Cognitive impairment is a major complication of schizophrenia that often exacerbates disability (Brown et al., 2023; Gebreegziabhere et al., 2022; Jauhar et al., 2022; McCutcheon et al., 2023; Watson et al., 2022; Zwir et al., 2023). Although previous studies reported that some second-generation atypical anti-psychotics, such as quetiapine and olanzapine, improved cognitive performance in patients with schizophrenia (Baldez et al., 2021; Feber et al., 2023; McCutcheon et al., 2023; Veselinović and Neuner, 2022), results were inconsistent (Baldez et al., 2021; Feber et al., 2023; McCutcheon et al., 2023; Veselinović and Neuner, 2022). Due to the urgent need to improve cognition in patients with schizophrenia, several brain regions were identified as potential target sites for drug therapy (Bast et al., 2017; Feber et al., 2023; Henkel et al., 2022; Javitt, 2022; Khalil et al., 2022; McCutcheon et al., 2023; Sohal, 2022; Spark et al., 2022). Many studies have associated dysfunction of the prefrontal cortex (PFC) with cognitive impairment in animal models of schizophrenia and in patients with schizophrenia (Brown et al., 2023; Hwang et al., 2023; Kutlu et al., 2023; Lotan et al., 2023; Smucny et al., 2022; Yan and Rein, 2022; Zwir et al., 2023). Hence, studies to characterize the neural activity of the PFC and to evaluate treatment strategies that target the pathogenesis of cognitive impairment are urgently needed (Brown et al., 2023; Hwang et al., 2023; Javitt, 2022; Kutlu et al., 2023; Lotan et al., 2023; Vita et al., 2022; Zwir et al., 2023).

Lithium, used as a mood-stabilizer since the early 1960s (Rybakowski, 2020), may exert neuroprotection and prevent and/or improve cognitive impairments of dementia and mild cognitive impairment (MCI), and may also mitigate bipolar disorder, even when used in low doses (Fessel, 2023; Ghanaatfar et al., 2022; Ishii et al., 2021). Previous research has shown that lithium benefits patients with chronic schizophrenia (Collins et al., 1991; Kelly et al., 2006; Simhandl et al., 1996; Vincenzi et al., 2016), but that the duration of improvement varies. However, results of lithium therapy have been inconsistent. A four-week clinical trial showed no symptomatic improvement (Small et al., 2003). Moreover, in terms of schizophrenia-associated cognopathy, few clinical trials have evaluated lithium as a monotherapy or as an adjunct in combination with anti-psychotic agents; and few preclinical studies have compared different dosing regimens of lithium monotherapy or lithium as an adjunct to anti-psychotic agents in improving cognitive impairments; thus, the potential benefits of different doses of lithium are unknown (Mecê et al., 2022; Terao et al., 2022).

Two-photon calcium imaging displays neural function that includes cerebral activity in the C57BL/6 murine model of schizophrenia (Hamm et al., 2017; Hamm et al., 2020; Yoon et al., 2022; Yuryev et al., 2018; Zhuo et al., 2022). Accumulating evidence suggests that two-photon calcium imaging can associate altered Ca2+ activity in the PFC with cognitive or behavioral performance in murine models (Druart et al., 2021; Pittolo et al., 2022; Schamiloglu et al., 2023; Spellman et al., 2021; Witztum et al., 2023). More notably, a previous study reported that lithium can stabilize abnormal Ca2+ signaling in hippocampal neurons and subsequently normalize downstream effects in a murine model of Alzheimer's disease neuropathology and enhance synaptic plasticity in young mice with Alzheimer's disease (Wiseman et al., 2023). However, to the best of our knowledge, no studies have used two-photon calcium imaging to observe the relationship between lithium treatment and Ca2+ activity in the PFC in the C57BL/6 murine model of schizophrenia. More notably, no preclinical study has investigated the relationship between lithium treatment strategy, PFC Ca2+ activity, and cognitive performance.

Previous research has associated PFC dysfunction with cognitive impairment; and has shown that low-dose lithium can ameliorate cognitive impairments of dementia and mild cognitive impairment; and that two-photon calcium imaging can display PFC Ca2+ activity in the C57BL/6 murine model of schizophrenia. Based on this background, in vivo studies of lithium mono- and adjunctive therapies to improve schizophrenia-related cognitive impairments are both theoretically plausible and technically feasible. Therefore, we postulated that the effects of lithium mono- and adjunctive therapies on schizophrenia-associated cognopathy could be evaluated by two-photon calcium imaging and cognitive and behavioral testing.