Neonatal handling enhances behavioural and attentional domains, and frontocortical synaptic maturation in rat models of schizophrenia-like behaviour and anxiety-related responses

The Roman inbred rat strains are a neurodevelopmental model, with the Roman High Avoidance (RHA) presenting specific behaviours and frontal cortex (FC) gene expression changes relevant to schizophrenia symptoms. We wanted to assess the potentially positive modulatory and enduring effects of neonatal handling (NH) on the innate traits associated with both the RHA and their counterpart Roman Low Avoidance (RLA). Male rats received NH or were left untreated (controls). Two different age groups were considered: adolescent and adults. The assessment encompassed exploratory behaviour, social behaviour, anxiety-related behaviour (self-grooming), sensorimotor gating (prepulse inhibition; PPI), and the analysis of gene expression associated with synaptic processes, cortical maturation, and neuroplasticity in the FC. In adolescent rats, NH increased novelty exploration and activity, and reduced novelty-induced self-grooming in RLAs, whereas it improved PPI in RHAs. In adult rats, NH increased novelty-induced activity in both strains, reduced self-grooming in RLA rats, and enhanced social interaction and PPI in RHAs. NH produced significant effects on gene expression in adolescent RHA rats. These effects were observed at the presynaptic level by a reduction of Snap25 and increases of Cables1 and Cdk5, and at the postsynaptic level by increases of Grin2b, Homer1 and Nrg1, as well as by a NH-induced enhancement of Bdnf. NH also increased Nrg1 and Bdnf expression in adult RLA rats. These findings show for the first time that NH is able to modulate several genetically linked synaptic/neuroplasticity alterations in RHA vs. RLA rats, which are paralleled by NH-induced improvements in novelty exploration, social behaviour and sensorimotor gating (PPI).