Developmental Trajectory and Parental Behaviour Contribution to the Advanced Paternal Age Effects on Autism-Related Phenotypes in Mice

Friday, May 16, 2014
Atrium Ballroom (Marriott Marquis Atlanta)
M. Janecka1, A. Manduca2, R. Smith1, L. Schalkwyk1, J. Mill1,3, V. Trezza2, A. Reichenberg4,5 and C. Fernandes1, (1)Social, Genetic and Developmental Psychiatry, King's College London, London, United Kingdom, (2)Department of Science, Roma Tre University, Rome, Italy, (3)Medical School, University of Exeter, Exeter, United Kingdom, (4)Icahn School of Medicine at Mount Sinai, New York, NY, (5)Psychological Medicine, King's College London, London, United Kingdom

Advanced paternal age (APA) has been reliably linked to a host of adverse outcomes in offspring, ranging from congenital spontaneous conditions to complex disorders like schizophrenia and autism. Previous studies reported deficits in several behavioural domains in the mouse models of APA, but not their developmental trajectory; also, they failed to show unequivocally that these effects arise de novo in offspring, rather than are parentally-inherited. 


Our study used inbred C57BL/6J mice to investigate the effects of APA on offspring, both during early development and in adulthood, focusing on the behavioural domains in which autistic individuals show impairment. Parental behaviour was also assessed in order to eliminate possible confounding factors. 


Three groups of offspring of (i) young (8 weeks old fathers), (ii) old (40 week old fathers) and (iii) very old fathers (48 week old fathers) were tested through a battery of behavioural tasks. The tests assessed both early development (emergence of critical reflexes, motor and physical landmarks, and social development), and behaviour in adulthood. The latter battery included following tests: homecage (locomotor activity), open field (anxiety), holeboard (exploration), 3 chamber social approach (social preference), social interaction, olfactory habituation/dishabituation (olfaction and olfactory memory), marble burying test (repetitive behaviour), rotarod (motor learning) and Morris water maze (spatial learning and memory). Majority of the tests run on adult offspring also were run on fathers, in order to eliminate paternal effects that were not related to the father’s age at conception. Also, a separate battery was designed for mothers, to assess the effects of potentially confounding maternal effects on pup development.


We have observed differences in motor and social domains in the offspring of old and very old fathers, both early in development and in adulthood. No corresponding group differences in paternal behaviour or dam-pup interactions were recorded.


Offspring of old and very old fathers displayed differences in social and motor domains, which are often affected in individuals with autism. These were visible already at postnatal days 10-21, and persisted till adulthood, underscoring the importance of looking at developmental trajectories in mouse models. None of these effects could be reliably explained by parental behavioural profiles, suggesting that APA effects arise de novo in the offspring generation. Further investigation will try to elucidate whether these effects can persist through generations (three generations will be tested in total) and if a perinatal dietary intervention (folic acid enrichment) can reverse them.

See more of: Animal Models
See more of: Animal Models