Variable channel expression in identified single and electrically coupled neurons in different animals

Schulz, David J.; Goaillard, Jean-Marc; Marder, Eve

doi:10.1038/nn1639

Cited by 426 publications

(532 citation statements)

References 41 publications

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“…Therefore, altered neuronal network states in BD arise from different sets of risk variants in different individuals, showing that in BD these unstable physiological network fates can be reached by many distinct molecular mechanisms (31). Theoretical and experimental studies in animal models have demonstrated that identical activity in neuronal circuits can arise from many different patterns of ion channel gene expression (32,33). Similarly, we hypothesize that cellular differences in neuronal excitability underlying susceptibility to mania and depression can arise from distinct combinations of ion channel variants.…”

Section: Discussionmentioning

confidence: 99%

Rare variants in neuronal excitability genes influence risk for bipolar disorder

Ament

Szelinger

Glusman

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

166

135

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We sequenced the genomes of 200 individuals from 41 families multiply affected with bipolar disorder (BD) to identify contributions of rare variants to genetic risk. We initially focused on 3,087 candidate genes with known synaptic functions or prior evidence from genomewide association studies. BD pedigrees had an increased burden of rare variants in genes encoding neuronal ion channels, including subunits of GABA A receptors and voltage-gated calcium channels. Four uncommon coding and regulatory variants also showed significant association, including a missense variant in GABRA6. Targeted sequencing of 26 of these candidate genes in an additional 3,014 cases and 1,717 controls confirmed rare variant associations in ANK3, CACNA1B, CACNA1C, CACNA1D, CACNG2, CAMK2A, and NGF. Variants in promoters and 5′ and 3′ UTRs contributed more strongly than coding variants to risk for BD, both in pedigrees and in the case-control cohort. The genes and pathways identified in this study regulate diverse aspects of neuronal excitability. We conclude that rare variants in neuronal excitability genes contribute to risk for BD. by episodes of mania and depression (1). Episodes of mania are marked by elevated or alternatively irritable mood, grandiosity, racing thoughts, rapid speech, diminished need for sleep, and risk-taking behavior. Depression includes sadness, low energy and motivation, decreased ability to experience pleasure, insomnia, and appetite changes. Psychosis with hallucinations and delusions can occur in either state. BD affects 1-2% of the US population, and if untreated, up to 15% of patients die from suicide. Twin and family studies suggest that heritable causes explain 60-80% of lifetime risk for BD (2), with an approximate eightfold relative risk in the siblings of BD probands (3). Several common genetic markers have shown significant and replicable associations in genome-wide association studies (GWASs), including a region near a voltage-gated calcium channel, CACNA1C, and another near a synaptic scaffolding gene, ANK3 (4). Additive effects of common loci detectable on commercially available genomic arrays may be used to predict about 25% of the risk for BD (5), but typically the function and exact location of the causative variants linked to these loci is unknown.Rare variants may explain additional risk for BD. It is possible that one or a few rare variants of large effect dramatically increase disease risk, resulting in an inheritance model resembling monogenic inheritance in a given family. However, four exomesequencing and whole-genome sequencing (WGS) studies of BD pedigrees have detected few, if any, plausible variants of large effect (6-9). An alternative oligogenic model posits that different combinations of several uncommon or rare variants of moderate effect cluster in affected individuals and collectively cause disease.To test the hypothesis that rare variants contribute to risk for BD, we sequenced the genomes of 200 individuals from 41 multiply affected BD pedigrees of European ancestry. We seque...

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Section: Discussionmentioning

confidence: 99%

Rare variants in neuronal excitability genes influence risk for bipolar disorder

Ament

Szelinger

Glusman

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

166

135

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“…Ionic channel gating and vesicle release vary stochastically (Sakmann and Neher 2009;Yang and Xu-Friedman 2013), channel number and synaptic strengths vary (Roffman et al 2012;Schulz et al 2006), neuron properties may vary (Benjamin 1976), motor neuronal output varies (Williams et al 2013), neuromodulation alters responses (Marder 2012), body mechanics alters responses to neural output (Chiel et al 2009), and environmental loads may vary unexpectedly (Johansson and Westling 1988).…”

mentioning

confidence: 99%

Motor neuronal activity varies least among individuals when it matters most for behavior

