@article {1669, title = {Setd5 haploinsufficiency alters neuronal network connectivity and leads to autistic-like behaviors in mice.}, journal = {Transl Psychiatry}, volume = {9}, year = {2019}, month = {2019 01 17}, pages = {24}, abstract = {

SETD5, a gene linked to intellectual disability (ID) and autism spectrum disorder (ASD), is a member of the SET-domain family and encodes a putative histone methyltransferase (HMT). To date, the mechanism by which SETD5 haploinsufficiency causes ASD/ID remains an unanswered question. Setd5 is the highly conserved mouse homolog, and although the Setd5 null mouse is embryonic lethal, the heterozygote is viable. Morphological tracing and multielectrode array was used on cultured cortical neurons. MRI was conducted of adult mouse brains and immunohistochemistry of juvenile mouse brains. RNA-Seq was used to investigate gene expression in the developing cortex. Behavioral assays were conducted on adult mice. Setd5 cortical neurons displayed significantly reduced synaptic density and neuritic outgrowth in vitro, with corresponding decreases in network activity and synchrony by electrophysiology. A specific subpopulation of fetal Setd5 cortical neurons showed altered gene expression of neurodevelopment-related genes. Setd5 animals manifested several autism-like behaviors, including hyperactivity, cognitive deficit, and altered social interactions. Anatomical differences were observed in Setd5 adult brains, accompanied by a deficit of deep-layer cortical neurons in the developing brain. Our data converge on a picture of abnormal neurodevelopment driven by Setd5 haploinsufficiency, consistent with a highly penetrant risk factor.

}, keywords = {Animals, Autism Spectrum Disorder, Behavior, Animal, Brain, Female, Genetic Predisposition to Disease, Haploinsufficiency, Heterozygote, Magnetic Resonance Imaging, Male, Methyltransferases, Mice, Mice, Knockout, Mutation, Neurons}, issn = {2158-3188}, doi = {10.1038/s41398-018-0344-y}, author = {Moore, Spencer M and Seidman, Jason S and Ellegood, Jacob and Gao, Richard and Savchenko, Alex and Troutman, Ty D and Abe, Yohei and Stender, Josh and Lee, Daehoon and Wang, Sicong and Voytek, Bradley and Lerch, Jason P and Suh, Hoonkyo and Glass, Christopher K and Muotri, Alysson R} } @article {163, title = {Genes involved in sex pheromone discrimination in Drosophila melanogaster and their background-dependent effect.}, journal = {PLoS One}, volume = {7}, year = {2012}, month = {2012}, pages = {e30799}, abstract = {

Mate choice is based on the comparison of the sensory quality of potential mating partners, and sex pheromones play an important role in this process. In Drosophila melanogaster, contact pheromones differ between male and female in their content and in their effects on male courtship, both inhibitory and stimulatory. To investigate the genetic basis of sex pheromone discrimination, we experimentally selected males showing either a higher or lower ability to discriminate sex pheromones over 20 generations. This experimental selection was carried out in parallel on two different genetic backgrounds: wild-type and desat1 mutant, in which parental males showed high and low sex pheromone discrimination ability respectively. Male perception of male and female pheromones was separately affected during the process of selection. A comparison of transcriptomic activity between high and low discrimination lines revealed genes not only that varied according to the starting genetic background, but varied reciprocally. Mutants in two of these genes, Shaker and quick-to-court, were capable of producing similar effects on discrimination on their own, in some instances mimicking the selected lines, in others not. This suggests that discrimination of sex pheromones depends on genes whose activity is sensitive to genetic context and provides a rare, genetically defined example of the phenomenon known as "allele flips," in which interactions have reciprocal effects on different genetic backgrounds.

