4522(98)00596-x
Pourcho RG, Goebel DJ (1988a) Colocalization of substance P and gamma-aminobutyric acid in amacrine cells of the cat retina. Brain Res 447(1):164–168. https://doi.org/10.1016/0006-8993(88)90979-1
Pourcho RG, Goebel DJ (1988b) Substance P-like immunoreactive amacrine cells in the cat retina. J Comp Neurol 275(4):542–552. https://doi.org/10.1002/cne.902750405
Qiao LN, Liu JL, Tan LH, Yang HL, Zhai X, Yang YS (2017) Effect of electroacupuncture on thermal pain threshold and expression of calcitonin-gene related peptide, substance P and γ-aminobutyric acid in the cervical dorsal root ganglion of rats with incisional neck pain. Acupunct Med 35(4):276–283. https://doi.org/10.1136/acupmed-2016-011177
Quattrochi LE, Stabio ME, Kim I, Ilardi MC, Michelle Fogerson P, Leyrer ML, Berson DM (2019) The M6 cell: a small-field bistratified photosensitive retinal ganglion cell. J Comp Neurol 527(1):297–311. https://doi.org/10.1002/cne.24556
Rosenkranz MA (2007) Substance P at the nexus of mind and body in chronic inflammation and affective disorders. Psychol Bull 133(6):1007–1037. https://doi.org/10.1037/0033-2909.133.6.1007
Sakagami K, Chen B, Nusinowitz S, Wu H, Yang X-J (2012) PTEN regulates retinal interneuron morphogenesis and synaptic layer formation. Mol Cell Neurosci 49:171–183
Seleem AA (2015) Expression of alpha-synuclein during eye development of mice (Mus musculus), chick (Gallus gallus domisticus) and fish (Ctenopharyngodon idella) in a comparison study. Tissue Cell 47(4):359–365. https://doi.org/10.1016/j.tice.2015.04.004
Seleem AA (2020) Immunohistochemical localization of alpha-synuclein in the retina of some nocturnal and diurnal animals. Biotechnic Histochem 95(5):360–372. https://doi.org/10.1080/10520295.2019.1703218
Sham CW, Chan AM, Kwong JMK, Caprioli J, Nusinowitz S, Chen B, Lee JG, Gandhi NM, Francisco LM, Sharpe AH, Chen L, Braun J, Gordon LK (2012) Neuronal programmed cell death-1 ligand expression regulates retinal ganglion cell number in neonatal and adult mice. J Neuro-Ophthalmol Off J North Am Neuro-Ophthalmol Soc 32:227–237
Shekhar K, Lapan SW, Whitney IE, Tran NM, Macosko EZ, Kowalczyk M, Adiconis X, Levin JZ, Nemesh J, Goldman M, McCarroll SA, Cepko CL, Regev A, Sanes JR (2016) Comprehensive classification of retinal bipolar neurons by single-cell transcriptomics. Cell 166(5):1308-1323.e1330. https://doi.org/10.1016/j.cell.2016.07.054
Shen H, Li J, Heisler-Taylor T, Makin R, Yang H, Mavlyutov TA, Gelfand B, Cebulla CM, Guo LW (2021) TMEM97 ablation aggravates oxidant-induced retinal degeneration. Cell Signal 86:110078. https://doi.org/10.1016/j.cellsig.2021.110078
Shibata S, Tsuneyoshi A, Hamada T, Tominaga K, Watanabe S (1992) Effect of substance P on circadian rhythms of firing activity and the 2-deoxyglucose uptake in the rat suprachiasmatic nucleus in vitro. Brain Res 597(2):257–263. https://doi.org/10.1016/0006-8993(92)91482-t
Snijdelaar DG, Dirksen R, Slappendel R, Crul BJ (2000) Substance P. Eur J Pain 4(2):121–135. https://doi.org/10.1053/eujp.2000.0171
Sonoda T, Li JY, Hayes NW, Chan JC, Okabe Y, Belin S, Nawabi H, Schmidt TM (2020) A noncanonical inhibitory circuit dampens behavioral sensitivity to light. Science 368(6490):527–531. https://doi.org/10.1126/science.aay3152
Sosula L, Glow PH (1970) A quantitative ultrastructural study of the inner plexiform layer of the rat retina. J Comp Neurol 140(4):439–477. https://doi.org/10.1002/cne.901400405
Surguchov A, McMahan B, Masliah E, Surgucheva I (2001) Synucleins in ocular tissues. J Neurosci Res 65(1):68–77. https://doi.org/10.1002/jnr.1129
Suvas S (2017) Role of substance P neuropeptide in inflammation, wound healing, and tissue homeostasis. J Immunol 199(5):1543–1552. https://doi.org/10.4049/jimmunol.1601751
