Background Toxoplasma gondii is a pathogen implicated in psychiatric disorders. As elevated antibodies to T. gondii are also present in non-symptomatic individuals, we hypothesized that the age during first exposure to the pathogen may affect symptom manifestation. We tested this hypothesis by evaluating neurobehavioral abnormalities and the immune response in mice following adolescent or adult T. gondii infection. Methods Mice were infected with T. gondii at postnatal day 33 (adolescent/juvenile) or61 (adult). At 8 weeks post-infection (wpi), pre-pulse inhibition of the acoustic startle (PPI) in mice administered MK-801 (0.1 and 0.3 mg/kg) and amphetamine (5 and 10 mg/kg) was assessed. Peripheral (anti-T. gondii, C1q-associated IgG and anti-GLUN2 antibodies) and central (C1q and Iba1) markers of the immune response were also evaluated. In addition, regional brain expression of N-methyl-D-aspartate receptor (NMDAR) subunits (GLUN1 and GLUN2A), glutamatergic (vGLUT1, PSD95) and GABAergic (GAD67) markers, and monoamines (DA, NE, 5-HT) and their metabolites were measured. Results Juvenile and adult infected mice exhibited opposite effects of MK-801 on PPI, with decreased PPI in juveniles and increased PPI in adults. There was a significantly greater elevation of GLUN2 autoantibodies in juvenile- compared to adult-infected mice. In addition, age-dependent differences were found in regional expression of NMDAR subunits and markers of glutamatergic, GABAergic, and monoaminergic systems. Activated microglia and C1q elevations were found in both juvenile- and adult-T. gondii infected mice. Conclusions Our study demonstrates that the age at first exposure to T. gondii is an important factor in shaping distinct behavioral and neurobiological abnormalities. Elevation in GLUN2 autoantibodies or complement protein C1q may be a potential underlying mechanism. A better understanding of these age-related differences may lead to more efficient treatments of behavioral disorders associated with T. gondii infection.

Recent studies have advanced our understanding of the role of the cerebellum in non-motor behaviors. Abnormalities in the cerebellar structure have been demonstrated to produce changes in emotional, cognitive, and social behaviors resembling clinical manifestations observed in patients with autism spectrum disorders (ASD) and schizophrenia. Several animal models have been used to evaluate the effects of relevant environmental and genetic risk factors on the cerebellum development and function. However, very few models of ASD and schizophrenia selectively target the cerebellum and/or specific cell types within this structure. In this review, we critically evaluate the strength and weaknesses of these models. We will propose that the future progress in this field will require time- and cell type-specific manipulations of disease-relevant genes, not only selectively in the cerebellum, but also in frontal brain areas connected with the cerebellum. Such information can advance our knowledge of the cerebellar contribution to non-motor behaviors in mental health and disease.