}, keywords = {Animals, Animals, Genetically Modified, Behavior, Animal, Breeding, Courtship, Drosophila melanogaster, Female, Genes, Insect, Male, Mutation, Olfactory Perception, Reproduction, Sex Attractants, Sexual Behavior, Animal, Species Specificity}, issn = {1932-6203}, doi = {10.1371/journal.pone.0030799}, author = {Houot, Benjamin and Fraichard, St{\'e}phane and Greenspan, Ralph J and Ferveur, Jean-Fran{\c c}ois} } @article {142, title = {Selection, gene interaction, and flexible gene networks.}, journal = {Cold Spring Harb Symp Quant Biol}, volume = {74}, year = {2009}, month = {2009}, pages = {131-8}, abstract = {

Recent results from a variety of different kinds of experiments, mainly using behavior as an assay, and ranging from laboratory selection experiments to gene interaction studies, show that a much wider range of genes can affect phenotype than those identified as "core genes" in classical mutant screens. Moreover, very pleiotropic genes can produce specific phenotypes when mild variants are combined. These studies also show that gene networks readily change configuration and the relationships between interacting genes in response to the introduction of additional genetic variants, suggesting that the networks range widely and have a high degree of flexibility and malleability. Such flexibility, in turn, offers a plausible mechanism for the molding of phenotypes through microevolution, as a prerequisite to making a suitable environment for the acceptance of newly arising large-effect mutations in the transition from microevolution to macroevolution.

}, keywords = {Animals, Biological Evolution, Drosophila melanogaster, Epistasis, Genetic, Escherichia coli, Female, Gene Regulatory Networks, Genes, Insect, Genetic Association Studies, Male, Models, Genetic, Mutation, Selection, Genetic}, issn = {1943-4456}, doi = {10.1101/sqb.2009.74.029}, author = {Greenspan, R J} } @article {147, title = {Dopaminergic modulation of arousal in Drosophila.}, journal = {Curr Biol}, volume = {15}, year = {2005}, month = {2005 Jul 12}, pages = {1165-75}, abstract = {

BACKGROUND: Arousal levels in the brain set thresholds for behavior, from simple to complex. The mechanistic underpinnings of the various phenomena comprising arousal, however, are still poorly understood. Drosophila behaviors have been studied that span different levels of arousal, from sleep to visual perception to psychostimulant responses.

RESULTS: We have investigated neurobiological mechanisms of arousal in the Drosophila brain by a combined behavioral, genetic, pharmacological, and electrophysiological approach. Administration of methamphetamine (METH) suppresses sleep and promotes active wakefulness, whereas an inhibitor of dopamine synthesis promotes sleep. METH affects courtship behavior by increasing sexual arousal while decreasing successful sexual performance. Electrophysiological recordings from the medial protocerebrum of wild-type flies showed that METH ingestion has rapid and detrimental effects on a brain response associated with perception of visual stimuli. Recordings in genetically manipulated animals show that dopaminergic transmission is required for these responses and that visual-processing deficits caused by attenuated dopaminergic transmission can be rescued by METH.

CONCLUSIONS: We show that changes in dopamine levels differentially affect arousal for behaviors of varying complexity. Complex behaviors, such as visual perception, degenerate when dopamine levels are either too high or too low, in accordance with the inverted-U hypothesis of dopamine action in the mammalian brain. Simpler behaviors, such as sleep and locomotion, show graded responses that follow changes in dopamine level.

}, keywords = {Animals, Animals, Genetically Modified, Arousal, Brain, Dopa Decarboxylase, Dopamine, Dose-Response Relationship, Drug, Drosophila, Drosophila Proteins, Dynamins, Electrophysiology, Methamphetamine, Mutation, Sexual Behavior, Animal, Sleep, Visual Perception}, issn = {0960-9822}, doi = {10.1016/j.cub.2005.05.025}, author = {Andretic, Rozi and van Swinderen, Bruno and Greenspan, Ralph J} } @article {149, title = {Salience modulates 20-30 Hz brain activity in Drosophila.}, journal = {Nat Neurosci}, volume = {6}, year = {2003}, month = {2003 Jun}, pages = {579-86}, abstract = {

Fruit flies selectively orient toward the visual stimuli that are most salient in their environment. We recorded local field potentials (LFPs) from the brains of Drosophila melanogaster as they responded to the presentation of visual stimuli. Coupling of salience effects (odor, heat or novelty) to these stimuli modulated LFPs in the 20-30 Hz range by evoking a transient, selective increase. We demonstrated the association of these responses with behavioral tracking and initiated a genetic approach to investigating neural correlates of perception.

