Histol Histopathol (2003) 18: 1219-1242 Histology and http://www.hh.um.es Histopathology Cellular and Molecular Biology Review Expression of neuropeptides and their receptors in the developing retina of mammals P. Bagnoli1, M. Dal Monte1 and G. Casini2 1Dipartimento di Fisiologia e Biochimica "G.Moruzzi", Università di Pisa, Pisa, Italy and 2Dipartimento di Scienze Ambientali, Università della Tuscia, Viterbo, Italy Summmary. The present review examines various Key words: Peptidergic systems, Retinal cells, aspects of the developmental expression of Maturation, Trophic actions neuropeptides and of their receptors in mammalian retinas, emphasizing their possible roles in retinal maturation. Different peptidergic systems have been Introduction investigated with some detail during retinal development, including substance P (SP), somatostatin The identification of peptide signaling molecules (SRIF), vasoactive intestinal polypeptide (VIP), pituitary began in the first half of the last century with substance adenylate cyclase-activating polypeptide (PACAP), P (SP; Hökfelt et al., 2001) and it has proceeded during neuropeptide Y (NPY), opioid peptides and the last 30 years with the discovery of numerous corticotrophin-releasing factor (CRF). Overall, the peptides, the characterization of their receptors and the developmental expression of most peptides is exploitation of their physiological actions in the body. characterized by early appearance, transient features and Peptidergic messengers were originally isolated (mainly) achievement of the mature pattern at the time of eye from the gut or from the hypothalamus and they were opening. Concerning possible developmental actions of interpreted as gastrointestinal or hypothalamic neuropeptides, recent studies imply a role of SP in the hormones. However, it soon appeared that peptides are modulation of cholinergic neurotransmission in early distributed to different organs or systems, including the postnatal rabbit retinas, when cholinergic cells nervous system where they have been designated participate in the retinal spontaneous waves of activity. "neuropeptides" (Hökfelt et al., 2000). Peptides are In addition, the presence of transient SRIF expressing present in all parts of the nervous system, although each ganglion cells and recent observations in SRIF receptor peptide has its unique pattern of distribution. Initially, it knock-out mice indicate variegated roles of this peptide was assumed that these "peptidergic" systems were in the development of the retina and of retinofugal different from and complementary to previously projections. Furthermore, VIP and PACAP exert transmitter-characterized neurons, for example those of protective and growth-promoting actions that may the catecholamine and serotonin systems. Therefore, an sustain retinal neurons during their development, and important perspective on neuropeptides, and on chemical opioid peptides may control cell proliferation in the transmission in general, was added with the recognition developing retina. Finally, a peak in the expression of that peptides almost always coexist with one or more certain peptides, including VIP, NPY and CRF, is present classic transmitters (Lundberg, 1996). Functionally, around the time of eye opening, when the retina begins neuropeptides act as neuromodulatory substances, the analysis of structured visual information, suggesting presumably released extrasynaptically. Generally important roles of these peptides during this delicate speaking, neuropeptides act on specific receptors to phase of retinal development. In summary, although the modulate the functional properties of neurons, such as physiological actions of peptides during retinal their membrane excitability or their signal transduction development are far from being clarified, the data pathways. Modern techniques of neuropeptide reviewed herein indicate promising perspectives in this localization, molecular biology approaches, and the use field of study. of transgenic animals have prompted an enormous growth in the knowledge of neuropeptide expression and neuropeptide receptor pharmacology and diversity. Offprint requests to: Paola Bagnoli, Ph.D., Dipartimento di Fisiologia e However, in spite of the wide variety of information Biochimica "G. Moruzzi", Università degli Studi di Pisa, Via S. Zeno, 31, gathered on peptidergic systems and the availability of 56127 Pisa, Italy. Fax: +39-050-2213527. e-mail: [email protected] ultra-sensitive techniques, it has been difficult to define 1220 Peptides in retinal development an exact physiological role for many of the nervous system. This idea may arise considering that, in neuropeptides in the nervous system. There are, of the developing nervous system, neuropeptides, along