title: Network burst activity in hippocampal neuronal cultures: the role of synaptic and intrinsic currents.
abstract: The goal of this work was to define the contributions of intrinsic and synaptic mechanisms toward spontaneous network-wide bursting activity, observed in dissociated rat hippocampal cell cultures. This network behavior is typically characterized by short-duration bursts, separated by order of magnitude longer interburst intervals. We hypothesize that while short-timescale synaptic processes modulate spectro-temporal intraburst properties and network-wide burst propagation, much longer timescales of intrinsic membrane properties such as persistent sodium (Nap) currents govern burst onset during interburst intervals. To test this, we used synaptic receptor antagonists picrotoxin, 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX), and 3-(2-carboxypiperazine-4-yl)propyl-1-phosphonate (CPP) to selectively block GABAA, AMPA, and NMDA receptors and riluzole to selectively block Nap channels. We systematically compared intracellular activity (recorded with patch clamp) and network activity (recorded with multielectrode arrays) in eight different synaptic connectivity conditions: GABAA + NMDA + AMPA, NMDA + AMPA, GABAA + AMPA, GABAA + NMDA, AMPA, NMDA, GABAA, and all receptors blocked. Furthermore, we used mixed-effects modeling to quantify the aforementioned independent and interactive synaptic receptor contributions toward spectro-temporal burst properties including intraburst spike rate, burst activity index, burst duration, power in the local field potential, network connectivity, and transmission delays. We found that blocking intrinsic Nap currents completely abolished bursting activity, demonstrating their critical role in burst onset within the network. On the other hand, blocking different combinations of synaptic receptors revealed that spectro-temporal burst properties are uniquely associated with synaptic functionality and that excitatory connectivity is necessary for the presence of network-wide bursting. In addition to confirming the critical contribution of direct excitatory effects, mixed-effects modeling also revealed distinct combined (nonlinear) contributions of excitatory and inhibitory synaptic activity to network bursting properties.
authors.affiliation: Department of Pediatrics, The University of Chicago, Chicago, Illinois; Committee on Computational Neuroscience, The University of Chicago, Chicago, Illinois; jyothsna@uchicago.edu.
authors.forename: Jyothsna
authors.identifier: 0000-0002-4715-8994
authors.initials: J
authors.lastname: Suresh
authors.affiliation: Department of Pediatrics, The University of Chicago, Chicago, Illinois;
authors.forename: Mihailo
authors.initials: M
authors.lastname: Radojicic
authors.affiliation: Department of Pediatrics, The University of Chicago, Chicago, Illinois; The Computation Institute, The University of Chicago, Chicago, Illinois; and.
authors.forename: Lorenzo L
authors.initials: LL
authors.lastname: Pesce
authors.affiliation: Department of Pediatrics, The University of Chicago, Chicago, Illinois;
authors.forename: Anita
authors.initials: A
authors.lastname: Bhansali
authors.affiliation: Department of Pediatrics, The University of Chicago, Chicago, Illinois;
authors.forename: Janice
authors.initials: J
authors.lastname: Wang
authors.affiliation: Department of Pediatrics, The University of Chicago, Chicago, Illinois;
authors.forename: Andrew K
authors.initials: AK
authors.lastname: Tryba
authors.affiliation: Department of Pediatrics, The University of Chicago, Chicago, Illinois; Committee on Neurobiology, The University of Chicago, Chicago, Illinois.
authors.forename: Jeremy D
authors.initials: JD
authors.lastname: Marks
authors.affiliation: Department of Pediatrics, The University of Chicago, Chicago, Illinois; Committee on Computational Neuroscience, The University of Chicago, Chicago, Illinois; The Computation Institute, The University of Chicago, Chicago, Illinois; and Committee on Neurobiology, The University of Chicago, Chicago, Illinois.
authors.forename: Wim
authors.initials: W
authors.lastname: van Drongelen
mesh_terms: D000200:Action Potentials / Q000187:drug effects / Q000502:physiology*; D000818:Animals; D001703:Biophysics; D002478:Cells, Cultured; D004338:Drug Combinations; D004558:Electric Stimulation; D004622:Embryo, Mammalian; D006624:Hippocampus / Q000166:cytology*; D008959:Models, Neurological; D009415:Nerve Net / Q000187:drug effects / Q000502:physiology*; D009474:Neurons / Q000187:drug effects / Q000502:physiology*; D018377:Neurotransmitter Agents / Q000494:pharmacology; D018408:Patch-Clamp Techniques; D051381:Rats; D017207:Rats, Sprague-Dawley; D013057:Spectrum Analysis
chemical_list: D004338:Drug Combinations; D018377:Neurotransmitter Agents
keywords: epilepsy; multielectrode arrays; network bursting; pharmacology; synaptic mechanisms