Schizophrenia is a highly disabling psychopathology that places a significant burden on public health systems (Solmi et al., 2023). It is characterized by two types of symptoms: positive symptoms, which involve the amplification of certain functions (such as delusions and hallucinations), and negative symptoms, which reflect a loss of functioning (such as abulia, alogia, and social isolation) (American Psychiatric Association and Association, 2013). Negative symptoms have been linked to the degree of disability or autonomy experienced by individuals with this disorder (Correll and Schooler, 2020; Novick et al., 2015). Furthermore, these symptoms often respond poorly to the medications currently available for schizophrenia (Correll and Schooler, 2020), highlighting the need to investigate new treatment options. Social isolation is a key symptom that hinders individuals with schizophrenia from seeking appropriate psychological and pharmacological care (Novick et al., 2015). The hippocampus (HPC) is a brain region associated with the neurophysiopathology of schizophrenia symptoms, particularly those related to social functioning (Harrison, 2004).

Moreover, the hippocampus is crucial in organizing social processes by integrating efferent and afferent information, particularly in connection with the amygdala. These neural pathways process information related to social cues, social identification, social space, and bonding (Montagrin et al., 2018). Lipska and Weinberger (1994) proposed a rat model of schizophrenia in which an ibotenic acid (IA) lesion to the ventral hippocampus on postnatal day (PD) 7 results in social isolation, among other symptoms. This model could help investigate the neurobiological mechanisms underlying negative symptoms, providing a platform to disclose new treatments (Mitazaki et al., 2020). Furthermore, glutamate neurotransmission has been linked to the onset of schizophrenia symptoms, and several treatments targeting this system have shown promise (McCutcheon et al., 2020). Ketamine (KET), an NMDA receptor antagonist, has been shown to increase brain-derived neurotrophic factor (BDNF) levels, particularly with acute subanesthetic doses (Garcia et al., 2008). KET enhances BDNF levels through the blockade of GABA release in interneurons (Deyama and Duman, 2020), and it has been associated with therapeutic effects in various disorders due to its ability to induce plasticity-related changes via BDNF elevation (Garcia et al., 2008; Higgins et al., 2021). However, KET also has associated non-glutamatergic mechanisms, including effects on the monoaminergic system, where it inhibits transporter mechanisms (Mion and Villevieille, 2013). Despite being linked to the emergence of psychomimetic and psychotic symptoms in humans, acute subanesthetic doses of KET may help treat social isolation by promoting neuronal changes similar to those observed in other conditions (Higgins et al., 2021). Our previous study (Martínez-Torres et al., 2021) suggested that social isolation following neonatal ventral hippocampus lesion (NVHL) is associated with dendritic spines of pyramidal neuronal changes in the amygdala and reduced BDNF levels.

Treatments that promote plastic changes in pyramidal neurons may help alleviate symptoms of social isolation by influencing associated proteins such as BDNF and growth-associated protein 43 (GAP43). These proteins play a crucial role in the elongation of axonal and dendritic processes (Benowitz et al., 1990). Additionally, BDNF increases the presence of tyrosine receptor kinase B (TRKB), whose signaling pathway promotes neuronal survival and growth.

In this study, we evaluated the impact of a subanesthetic dose of KET administered to rats with NVHL on symptoms of social isolation. We also measured changes in the dendritic trees of pyramidal neurons of the amygdala and the presence of BDNF, TRKB, and GAP43.