Canalization of genetic and pharmacological perturbations in developing primary neuronal activity patterns. (January 2016)

• Record Type: Journal Article
• Authors: Charlesworth, Paul; Morton, Andrew; Eglen, Stephen J.; Komiyama, Noboru H.; Grant, Seth G.N.
• Is Part Of: Neuropharmacology. Volume 100(2016)
• Page Start: 47
• Page End: 55
• Publication Date: 2016-01
• Subjects: Synapse -- Neuron -- Network -- Mutation -- Canalization; Neuropsychopharmacology -- Periodicals; Autonomic Agents -- Periodicals; Neuropsychopharmacologie -- Périodiques; Neuropsychopharmacology; Periodicals; Electronic journals; 615.78
• DOI: 10.1016/j.neuropharm.2015.07.027
• Languages: English
• ISSNs: 0028-3908

Abstract

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'. Highlights: Development of network activity in cultures with synaptic mutations was recorded. Synchronous burst firing with theta periodicity was observed as cultures matured. Gria1 deletion and chronic NMDA-R blockade disrupted network activity patterns. Dlg2 knockout disrupted network activity, other synaptic genes had minimal effects. Network activity phenotypes early in development were canalized as cultures matured.