Taguchi K, Watanabe Y, Tsujimura A, Tanaka M (2016) Brain region-dependent differential expression of alpha-synuclein. J Comp Neurol 524(6):1236–1258. https://doi.org/10.1002/cne.23901
Thomas CN, Bernardo-Colón A, Courtie E, Essex G, Rex TS, Blanch RJ, Ahmed Z (2021) Effects of intravitreal injection of siRNA against caspase-2 on retinal and optic nerve degeneration in air blast induced ocular trauma. Sci Rep 11(1):16839. https://doi.org/10.1038/s41598-021-96107-y
Tirassa P, Schirinzi T, Raspa M, Ralli M, Greco A, Polimeni A, Possenti R, Mercuri NB, Severini C (2021) What substance P might tell us about the prognosis and mechanism of Parkinson’s disease? Neurosci Biobehav Rev 131:899–911. https://doi.org/10.1016/j.neubiorev.2021.10.008
Totterdell S, Meredith GE (2005) Localization of alpha-synuclein to identified fibers and synapses in the normal mouse brain. Neuroscience 135(3):907–913. https://doi.org/10.1016/j.neuroscience.2005.06.047
Totterdell S, Hanger D, Meredith GE (2004) The ultrastructural distribution of alpha-synuclein-like protein in normal mouse brain. Brain Res 1004(1–2):61–72. https://doi.org/10.1016/j.brainres.2003.10.072
Vargas KJ, Schrod N, Davis T, Fernandez-Busnadiego R, Taguchi YV, Laugks U, Lucic V, Chandra SS (2017) Synucleins have multiple effects on presynaptic architecture. Cell Rep 18(1):161–173. https://doi.org/10.1016/j.celrep.2016.12.023
Versaux-Botteri C, Nguyen-Legros J, Vigny A, Raoux N (1984) Morphology, density and distribution of tyrosine hydroxylase-like immunoreactive cells in the retina of mice. Brain Res 301(1):192–197. https://doi.org/10.1016/0006-8993(84)90423-2
Veys L, Vandenabeele M, Ortuño-Lizarán I, Baekelandt V, Cuenca N, Moons L, De Groef L (2019) Retinal α-synuclein deposits in Parkinson’s disease patients and animal models. Acta Neuropathol 137(3):379–395. https://doi.org/10.1007/s00401-018-01956-z
Veys L, Devroye J, Lefevere E, Cools L, Vandenabeele M, De Groef L (2021) Characterizing the retinal phenotype of the Thy1-h[A30P]α-syn mouse model of Parkinson’s disease. Front Neurosci 15:726476. https://doi.org/10.3389/fnins.2021.726476
Vuong HE, Hardi CN, Barnes S, Brecha NC (2015) Parallel inhibition of dopamine amacrine cells and intrinsically photosensitive retinal ganglion cells in a non-image-forming visual circuit of the mouse retina. J Neurosci 35(48):15955–15970. https://doi.org/10.1523/jneurosci.3382-15.2015
Watt CB, Florack VJ (1993a) Colocalization of glycine in substance P-amacrine cells of the larval tiger salamander retina. Vis Neurosci 10(5):899–906. https://doi.org/10.1017/s0952523800006106
Watt CB, Florack VJ (1993b) Double-label analyses of the coexistence of somatostatin with GABA and glycine in amacrine cells of the larval tiger salamander retina. Brain Res 617(1):131–137. https://doi.org/10.1016/0006-8993(93)90623-u
Watt CB, Florack VJ, Walker RB (1993) Quantitative analyses of the coexistence of gamma-aminobutyric acid in substance P-amacrine cells of the larval tiger salamander retina. Brain Res 603(1):111–116. https://doi.org/10.1016/0006-8993(93)91305-c
Watt CB, Glazebrook PA, Florack VJ (1994) Localization of substance P and GABA in retinotectal ganglion cells of the larval tiger salamander. Vis Neurosci 11(2):355–362. https://doi.org/10.1017/s0952523800001693
Wiechmann AF (1996) Recoverin in cultured human retinoblastoma cells: enhanced expression during morphological differentiation. J Neurochem 67(1):105–110. https://doi.org/10.1046/j.1471-4159.1996.67010105.x
Wulle I, Schnitzer J (1989) Distribution and morphology of tyrosine hydroxylase-immunoreactive neurons in the developing mouse retina. Brain Res Dev Brain Res 48(1):59–72. https://doi.org/10.1016/0165-3806(89)90093-x
