Session 4: Neurotransmitters Systems in Autism

Hendricks, T.J., Fyodorov, D, Wegman, L, Yamamoto, B, and Deneris, E.S.
Case Western Reserve University, School of Medicine, Department of Neurosciences

The monamine neurotransmitter serotonin (5-HT) modulates many CNS functions via an extensive axonal projection system originating in cell bodies located the midbrain/hindbrain raphe nuclei. Abnormalities of the 5-HT system are implicated in several common psychiatric disorders including autism. Although the neurobiological role of this system and its relevance to psychiatry are well-established the molecular genetic mechanisms that regulate its development and phenotypic maintenance are poorly understood.

We have identified an ETS domain transcription factor gene, Pet-1, which is expressed in the brain specifically in serotonergic neurons; no Pet-1 RNA expression is observed elsewhere in the rodent brain. The onset of Pet-1 expression occurs just prior to the appearance of 5-HT immunoreactivity in the developing hindbrain. Pet-1 expression appears to be maintained by all differentiated 5-HT neurons of the embryonic hindbrain and adult raphe nuclei. Its cell type specificity and onset of expression suggest a role for this transcription factor in the differentiation and/or maintenance of 5-HT neurons. We have begun to test this idea by using homologous recombination to create a null allele in which the entire protein-coding region of the murine Pet-1 locus is eliminated. In mice homozygous for this allele, a striking deficiency of 5-HT immunoreactivity is evident at E12.5 in both the rostral and caudal serotonergic neuron domains of the hindbrain. In adult homozygous null mice, the 5-HT deficiency is uniform across all nine raphe nuclei. Moreover, decreased numbers of 5-HT immunoreactive fibers are seen in cortex and other 5-HT target fields. HPLC analysis indicates an 83% and 80% deficiency in adult cerebral cortex and a 90% and 95% deficiency in adult caudate of 5-HT and 5-HIAA, respectively. In contrast, no deficiency of dopamine or its metabolites was found in homozygous null caudate. The defect is accompanied by an absence of some 5-HT neuron cell bodies and a deficiency of tryptophan hydroxylase gene expression. These data indicate that Pet-1 is required for the normal development of the central 5-HT system. Supported by RO1 MH62723.

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