a1 Department of Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Southern California, Los Angeles, CA, USA
a2 Program in Neuroscience, University of Mississippi Medical Center, Jackson, MS, USA
a3 Department of Surgery, University of Mississippi Medical Center, Jackson, MS, USA
a4 Department of Neurobiology and Anatomical Sciences, University of Mississippi Medical Center, Jackson, MS, USA
a5 Department of Psychiatry and Human Behavior, University of Mississippi Medical Center, Jackson, MS, USA
a6 Guy Everett' Laboratory Department of Neuroscience ‘B. B. Brodie’, University of Cagliari, Monserrato, CA, Italy
a7 Department of Psychological and Brain Sciences and Program in Neuroscience, Indiana University, Bloomington, IN, USA
a8 Department of Cell and Neurobiology, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA
Converging lines of evidence show that a sizable subset of autism-spectrum disorders (ASDs) is characterized by increased blood levels of serotonin (5-hydroxytryptamine, 5-HT), yet the mechanistic link between these two phenomena remains unclear. The enzymatic degradation of brain 5-HT is mainly mediated by monoamine oxidase (MAO)A and, in the absence of this enzyme, by its cognate isoenzyme MAOB. MAOA and A/B knockout (KO) mice display high 5-HT levels, particularly during early developmental stages. Here we show that both mutant lines exhibit numerous behavioural hallmarks of ASDs, such as social and communication impairments, perseverative and stereotypical responses, behavioural inflexibility, as well as subtle tactile and motor deficits. Furthermore, both MAOA and A/B KO mice displayed neuropathological alterations reminiscent of typical ASD features, including reduced thickness of the corpus callosum, increased dendritic arborization of pyramidal neurons in the prefrontal cortex and disrupted microarchitecture of the cerebellum. The severity of repetitive responses and neuropathological aberrances was generally greater in MAOA/B KO animals. These findings suggest that the neurochemical imbalances induced by MAOA deficiency (either by itself or in conjunction with lack of MAOB) may result in an array of abnormalities similar to those observed in ASDs. Thus, MAOA and A/B KO mice may afford valuable models to help elucidate the neurobiological bases of these disorders and related neurodevelopmental problems.
(Received March 29 2012)
(Reviewed April 29 2012)
(Revised May 16 2012)
(Accepted June 01 2012)
(Online publication July 31 2012)
c1 Address for correspondence: J. C. Shih, Department of Pharmacology and Pharmaceutical Science, School of Pharmacy, University of Southern California, PSC 518, 1985 Zonal Ave, Los Angeles, CA 90089, USA. Tel.: 323 442 1441 Fax: 323 442 3229 Email: email@example.com
* These authors contributed equally to this work.