Cullins

Shaw

Gill

et al. 2015

Journal of Neurophysiology

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How does motor neuronal variability affect behavior? To explore this question, we quantified activity of multiple individual identified motor neurons mediating biting and swallowing in intact, behaving Aplysia californica by recording from the protractor muscle and the three nerves containing the majority of motor neurons controlling the feeding musculature. We measured multiple motor components: duration of the activity of identified motor neurons as well as their relative timing. At the same time, we measured behavioral efficacy: amplitude of grasping movement during biting and amplitude of net inward food movement during swallowing. We observed that the total duration of the behaviors varied: Within animals, biting duration shortened from the first to the second and third bites; between animals, biting and swallowing durations varied. To study other sources of variation, motor components were divided by behavior duration (i.e., normalized). Even after normalization, distributions of motor component durations could distinguish animals as unique individuals. However, the degree to which a motor component varied among individuals depended on the role of that motor component in a behavior. Motor neuronal activity that was essential for the expression of biting or swallowing was similar among animals, whereas motor neuronal activity that was not essential for that behavior varied more from individual to individual. These results suggest that motor neuronal activity that matters most for the expression of a particular behavior may vary least from individual to individual. Shaping individual variability to ensure behavioral efficacy may be a general principle for the operation of motor systems.

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“…Some neuronal networks, for example, can produce rhythmic outputs that are remarkably stable in the face of clear differences in the detailed makeup of the neurons that compose them (Schulz et al 2006, Marder 2011. At the same time, external inputs can change the functioning of both individual neurons and the networks as a whole (Nusbaum and Blitz 2012).…”

Section: Challenge 1: Understanding Living Organisms As Multiscale Symentioning

confidence: 99%

Addressing Grand Challenges In Organismal Biology: The Need For Synthesis

Padilla¹,

Daniel²,

Dickinson³

et al. 2014

BioScience

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Animals are complex systems operating at multiple spatial and temporal scales, facing the challenge of how to change in appropriate ways, degrees, and times, in response to the diverse internal and external influences to which they are exposed. Discovering the system-level attributes of organisms that make them resilient or robust-or sensitive or fragile-to change presents a grand challenge for biology. Knowledge of these attributes and the underlying mechanisms controlling them is crucially needed to predict how organisms will respond to short-and long-term changes in internal and external environments, including those driven by climate change. Organismal biologists require novel approaches that extend beyond traditional disciplinary boundaries, especially when they partner with mathematicians and engineers. Pursuing this research enterprise will not only give us a deeper understanding of how organisms will face future challenges, but it will also reveal nature-inspired solutions in complex engineered systems, both of which will benefit science and society.Keywords: organismal biology, grand challenges, integrative biology, systems engineering, predictive modeling Animals are inherently complex and are composed of multiple interconnected elements. They and their component elements must have the capacity to maintain stability and to simultaneously change in response to internal and external stimuli. For example, young animals must be able to process neurosensory inputs as they move through the environment while their brains and nervous systems continue to develop. As they grow and develop, structures used for locomotion may simultaneously change in their function and control because of changes in size and morphology (Hale 2014). Those same animals must maintain the internal physiological function of all of their systems throughout ontogeny and as they experience shifting internal 1 Dianna K. Padilla (padilla@stonybrook.edu) is a professor in the Department of Ecology and Evolution at Stony Brook University, in Stony Brook, New York. Thomas L. Daniel is a professor, in the Department of Biology, Billie J. Swalla is the director of and a professor in the the Friday Harbor Laboratories and in the Department of Biology, and Daniel Grünbaum is an associate professor in the School of Oceanography at the University of Washington, in Seattle. Patsy Dickinson is a professor in the Department of Biology and in the Neuroscience Program at Bowdoin College, in Brunswick, Maine. Cheryl Hayashi is a professor in the Department of Biology at the University of California, Riverside. Donal T. Manahan is a professor in the Department of Biological Sciences at the University of Southern California, in Los Angeles. James H. Marden is a professor in the Department of Biology at Pennsylvania State University, in State College. Brian Tsukimura is a professor in the Department of Biology at California State University, Fresno. 2 and external environments. In addition, animals and animal systems exhibit many nonlinear and time-dependent ...

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Variable channel expression in identified single and electrically coupled neurons in different animals

Cited by 426 publications

References 41 publications

Rare variants in neuronal excitability genes influence risk for bipolar disorder

Rare variants in neuronal excitability genes influence risk for bipolar disorder

Motor neuronal activity varies least among individuals when it matters most for behavior

Addressing Grand Challenges In Organismal Biology: The Need For Synthesis

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