Schizophrenia, a profoundly impactful neuropsychiatric disorder, has been the subject of extensive research using animal models. However, certain important aspects remain understudied, including assumed long-term consequences of psychotic episodes on negative symptoms development and progression. Addressing these limitations, we proposed a novel animal model in male rats based on early postnatal immune activation triggered by lipopolysaccharide (LPS), serving as the predisposing factor (1st hit). As the 2nd hit, representing psychotic-like episodes, we implemented a multi-episodic co-treatment with dizocilpine (MK-801) and amphetamine (AMP), spanning multiple developmental periods. The animals were tested in two social behavioral assays in adolescence and adulthood to investigate whether a social deficit would arise. In addition, we evaluated the level of oxytocin (OT), a neuropeptide relevant to social behavior, in selected brain regions. In the social interaction test, when animals could freely interact in the open field and express their social behavioral profile entirely, social behavior decreased in adolescent experimental animals. In the social approach test in the Y maze, all animals, irrespective of treatment, preferred conspecific over an indifferent object and novel rat over a familiar rat. Further, the results revealed that the OT content in the hypothalamus increased with age. In the proposed model, social interaction in the open field was decreased in adolescent but not in adult rats, indicating that the pharmacological manipulations caused only transient age-dependent changes. The study was thus in certain aspects successful in creating a novel approach to model social deficit potentially relevant to schizophrenia; other findings require further investigation.

• Keywords
• Animal model, Oxytocin, Schizophrenia, Social behavior, Two-hit model, negative symptom,
• Publication type
• Journal Article MeSH

Maternal immune activation (MIA) during pregnancy represents an important environmental factor in the etiology of schizophrenia and autism spectrum disorders (ASD). Our goal was to investigate the impacts of MIA on the brain and behavior of adolescent and adult offspring, as a rat model of these neurodevelopmental disorders. We injected bacterial lipopolysaccharide (LPS, 1 mg/kg) to pregnant Wistar dams from gestational day 7, every other day, up to delivery. Behavior of the offspring was examined in a comprehensive battery of tasks at postnatal days P45 and P90. Several brain parameters were analyzed at P28. The results showed that prenatal immune activation caused social and communication impairments in the adult offspring of both sexes; males were affected already in adolescence. MIA also caused prepulse inhibition deficit in females and increased the startle reaction in males. Anxiety and hypolocomotion were apparent in LPS-affected males and females. In the 28-day-old LPS offspring, we found enlargement of the brain and decreased numbers of parvalbumin-positive interneurons in the frontal cortex in both sexes. To conclude, our data indicate that sex of the offspring plays a crucial role in the development of the MIA-induced behavioral alterations, whereas changes in the brain apparent in young animals are sex-independent.

• Keywords
• autism, chronic bacterial infection, development, lipopolysaccharide, macrocephaly, maternal immune activation, parvalbumin-positive interneurons, prenatal infection, schizophrenia, sex differences,
• MeSH
• Behavior, Animal * MeSH
• Immunohistochemistry MeSH
• Immunomodulation * MeSH
• Interneurons metabolism   MeSH
• Rats MeSH
• Lipopolysaccharides immunology   MeSH
• Maternal Exposure MeSH
• Microglia immunology   metabolism   MeSH
• Brain immunology   metabolism   MeSH
• Parvalbumins metabolism   MeSH
• Sex Factors MeSH
• Social Behavior MeSH
• Pregnancy MeSH
• Animals MeSH
• Check Tag
• Rats MeSH
• Male MeSH
• Pregnancy MeSH
• Female MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Names of Substances
• Lipopolysaccharides MeSH
• Parvalbumins MeSH

The McGill-R-Thy1-APP transgenic rat is an animal model of the familial form of Alzheimer's disease (AD). This model mirrors several neuropathological hallmarks of the disease, including the accumulation of beta-amyloid and the formation of amyloid plaques (in homozygous animals only), neuroinflammation and the gradual deterioration of cognitive functions even prior to plaque formation, although it lacks the tauopathy observed in human victims of AD. The goal of the present study was a thorough characterization of the homozygous model with emphasis on its face validity in several domains of behavior known to be affected in AD patients, including cognitive functions, motor coordination, emotionality, sociability, and circadian activity patterns. On the behavioral level, we found normal locomotor activity in spontaneous exploration, but problems with balance and gait coordination, increased anxiety and severely impaired spatial cognition in 4-7 month old homozygous animals. The profile of social behavior and ultrasonic communication was altered in the McGill rats, without a general social withdrawal. McGill rats also exhibited changes in circadian profile, with a shorter free-running period and increased total activity during the subjective night, without signs of sleep disturbances during the inactive phase. Expression of circadian clock gene Bmal1 was found to be increased in the parietal cortex and cerebellum, while Nr1d1 expression was not changed. The clock-controlled gene Prok2 expression was found to be elevated in the parietal cortex and hippocampus, which might have contributed to the observed changes in circadian phenotype. We conclude that the phenotype in the McGill rat model is not restricted to the cognitive domain, but also includes gait problems, changes in emotionality, social behavior, and circadian profiles. Our findings show that the model should be useful for the development of new therapeutic approaches targeting not only memory decline but also other symptoms decreasing the quality of life of AD patients.

• Keywords
• Alzheimer's disease, amyloid precursor protein, circadian system, cognition, rat, social behavior, transgenic,
• Publication type
• Journal Article MeSH