C Pharmacology & Toxicology 2002, 91, 153–157. Copyright C Printed in Denmark . All rights reserved ISSN 0901-9928 Annotations & Reflections Excitotoxic Mechanisms of Apoptosis in the Mammalian Visual System Following Monocular Visual Deprivation Carlo Nucci 1 , Silvia Piccirilli 2 , Robert Nistico ` 2,3 , Luciano Cerulli 1 and Giacinto Bagetta 2,3 1 Physiopathological Optics, Department of Biopathology, University of Rome Tor Vergata, Rome; 2 Mondino-Tor Vergata Center for Experimental Neurobiology, University of Rome Tor Vergata, Rome; and 3 Department of Pharmacobiology, University of Calabria at Cosenza, Italy (Received February 28, 2002; Accepted March 20, 2002) The visual system in new-born mammals is extremely suscep- tible to plastic adaptation in response to non-physiological visual experience. For instance, brief occlusion of the vision in one eye (monocular deprivation) during early postnatal life causes an almost total loss of visual responses from the deprived eye in cortical neurones. As a consequence, vision in the occluded eye is impaired and the eye becomes blind (Wie- sel & Hubel 1963). The sensitivity to monocular deprivation is limited to a time period, also referred to as the critical period; at the end of this period, ocular preference of cortical neurones is stabilized and will no longer be influenced by ma- nipulation of the visual environment. Similar forms of deprivation-induced synaptic depression have been observed in many species, including monkeys (Hu- bel & Wiesel 1977), rats (Fagiolini et al. 1994) and mice (Gor- don & Stryker 1996). It is well known that in human beings during post-natal life, altered visual experience, such as mono- or binocular visual deprivation (i.e. congenital catar- act, ptosis) or abnormal visual stimulation (strabismus, anisometropia), induces a progressive decline of the visual performances of the affected eye causing a neurophthalmol- ogic disease termed amblyopia. During the last three dec- ades, many studies have been devoted to the understanding of the mechanisms underlying this disease but only recently new insights have been gained. Here we focus on the recent discovery of the mechanisms underlying neuronal cell death caused by monocular deprivation in the lateral geniculate nu- cleus that we believe open new venues for novel therapeutic approaches to the treatment of amblyopia in man. Morphologic changes induced by monocular deprivation Several studies show that the lateral geniculate nucleus is the relay station of the visual system most affected by mon- Author for correspondence: Giacinto Bagetta, Department of Phar- macobiology, University of Calabria, 87036 Arcavacata di Rende (CS), Italy (fax π39–0984–493462, e-mail gbagett/tin.it). ocular deprivation. Wiesel & Hubel (1963) were the first to discover that in the deprived laminae of the lateral genicu- late nucleus of young cats (those receiving afferents from the closed eye), the diameter of the neuronal cell bodies is about two-thirds of that of neurones in the experienced layers. This observation has also been reported post mortem in the lateral geniculate nucleus of patients suffering of am- blyopia (von Noorden & Crawford 1992), thus confirming the usefulness of the animal model to dissect the pathophys- iology of the disease. Interestingly, of the two main classes of relay cells in the lateral geniculate nucleus, deprived Y cells seem particularly sensitive to physiological, metabolic and morphological effects elicited by deprivation (Sher- man & Spear 1982; Guimaraes et al. 1990). Our recent studies have shown that monocular depri- vation causes cell death of the apoptotic type in the lateral geniculate nucleus of new-born rats (Nucci et al. 1998 & 2000a & b) (fig. 1). In fact, under these experimental con- ditions, high magnification light microscopy analysis of tissue sections from the brain of monocular deprivation rats stained with haematoxylin and eosin revealed the occur- rence of marginalisation and condensation of the nuclear matrix (Nucci et al. 1998 & 2000a & b). Fragmentation of nuclear DNA has also been confirmed by the observation in adjacent tissue sections, obtained from rats monocularly deprived for 2, 7 and 14 days, of lateral geniculate nucleus cells positive to the terminal deoxynucleotidyl transferase (TdT)-mediated dUTP-biotin nick end-labeling (TUNEL) technique (Gavrieli et al. 1992). Finally, cell death by mon- ocular deprivation was accompanied by the appearance in the lateral geniculate nucleus of cells immunopositive for the tumour suppressor protein p53 (Nucci et al. 1999a&b), a gene product activated by cellular damage. Collectively, these three criteria support the hypothesis that cell death caused by monocular deprivation in the lateral geniculate nucleus of rat pups may be of the apoptotic type (Clarke et al. 1993; Kerr et al. 1987). As a consequence of cell death, we observed that the number of viable cells in the deprived