A decreased response to the NMDAR antagonist MK-801 is shown by pharmacological MRI in a maternal immune activation model

• ¹ University of Antwerp, Translational Neurosciences, Belgium
• ² University of Antwerp, Biomedical Sciences, Belgium

Introduction. Maternal immune activation (MIA) is a primer for several neurological disorders including schizophrenia. Hypofunction of the NMDA receptor (NMDAR) is currently the most accepted hypothesis regarding the pathophysiology of schizophrenia. One of the best animal models for schizophrenia is the MIA model1. Altered NMDAR function is commonly tested in this model by assessing the hyperlocomotor response to the NMDAR antagonist MK-801. However, the outcome of this test has been inconsistent. A differential response to MK-801 has been described in MIA offspring depending on the presence of maternal weight loss2. The aim of this study was to assess the response to MK-801 using pharmacological MRI (phMRI) in MIA offspring. Methods. Pregnant Wistar dams were injected with 4 mg/kg Poly I:C (MIA) or saline on gestational day 15 and weight change was recorded at 24h post-injection. Male offspring of dams that lost (Poly I:C WL, n=14) and gained weight post-MIA (Poly I:C WG, n=8) and control offspring (n=7) were subjected to phMRI and behavioural assessment with 0.2 mg/kg MK-801 in adulthood. For phMRI, coronal scans were continuously acquired on a 7T PharmaScan (Bruker) 10min before until 30min after i.v. MK-801 administration under 2% isoflurane. Breathing rate and blood oxygenation were monitored. Pre- and post-processing was performed in SPM12. Statistical analysis was done to explore BOLD signal differences between pre- and post-MK-801 in the three groups for the following regions of interest: anterior cingulate cortex, motor cortex, striatum, thalamus and hippocampus. For the behavioural test, locomotion was recorded 1h before until 3h after s.c. injection with MK-801. Results. PhMRI showed that Poly I:C WG offspring had a smaller response to MK-801 compared to controls in striatum and thalamus (p≤0.05), anterior cingulate cortex and motor cortex (p<0.1) but not in hippocampus. Poly I:C WL offspring only exhibited a smaller response in thalamus vs controls (p≤0.05). In the behavioural test, Poly I:C WG offspring showed a slightly attenuated hyperlocomotor response to MK-801 vs controls. Conclusion. PhMRI showed a differential response to MK-801 in MIA offspring, primarily in Poly I:C WG offspring. The behavioural read-out showed a subtle difference between Poly I:C WG offspring and controls. PhMRI may prove to be a more sensitive alternative to assess altered responses to MK-801 than the classic behavioural read-out. References. 1Zuckerman et al., 2003; 2Missault et al., 2014.