Apomorphine susceptibility and prenatal infection alter neurodevelopment, synaptic density and anticipatory behavior in rats

Kate Witt, Meyrick Kidwell, Janine Doorduin, Erik.F.J. de Vries, Iris E. Sommer, Darren J. Day, Bart A. Ellenbroek, Cyprien G.J. Guerrin
Progress in Neuro-Psychopharmacology and Biological Psychiatry. 2025-10-01; 142: 111490
DOI: 10.1016/j.pnpbp.2025.111490

1. Prog Neuropsychopharmacol Biol Psychiatry. 2025 Oct 2;142:111490. doi:
10.1016/j.pnpbp.2025.111490. Epub 2025 Sep 9.

Apomorphine susceptibility and prenatal infection alter neurodevelopment,
synaptic density and anticipatory behavior in rats.

Witt K(1), Kidwell M(1), Doorduin J(2), de Vries EFJ(2), Sommer IE(3), Day
DJ(4), Ellenbroek BA(1), Guerrin CGJ(5).

Author information:
(1)Behavioural Neurogenetics Group, Victoria University of Wellington, PO Box
600, Wellington, New Zealand.
(2)Department of Nuclear Medicine and Molecular Imaging, University Medical
Center Groningen, University of Groningen, Hanzeplein 1, 9713 GZ Groningen, the
Netherlands.
(3)Department of Biomedical Sciences, University Medical Center Groningen,
University of Groningen, 9713 GZ Groningen, the Netherlands.
(4)School of Biological Sciences, Victoria University of Wellington, PO Box 600,
6104 Wellington, New Zealand.
(5)Department of Nuclear Medicine and Molecular Imaging, University Medical
Center Groningen, University of Groningen, Hanzeplein 1, 9713 GZ Groningen, the
Netherlands; Behavioural Neurogenetics Group, Victoria University of Wellington,
PO Box 600, Wellington, New Zealand; Department of Medical Neuroscience, Donders
Institute for Brain, Cognition and Behavior, Radboud University Medical Center,
Nijmegen, the Netherlands. Electronic address: .

Schizophrenia is a complex psychiatric disorder, driven by genetic and
environmental factors. While individual risk genes have limited impact,
polygenic susceptibility increases the likelihood of schizophrenia and heightens
sensitivity to environmental stressors, such as prenatal immune activation. Yet,
preclinical studies often focused on single-gene mutations, leaving polygenic
influences largely unexplored. Using the apomorphine-susceptible (APO-SUS) rat
model, which exhibits schizophrenia-like features, we investigated how polygenic
susceptibility influences early neurodevelopment, synaptic density, and
behavior, and how these effects are modulated by prenatal immune activation.
APO-SUS rats demonstrated early neurodevelopmental abnormalities, including a
reduced number and duration of separation-induced ultrasonic vocalizations
(USVs), increased principal frequency of USVs, and reduced heart rate
variability (HRV), indicative of heightened sympathetic dominance commonly seen
in psychiatric disorders. These effects were particularly pronounced in females.
Male APO-SUS rats exhibited elevated synaptophysin levels, a presynaptic marker
for synaptic density, in the frontal cortex during adolescence and in the
hippocampus during adulthood. Interestingly, prenatal immune activation
counteracted some of these changes, preventing HRV reduction and normalizing
synaptophysin levels. Male and female APO-SUS rats, as well as Wistar male rats
exposed to prenatal immune activation, showed anticipatory behavior during
adolescence, but not in adulthood. Our results suggest that polygenic
susceptibility induces early neurodevelopmental changes and that genetic and
environmental risk factors do not always act synergistically; sometimes
counterbalancing each other. Future studies should explore how early
neurodevelopmental changes, such as alterations in USVs and HRV, influence later
behavioral outcomes in polygenic models of schizophrenia.

DOI: 10.1016/j.pnpbp.2025.111490
PMID: 40935232 [Indexed for MEDLINE]

Conflict of interest statement: Declaration of competing interest The authors
declare that they have no known competing financial interests or personal
relationships that could have appeared to influence the work reported in this
paper.