course, examples of neuropeptide participation in with their receptors, are usually expressed at early times, specific functions or hints of neuropeptide involvement when synaptic connections are still immature. In in certain behavioral states or mental diseases. For addition, transient expression of neuropeptides or instance, SP and opioid peptides are involved in the developmentally regulated peptide expression have been transmission and modulation of pain (Harrison and reported in distinct brain regions, suggesting peptides Geppetti, 2001; Przewlocki and Przewlocka, 2001); SP may mediate functional interactions associated with the and its receptor (the neurokinin 1 receptor, NK1) are morphological and functional development of the implicated in depression (Harrison and Geppetti, 2001; nervous system. During this period, neuropeptides may Rupniak, 2002) and in memory-promoting, reinforcing affect a variety of parameters, including cell division, and anxiolytic-like effects (Hasenohrl et al., 2000); SP, neuronal survival, neurite sprouting, growth cone colecystokinin and opioid peptides participate in the motility, and neuronal and glial phenotype (Emerit et al., regulation of aggressive behavior (Siegel et al., 1999); 1992; Müller et al., 1995; DiCicco-Bloom et al., 1998, opioid peptides may regulate striatal output pathways 2000; Gressens, 1998; Hauser and Mangoura, 1998; and motor behavior (Steiner and Gerfen, 1998); pituitary Lindholm et al., 1998; Raffa, 1998; Schwartz et al., adenylate cyclase-activating polypeptide (PACAP) is 1998; Yew et al., 1999; Gozes and Brenneman, 2000; involved in the regulation of hypothalamic Kwong et al., 2000; Hansel et al., 2001a,b; Waschek, neurosecretion, homeostatic control of circadian clock 2002). Some of these actions are direct while others are and learning and memory processes (Zhou et al., 2002); mediated by the production of neurotrophic factors from vasoactive intestinal polypeptide (VIP) modulates the glial cells (Gozes and Brenneman, 2000). strength of glutamate-mediated neurotransmission in the Neuroprotective and/or neural growth-related actions cortex (Magistretti et al., 1998); somatostatin have been well documented for tachykinin peptides, VIP, (somatotropin release-inhibiting factor, SRIF) affects PACAP, SRIF, NPY and opioid peptides (Emerit et al., electrophysiological properties of neurons and 1992; DiCicco-Bloom et al., 1998; Gressens, 1998; modulates classical neurotransmission with effects on Hauser and Mangoura, 1998; Raffa, 1998; Schwartz et cognitive, locomotor, sensory, and autonomic functions al., 1998; Gozes and Brenneman, 2000; Hansel et al., (Patel, 1999); corticotropin releasing factor (CRF) is 2001a, b; Waschek, 2002; Zagon et al., 2002; Zhou et implicated in stress-related disorders such as anxiety and al., 2002). depression (Reul and Holsboer, 2002), in learning and The present paper will focus on the relevant aspects memory (Croiset et al., 2000), in pain and analgesia of neuropeptide expression during development in a (Lariviere and Melzack, 2000) and in the modulation of specific region of the central nervous system, the retina. ingestive behavior (Heinrichs and Richard, 1999); and A comprehensive examination of the peptidergic neuropeptide Y (NPY) may have a role in neuronal systems of the brain or a detailed description of the excitability, learning and memory, anxiety-related peptidergic cell populations of the mature retina are far behaviors, feeding, regulation of blood pressure and beyond our scopes, and these aspects have been circadian rhythm (Thorsell and Heilig, 2002). Given the extensively treated in many recent and past review wide spectrum of (possible) neuropeptide actions, a works. However, before presenting the available data on novel approach in the study of neuropeptides has been neuropeptide expression in developing retinas, we think undertaken in recent years based on the production of it is necessary to briefly recapitulate the main peptide analogs with agonistic or antagonistic properties. peptidergic systems in view of their possible roles in These lines of research have produced a variety of neural development and to summarize the organizational peptide and nonpeptide agonists and antagonists that are plan of the mammalian retina as well as its development. specific for distinct peptide receptor subtypes, including SP (Hökfelt et al., 2001), SRIF (Hannon et al., 2002), Peptidergic systems and neural development VIP (see for instance Levy et al., 2002; Reed et al., 2002), CRF (Takahashi, 2001) and TRH (Kubek and In this section, main peptidergic systems which have Garg, 2002) receptors. These compounds constitute been found to be involved in developmental processes of important new tools to investigate the functional