Schizophrenia is considered a neurodevelopmental disorder, with onset during adolescence or early adulthood in 80% of cases [1]. It shows no clear signs of behavioral dysfunction during childhood; social isolation is frequent during prodromal period [2], and social cognition (SC) is severely impaired during the course of the disease [3]. More than half of the genes linked with schizophrenia are involved in events that occur in late prenatal and early post natal period, like neuronal migration and synaptic formation and stabilization [4], which suggests that the disease begin before adolescence but becomes clinically significant in this period; probably during prefrontal cortex maturation [5].

SC is a prefrontal function referred to the capacity of identify the mental status about conspecifics, which depend of a correct glutamatergic transmission [6], widely impaired in schizophrenia [7]. In this framework, major psychiatric disorder and specifically schizophrenia, cannot be cured after onset, but could be effectively prevented modulating neurotransmitters and/or their receptors during early developmental period [8]. Actually, all antipsychotic drugs such Haloperidol, a dopaminergic receptor antagonist, let the progression of the disease [9,10], which suggest the needs to develop preventive treatment options; additionally the effects of this kind of antipsychotic drug on pre symptomatic phase of schizophrenia are unknown [8]. Memantine (MEM) is a N-Methyl D-Aspartate Receptor (NMDAR) low-affinity voltage-dependent uncompetitive antagonist, which is capable of regulate its high or low functioning states [11], usually disrupted in neonatal brains of rodents models of schizophrenia [12], rather than dopaminergic system, whose alteration seems to be the result of NMDA receptor dysfunction [13]. We propose that MEM administrated in neonatal period, is capable to prevent this situation and ensure a correct SC development. Previous report suggest the beneficial effect of MEM in social isolation in adult rat models on the glutamatergic dysfunction [14], but there are no evidence of pharmacological intervention in early stages of life.

All animal handling was conducted in accordance to the Guide for the Care and Use of Laboratory Animals [15]. Pregnant Sprague-Dawley rats on the 12^th gestational day were obtained from our campus' animal facility and housed in individually cages in a light-dark 12/12 hours schedule with food and water ad libitum. The day of birth was designated as post natal day (PND) 0. On PND 2, dams were removed from their maternity cages to adjacent cages. Male pups were exposed separately, every day to 180 minutes (8:00 am to 11:00 am) period of maternal deprivation from PND 2 to 14 inclusive; in stainless steel cage (6×6×12 cm), preserving a body temperature of 36℃.

Fifteen (15) pregnant rats, conform two working groups after the delivery. Maternal deprivation group (15 male pups) in which were applied the model of maternal deprivation during PND 2 to 14 (described above), involved the MEM sub group (n=5) received MEM (10 mg·Kg^-1), at neuroprotective dose [16], the saline solution sub group (n=5) and Haloperidol subgroup (HAL; conventional antipsychotic; 0.25 mg·Kg^-1) at psychoactive dose [14]. Non-maternal deprivation group (n=15) did not take part in the maternal separation model, involved MEM subgroup (n=5) received MEM (10 mg·Kg¹), HAL (0.25 mg·Kg^-1) (n=5) and saline treated group (n=5). Drug's were calculated daily in basis to the body weight, and injected subcutaneously, immediately after three hours of isolation. Finally, pups got back to their mother. The final volume of the drug and solution injected were 0.1 mL. In an earlier stage of the study, intraperitoneal injection caused severe injuries and death to the pups.

SC was evaluated trough the social interaction test (SIT, vide infra) which was applied at five (5) weeks (adolescent period) and 8 weeks of age (adult period).

In the present study, MEM or HAL treatment at early postnatal stages was tested for the first time in the maternal deprivation rat model evaluating 4 different behavior parameters of SC [19], i.e., AL, RP, TTD and DP obtained from the social interaction test, in two critical periods (adolescence and adulthood), obeying the paradigm that SC is impaired in schizophrenia even before the onset of the disease [3]. Saline non-deprivation group normally displays high values of AL, low degree of recognition behavior, medium TTD and peripheral cage distribution pattern at five (5) weeks of ages (adolescent period). Those changes could occur during the normally immature prefrontal cortex [19]. Three weeks later (early adult period), AL and TTD remain constant, RP increases notably and the cage distribution changes to a central pattern, which suggest prefrontal cortex maturation [19]. The maternal deprivation group, shows a low amount of AL, high values of RP and TTD, and a central cage pattern at 5 weeks of ages; three weeks later AL persist low, RP and TTD showing a notably reduction while cage distribution pattern become angled, which suggest that the maternal deprivation at early neonatal stages induces a schizophrenic like behavior in early adult life (8 weeks of age), preceded of a prodromal disinhibition (5 weeks of age) [20]. These behavioral abnormalities strongly suggest a SC dysfunction, probably for incomplete maturation of prefrontal cortex [20].

Schizophrenia is a neurodevelopmental disorder which involves extensive abnormalities in prefrontal cortex, determining neuropsychological and behavioral alterations, emerging clinically in the adolescent period with a deficit in SC, just when prefrontal cortex is at the end of its maturation process [5,21]. The early maternal deprivation model induces prefrontal changes that persist in adult rat brain, generating behavioral disturbances in adult life that reminiscence schizophrenic's symptom [22,23].

The pharmacological reversion by MEM of abnormalities in social cognition induced by early maternal deprivation, suggest that MEM effectively prevents social cognition impairment in adulthood. That beneficial effect is possible modulating the glutamatergic system in early neonatal period [4]. In the other hand, HAL induced a severe impairment of social cognition similar to those induced by the maternal deprivation, suggesting that HAL, given in neonatal period induces SC impairment in early adulthood and could represent by itself a new model of drug induced schizophrenic behavior; maybe when dopaminergic receptors type 2 are antagonized in neonatal period. Finally, this results stand out the possibility to develop pharmacological preventive treatment for schizophrenia to ensure the complete develop of SC in adult life.