In search of lost time: cognitive and arginine metabolic correlates of temporal dysfunction in the MIA rat model of schizophrenia risk

Abnormal temporal perception is a hallmark characteristic of schizophrenia associated with cognitive impairment, however the relationship between these functions is yet to be characterised within translational models. Using the maternal immune activation (MIA) rat model, this study investigated the contribution of sustained attention and working memory capacity to temporal perception impairments via operant paradigms. In addition, we also investigated the involvement of L-arginine metabolites in timing and cognition via high performance liquid chromatography and liquid chromatography/mass spectrometry. Principally, we identified that underestimation of interval durations (2-8 s) in MIA rats was related to attentional capacity. MIA rats were found to exhibit impaired working memory maintenance, however this was not related to temporal perception. In addition, we identified evidence of MIA impacting PFC L-arginine metabolites, L-citrulline and putrescine, which both correlated with working memory maintenance impairments. MIA also appeared to produce discrete differences in glutamate levels depending on whether inflammation was incited early or late in gestation (gestation day 10/18). Following late gestation MIA exposure, higher glutamate levels in PFC corresponded with poorer sustained attention capacity. These findings represent the first direct identification of a timing-attention relationship within rodents, and provide clues regarding the potential involvement of elevated dopamine in timing-cognition pathology in schizophrenia. Moreover, we present preliminary evidence that changes in L-arginine metabolism have functional consequences for cognition. These outcomes commend the MIA rat model as a tool for potential future investigations exploring the biological instantiation of timing deficits.