Abstracts

A significant proportion of children diagnosed with autistic spectrum disorders presents with seizure abnormalities. Recent clinical data suggest that serotonin (5-HT) function is disrupted in autistic patients. Serotonin plays a significant role in brain development, in sleep-wake cycles, and in the modulation of cortical excitability. We hypothesized that disruption of the serotonin system in immature rats would lead to autism-relevant behaviors and aberrant patterns of brain excitability. To test this hypothesis, we have begun to characterize a model of [ldquo]hyperserotonemia[rdquo] developed by Whitaker-Azmitia and colleagues (Physiol. Behav. 2002: 75:403-410). Time-mated pregnant Sprague-Dawley rats were injected with a non-specific 5-HT receptor agonist, 5-methoxytryptamine (5-MT) (1mg/kg, s.c.), once a day from gestational day 12 through postnatal day 21 (P21); time-mated control animals were injected with saline. Immature animals (between P7 and P19) were tested on a battery of [ldquo]autism-relevant[rdquo] behavioral tasks (e.g., ultrasonic vocalization (USV) when separated from dam, open field exploration, negative geotaxis, response to tactile stimulation). They were then monitored with video/EEG telemetry, with subsets of animals sacrificed (at P27) for assessment of alterations in brain serotonergic innervation, using quantitative immunocytochemistry. 5-MT treatment led to inconsistent behavioral differences compared to saline-injected controls. At P19 (but not earlier), 5-MT pups exhibited decreased USV. There were no significant differences between 5-MT and saline pups on a negative geotaxis task, on open field exploration (with and without auditory stimulation), on response to tactile stimulation, and on spontaneous alternation in a Y-maze. Video/EEG recording showed a significant number of spike-like epileptiform events in 5-MT animals, but not in control rats. Immunocytochemistry for serotonin- including quantitative measurements of fiber immunoreactivity (IR) in selected brain regions - revealed significant increases (compared to age-matched controls) in hippocampal CA3 subfield and basolateral nucleus of the amygdala; 5-HT IR in central amygdala, neocortex (lamina V in parietal cortex) and lateral nucleus of the dorsal raphe showed no significant differences. Early 5-MT treatment failed to yield the expected range of behavioral changes in rat pups, although decreased USV in 5-MT-treated animals is arguably consistent with an autism-like deficit. The [ldquo]hyperserotonemic[rdquo] 5-MT model is associated with significant region-specific increases in serotonin fiber IR, a finding opposite to the initially hypothesized change. 5-MT treated pups did show EEG abnormalities that may be consistent with increased seizure propensity in some individuals with autism. (Supported by a grant from UC Davis M.I.N.D. Institute.)