Session 4: Neurotransmitters Systems in Autism

D.P. Holschneider ^1,2,6, K. Chen⁵, O.U. Scremin^6,7, I. Seif⁸, J.C. Shih^4,5

Depts. of (1)Psychiatry and the Behavioral Sciences, (2)Neurology, (4)Cell and Neurobiology, USC Keck School of Medicine, Dept. of( 5)Molecular Pharmacology and Toxicology, USC School of Pharmacy; (6)Greater Los Angeles VA Healthcare System; (7)Dept. of Physiology, UCLA School of Medicine, Los Angeles, CA; (8) Centre National de la Recherche Scientifique (CNRS), Orsay, France

Alterations in bioamines have been implicated as a factor in some cases of autism. Monoamine oxidase (MAO) A and B are isoenzymes located that play a central role in regulating tissue levels of biogenic amines. MAO-A preferentially metabolizes serotonin (5-HT) and norepinephrine (NE), whereas MAO-B has a higher affinity for phenylethylamine (PEA). Both forms of the enzyme metabolize dopamine (DA), though MAO-A in mice has a higher affinity for DA. This paper summarizes some of the current known phenotypic findings in mice with deficiencies in MAO-A and B (MAO-A/B KO) and those with a sole deficiency in MAO-A (MAO-A KO). MAO-A/B KO mice and MAO-A KO mice compared to wild-type controls demonstrate markedly elevated brain levels of 5-HT and to a lesser extent NE. MAO-AB KO mice additionally demonstrate elevations in PEA. MAO-A KO mice (and presumably MAO-A/B KO mice) show neurodevelopmental abnormalities, including abnormal development of somatosensory thalamocortical afferent fibers and retinal afferents, as well as a transient delay of the maturation of locomotor networks. Behavioral abnormalities in both MAO-A KO and MAO-AB KO mice include hyperreactivity, disrupted social interaction, increased classical fear conditioning and decreased amplitude of the acoustic startle response. Whereas MAO-A KO mice show prominent territorial aggression, MAO-A/B KO mice show more prominent anxiety-like behavior. Physiological abnormalities examined to date show decreased body weight of both MAO-A KO and MAO-AB KO mice, altered regional cerebral cortical blood flow in MAO-A KO mice, as well as altered autonomic function and heart rate dynamics in MAO-A/B KO mice. These observations suggest that phenotypes associated with low MAO activity are determined both by alterations in neurodevelopment, as well as by postnatal adaptational changes. These animals may be useful for studying the molecular mechanisms of monoamine functions.

Supported by NIMH grants RO1 MH NS62148 (DPH), RO1 MH 37020, R37 MH39085, KO5 MH 00796 and the Elsie Welin Professorship (JCS), the Veterans Administration and the Laubisch Endowment (OUS), and by the Whitaker Foundation RG-99-0331 (DPH).

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