The mammalian visual system has been a valuable model to study the development of topographical order as well as neuronal plasticity (Hooks and Chen, 2020; Majdan and Shatz, 2006; Nys et al., 2015; Simon and O'Leary, 1991, Simon and O'Leary, 1992). In rodent's superior colliculus, 95% of its afferents come from the contralateral retina. The balance between crossed and uncrossed retinal projections is crucial to determine proper synaptic stabilization. This phenomenon takes place during the critical period, which comprises the first three postnatal weeks. Many reports have demonstrated changes in visual connectivity following retinal deafferentation (Calford et al., 1999; Chagas et al., 2020; Chagas et al., 2019; Chino et al., 1992; Frost and Schneider, 1979; Hanson and Reese, 1993; Lund and Lund, 1976; Mendonca et al., 2010; Nys et al., 2015; Serfaty et al., 2005; Vasques et al., 2021). It has also been shown that the time course of retinotectal plasticity is rapid during the critical period and slow afterward (Chagas et al., 2019; Djavadian et al., 2001; Godement et al., 1980; Horton and Hocking, 1998; Serfaty et al., 2005; Woo et al., 1985). Several lines of evidence have pointed out the glial cells as an important component in regulating synaptic transmission both in normal brain function as well as in pathological conditions (Araque et al., 1999; Kim et al., 2018; Perez-Catalan et al., 2021; Ribeiro et al., 2022; Sancho et al., 2021). Previous studies have demonstrated changes in astroglial reactivity after aging and neuronal regeneration (Perez-Nievas and Serrano-Pozo, 2018; Rodriguez et al., 2016; Waller et al., 2021). In this scenario, reactive astrocytes could modulate neuronal activity directly or release trophic factors, which in turn regulate neuronal survival, neurite outgrowth or axonal guidance and remodeling at the lesioned side (Goodus et al., 2016; Liberto et al., 2004; Thompson and Sakiyama-Elbert, 2018).

Adenosine is an important neuromodulator, and its receptors, found in both neuronal and glial cells, are involved in different aspects of the normal and pathological CNS (Choudhury et al., 2019; Lopes et al., 2021; Rocha-Mendonça et al., 2015; Sebastiao and Ribeiro, 2009). We have previously demonstrated that, in the superior colliculus, A1 receptors (A1AR) are more evident during the early stages of development, while A2a receptors (A2aAR) are mainly expressed after the critical period. Also, systemic treatment with a potent inhibitor of adenosine deaminase (EHNA), which increases adenosine levels, induces a disruption in the retinotectal topography (Tavares Gomes et al., 2009). Furthermore, adenosine receptor blockade by caffeine leads to a dual effect on retinal lesion-induced plasticity, depending on the time-window of development (Cabral-Miranda et al., 2011).

The present study aimed to analyze the short and long-term effects of a monocular enucleation during and after the critical period of retinotectal projection, upon astrocytes reactivity using glial fibrillary acidic protein (GFAP) as a marker as well as on A1AR and A2aAR expression. This work also investigated the involvement of A2aAR on glial reactivity and in the plasticity induced by ME within the critical period.

We found a substantial increase in GFAP expression in the contralateral superior colliculus after monocular enucleation, following the time-course of retinotectal plasticity both within and out of the critical period of development. Also, adenosine receptors are modulated by ME and A2aAR blockade inhibits astrocyte reactivity and abolishes retinotectal plastic response, suggesting a permissive role for glial cells in neuronal plasticity is dependent on adenosine signaling.