title: Canalization of genetic and pharmacological perturbations in developing primary neuronal activity patterns.
abstract: The function of the nervous system depends on the integrity of synapses and the patterning of electrical activity in brain circuits. The rapid advances in genome sequencing reveal a large number of mutations disrupting synaptic proteins, which potentially result in diseases known as synaptopathies. However, it is also evident that every normal individual carries hundreds of potentially damaging mutations. Although genetic studies in several organisms show that mutations can be masked during development by a process known as canalization, it is unknown if this occurs in the development of the electrical activity in the brain. Using longitudinal recordings of primary cultured neurons on multi-electrode arrays from mice carrying knockout mutations we report evidence of canalization in development of spontaneous activity patterns. Phenotypes in the activity patterns in young cultures from mice lacking the Gria1 subunit of the AMPA receptor were ameliorated as cultures matured. Similarly, the effects of chronic pharmacological NMDA receptor blockade diminished as cultures matured. Moreover, disturbances in activity patterns by simultaneous disruption of Gria1 and NMDA receptors were also canalized by three weeks in culture. Additional mutations and genetic variations also appeared to be canalized to varying degrees. These findings indicate that neuronal network canalization is a form of nervous system plasticity that provides resilience to developmental disruption. This article is part of the Special Issue entitled 'Synaptopathy--from Biology to Therapy'.
authors.affiliation: Genes to Cognition Programme, Wellcome Trust Sanger Institute, Genome Campus, Hinxton, Cambridgeshire, CB10 1SA, UK. Electronic address: pc451@cam.ac.uk.
authors.forename: Paul
authors.initials: P
authors.lastname: Charlesworth
authors.affiliation: Genes to Cognition Programme, Wellcome Trust Sanger Institute, Genome Campus, Hinxton, Cambridgeshire, CB10 1SA, UK. Electronic address: am380@st-andrews.ac.uk.
authors.forename: Andrew
authors.initials: A
authors.lastname: Morton
authors.affiliation: Cambridge Computational Biology Institute, Department of Applied Mathematics and Theoretical Physics, University of Cambridge, Cambridge, CB3 0WA, UK. Electronic address: s.j.eglen@damtp.cam.ac.uk.
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Eglen
authors.affiliation: Genes to Cognition Programme, Wellcome Trust Sanger Institute, Genome Campus, Hinxton, Cambridgeshire, CB10 1SA, UK. Electronic address: nkomiya2@staffmail.ed.ac.uk.
authors.forename: Noboru H
authors.initials: NH
authors.lastname: Komiyama
authors.affiliation: Genes to Cognition Programme, Wellcome Trust Sanger Institute, Genome Campus, Hinxton, Cambridgeshire, CB10 1SA, UK. Electronic address: seth.grant@ed.ac.uk.
authors.forename: Seth G N
authors.initials: SG
authors.lastname: Grant
mesh_terms: D000200:Action Potentials; D000818:Animals; D002478:Cells, Cultured; D051528:Guanylate Kinases / Q000235:genetics; D006624:Hippocampus / Q000196:embryology* / Q000502:physiology*; D008565:Membrane Proteins / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009473:Neuronal Plasticity; D009474:Neurons / Q000502:physiology*; D018091:Receptors, AMPA / Q000235:genetics; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors / Q000502:physiology; D013569:Synapses / Q000235:genetics / Q000502:physiology*; D014633:Valine / Q000031:analogs & derivatives / Q000494:pharmacology
chemical_list: D051528:Guanylate Kinases; D008565:Membrane Proteins; D018091:Receptors, AMPA; D016194:Receptors, N-Methyl-D-Aspartate; D014633:Valine; C056639:2-amino-5-phosphopentanoic acid; C501445:Dlg2 protein, mouse
keywords: Canalization; Mutation; Network; Neuron; Synapse