The genetic basis of coordinated plasticity across functional units in a Lake Malawi cichlid mapping population.

Adaptive radiations are often stereotypical, as populations repeatedly specialize along conserved environmental axes. Phenotypic plasticity may be similarly stereotypical, as individuals respond to environmental cues. These parallel patterns of variation, which are often consistent across traits, have led researchers to propose that plasticity can facilitate predictable patterns of evolution along environmental gradients. This "flexible stem" model of evolution raises questions about the genetic nature of plasticity, including how complex is the genetic basis for plasticity? Is plasticity across traits mediated by many distinct loci, or few "global" regulators? To address these questions, we reared a hybrid cichlid mapping population on alternate diet regimes mimicking an important environmental axis. We show that plasticity across an array of ecologically relevant traits is generally morphologically integrated, such that traits respond in a coordinated manner, especially those with overlapping function. Our genetic data are more ambiguous. While our mapping experiment provides little evidence for global genetic regulators of plasticity, these data do contain a genetic signal for the integration of plasticity across traits. Overall, our data suggest a compromise between genetic modularity, whereby plasticity may evolve independently across traits, and low level but widespread genetic integration, establishing the potential for plasticity to experience coordinated evolution.

The mouse dorsal raphe nucleus as understood by temporal Fgf8 lineage analysis.

Fgf8 is expressed transiently during embryogenesis at the midbrain-hindbrain border, an area that gives rise to a variety of neuronal populations including the dorsal raphe (DR) nucleus. Using an inducible Fgf8-cre allele, we identified the populations of neurons defined by Fgf8 lineage at different stages of development. When Fgf8-cre expression is induced at embryonic day 7.5 (T-E7.5), in the adult the entire DR and part of the median raphe (MnR) have Fgf8 lineage. When induced at later timepoints, Fgf8 lineage progressively ebbs from the caudal and ventral aspect of this domain, particularly on the midline. Successively excluded from Fgf8- lineage at T-E9.5 are serotonin neurons in the MnR and caudal-intrafascicular DR, followed at T-E11.5 by ventral-middle and caudal-dorsal DR. The last to show Fgf8 lineage are those serotonin neurons in the lateral wings and those at the rostral-dorsal pole of DR nucleus. Thus, the temporal succession of Fgf8 lineage correlates with organizational features of serotonin neurons in these nuclei.

A 5-HT1D -receptor agonist protects Dravet syndrome mice from seizure and early death.

Mutations in the SCN1A gene encoding the Nav1.1 sodium channel cause several forms of epilepsy, the most severe is Dravet syndrome (DS). DS patients are at high risk for sudden death and seizures are often triggered by fever or hyperthermia. To improve understanding of how serotonergic ligands might influence DS in this study, we tested several drugs for their effect on hyperthermia-induced seizure using a mouse model of DS consisting of a heterozygous loss of function of Scn1A. We found that a mixed 5-HT2A/2C receptor agonist had no effect while a mixed 5-HT1B/D receptor agonist had a modest effect reducing the severity of seizures. Hypothesizing selective agonists may be more effective, we tested selective 5-HT1B and 5-HT1D receptor agonists, CP-93129 and GR-46611, respectively. Of these GR-46611 significantly increased the threshold of hyperthermia-induced seizure and lowered seizure severity. Given chronically at 1 mg kg-1  day-1 , GR-46611 also significantly improved survival of DS mice. Thus, 5-HT1D -receptors may represent a meaningful target for pharmacotherapy for DS with potential relevance for related forms of epilepsy, particularly those with a known sensory trigger such as heat.

Serotonin abnormalities in Dravet syndrome mice before and after the age of seizure onset.

Dravet syndrome (DS) is a genetic form of severe epilepsy often associated with mutation of the SCN1A gene encoding the voltage gated sodium channel Nav1.1. Typically refractive to conventional therapy, serotonin neurotransmission may be an innovative target for treatment. To further understand the role of serotonin in this disorder, in this study we examined the state of the endogenous serotonin system in an Scn1a+/- mouse model of DS. Examined at an age before seizures appear, we found the hypothermic effect of 5-HT1A receptor agonist administration was attenuated. HPLC analysis of brain monoamine content revealed modestly reduced serotonin levels in tissue samples of the midbrain that included the dorsal raphe nucleus but no changes elsewhere in the brain. The reduced sensitivity to 5-HT1A agonist administration seen at young ages reversed after the age of seizure development when mice showed an exaggerated hypothermic response. Likewise, adult DS mice showed a pronounced hypersensitivity to a 5-HT2A/2C agonist. As adults however monoamine levels were not detectably altered. Thus there are alterations in the endogenous serotonin system that both precede and follow the appearance of seizure in DS mice, most strikingly in the response to agonist administration.