Yang Q, Lin X, Xiao J, Zhong W, Wang F, Tan H, Rao B, Qu J, Zhang J (2023) Expression of α-Synuclein in the mouse retina is confined to inhibitory presynaptic elements. J Comp Neurol 531(10):1057–1107
Yazulla S, Studholme KM, Zucker CL (1985) Synaptic organization of substance P-like immunoreactive amacrine cells in goldfish retina. J Comp Neurol 231(2):232–238. https://doi.org/10.1002/cne.902310210
Yoo K, Son BK, Kim S, Son Y, Yu SY, Hong HS (2017) Substance P prevents development of proliferative vitreoretinopathy in mice by modulating TNF-α. Mol vis 23:933–943
Zalutsky RA, Miller RF (1990) The physiology of substance P in the rabbit retina. J Neurosci 10(2):394–402. https://doi.org/10.1523/jneurosci.10-02-00394.1990
Zhang J, Diamond JS (2006) Distinct perisynaptic and synaptic localization of NMDA and AMPA receptors on ganglion cells in rat retina. J Comp Neurol 498(6):810–820. https://doi.org/10.1002/cne.21089
Zhang J, Wang HH, Yang CY (2004) Synaptic organization of GABAergic amacrine cells in the salamander retina. Vis Neurosci 21(6):817–825. https://doi.org/10.1017/s0952523804216029
Zhang J, Tuo J, Cao X, Shen D, Li W, Chan CC (2013) Early degeneration of photoreceptor synapse in Ccl2/Cx3cr1-deficient mice on Crb1(rd8) background. Synapse 67(8):515–531. https://doi.org/10.1002/syn.21674
Zheng Y, Zhang L, Xie J, Shi L (2021) The emerging role of neuropeptides in Parkinson’s disease. Front Aging Neurosci 13:646726. https://doi.org/10.3389/fnagi.2021.646726
Zhou Z, Barrett RP, McClellan SA, Zhang Y, Szliter EA, van Rooijen N, Hazlett LD (2008) Substance P delays apoptosis, enhancing keratitis after Pseudomonas aeruginosa infection. Invest Ophthalmol vis Sci 49(10):4458–4467. https://doi.org/10.1167/iovs.08-1906
Ziche M, Morbidelli L, Pacini M, Geppetti P, Alessandri G, Maggi CA (1990) Substance P stimulates neovascularization in vivo and proliferation of cultured endothelial cells. Microvasc Res 40(2):264–278. https://doi.org/10.1016/0026-2862(90)90024-l
Acknowledgements
We thank Miss Yizhen Zhang for significant comments and helpful discussion.
Funding
This work was supported in part by Grants from National Key Research and Development Program of China (2022YFA1105503), State Key Laboratory of Neuroscience (SKLN-202103), Zhejiang Natural Science Foundation of China (Y21H120019), Zhejiang Provincial Health Commission Foundation of China (2021KY809).
Author information
Authors and Affiliations
Contributions
JZ designed and supervised the experiments. FLW, WHZ, QWY performed immuno-electron microscopy and immunofluorescence. FLW and WHZ wrote the draft of the manuscript. WNZ and XQL performed sectioning and part immunofluorescence. BLR and XL participated in the design of the experiments. JZ, FLW, and WHZ conducted data analysis. JZ wrote the final manuscript. All authors approved the final manuscript.
Corresponding author
Ethics declarations
Competing interests
The authors do not report any conflicts of interests.
Ethical approval
This study was performed in line with the principles of the Declaration of Helsinki. Approval was granted by the Ethics Committee of Wenzhou Medical University in accordance with the ARVO guidelines.
Additional information
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Rights and permissions
Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.
About this article
Cite this article
Wang, F., Zhong, W., Yang, Q. et al. Distribution and synaptic organization of substance P-like immunoreactive neurons in the mouse retina. Brain Struct Funct 228, 1703–1724 (2023). https://doi.org/10.1007/s00429-023-02688-x
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00429-023-02688-x