}, keywords = {Action Potentials, Animals, Attention, Behavior, Animal, Brain, Cues, Drosophila, Drosophila Proteins, Exploratory Behavior, Mutation, Neurons, Orientation, Retina, Smell, Synaptic Transmission, Thermosensing, Visual Pathways, Visual Perception}, issn = {1097-6256}, doi = {10.1038/nn1054}, author = {van Swinderen, Bruno and Greenspan, Ralph J} } @article {150, title = {Identification of genes involved in Drosophila melanogaster geotaxis, a complex behavioral trait.}, journal = {Nat Genet}, volume = {31}, year = {2002}, month = {2002 Aug}, pages = {349-53}, abstract = {

Identifying the genes involved in polygenic traits has been difficult. In the 1950s and 1960s, laboratory selection experiments for extreme geotaxic behavior in fruit flies established for the first time that a complex behavioral trait has a genetic basis. But the specific genes responsible for the behavior have never been identified using this classical model. To identify the individual genes involved in geotaxic response, we used cDNA microarrays to identify candidate genes and assessed fly lines mutant in these genes for behavioral confirmation. We have thus determined the identities of several genes that contribute to the complex, polygenic behavior of geotaxis.

}, keywords = {Animals, Animals, Genetically Modified, Behavior, Animal, DNA, Complementary, Drosophila melanogaster, Female, Genetics, Behavioral, Mutation, Oligonucleotide Array Sequence Analysis}, issn = {1061-4036}, doi = {10.1038/ng893}, author = {Toma, Daniel P and White, Kevin P and Hirsch, Jerry and Greenspan, Ralph J} } @article {152, title = {Correlates of sleep and waking in Drosophila melanogaster.}, journal = {Science}, volume = {287}, year = {2000}, month = {2000 Mar 10}, pages = {1834-7}, abstract = {

Drosophila exhibits a circadian rest-activity cycle, but it is not known whether fly rest constitutes sleep or is mere inactivity. It is shown here that, like mammalian sleep, rest in Drosophila is characterized by an increased arousal threshold and is homeostatically regulated independently of the circadian clock. As in mammals, rest is abundant in young flies, is reduced in older flies, and is modulated by stimulants and hypnotics. Several molecular markers modulated by sleep and waking in mammals are modulated by rest and activity in Drosophila, including cytochrome oxidase C, the endoplasmic reticulum chaperone protein BiP, and enzymes implicated in the catabolism of monoamines. Flies lacking one such enzyme, arylalkylamine N-acetyltransferase, show increased rest after rest deprivation. These results implicate the catabolism of monoamines in the regulation of sleep and waking in the fly and suggest that Drosophila may serve as a model system for the genetic dissection of sleep.

}, keywords = {Animals, Arylamine N-Acetyltransferase, Behavior, Animal, Biogenic Monoamines, Caffeine, Carrier Proteins, Circadian Rhythm, Cytochrome P-450 Enzyme System, Drosophila melanogaster, Drosophila Proteins, Fatty Acid Synthases, Female, Gene Dosage, Gene Expression Profiling, Genes, Insect, Homeostasis, HSC70 Heat-Shock Proteins, HSP70 Heat-Shock Proteins, Hydroxyzine, Mutation, Rest, Sleep, Transcription, Genetic, Wakefulness}, issn = {0036-8075}, author = {Shaw, P J and Cirelli, C and Greenspan, R J and Tononi, G} }