title: Mesoscale Architecture Shapes Initiation and Richness of Spontaneous Network Activity.
abstract: Spontaneous activity in the absence of external input, including propagating waves of activity, is a robust feature of neuronal networksin vivoandin vitroThe neurophysiological and anatomical requirements for initiation and persistence of such activity, however, are poorly understood, as is their role in the function of neuronal networks. Computational network studies indicate that clustered connectivity may foster the generation, maintenance, and richness of spontaneous activity. Since this mesoscale architecture cannot be systematically modified in intact tissue, testing these predictions is impracticablein vivoHere, we investigate how the mesoscale structure shapes spontaneous activity in generic networks of rat cortical neuronsin vitroIn these networks, neurons spontaneously arrange into local clusters with high neurite density and form fasciculating long-range axons. We modified this structure by modulation of protein kinase C, an enzyme regulating neurite growth and cell migration. Inhibition of protein kinase C reduced neuronal aggregation and fasciculation of axons, i.e., promoted uniform architecture. Conversely, activation of protein kinase C promoted aggregation of neurons into clusters, local connectivity, and bundling of long-range axons. Supporting predictions from theory, clustered networks were more spontaneously active and generated diverse activity patterns. Neurons within clusters received stronger synaptic inputs and displayed increased membrane potential fluctuations. Intensified clustering promoted the initiation of synchronous bursting events but entailed incomplete network recruitment. Moderately clustered networks appear optimal for initiation and propagation of diverse patterns of activity. Our findings support a crucial role of the mesoscale architectures in the regulation of spontaneous activity dynamics.SIGNIFICANCE STATEMENTComputational studies predict richer and persisting spatiotemporal patterns of spontaneous activity in neuronal networks with neuron clustering. To test this, we created networks of varying architecturein vitroSupporting these predictions, the generation and spatiotemporal patterns of propagation were most variable in networks with intermediate clustering and lowest in uniform networks. Grid-like clustering, on the other hand, facilitated spontaneous activity but led to degenerating patterns of propagation. Neurons outside clusters had weaker synaptic input than neurons within clusters, in which increased membrane potential fluctuations facilitated the initiation of synchronized spike activity. Our results thus show that the intermediate level organization of neuronal networks strongly influences the dynamics of their activity.
authors.affiliation: Bernstein Center Freiburg and okujeni@bcf.uni-freiburg.de.|Biomicrotechnology, IMTEK-Department of Microsystems Engineering, University of Freiburg, 79110 Freiburg, Germany.
authors.forename: Samora
authors.identifier: 0000-0001-7924-3651
authors.initials: S
authors.lastname: Okujeni
authors.affiliation: Bernstein Center Freiburg and.|Biomicrotechnology, IMTEK-Department of Microsystems Engineering, University of Freiburg, 79110 Freiburg, Germany.
authors.forename: Steffen
authors.initials: S
authors.lastname: Kandler
authors.affiliation: Bernstein Center Freiburg and.|Biomicrotechnology, IMTEK-Department of Microsystems Engineering, University of Freiburg, 79110 Freiburg, Germany.
authors.forename: Ulrich
authors.identifier: 0000-0002-4583-0425
authors.initials: U
authors.lastname: Egert
mesh_terms: D000200:Action Potentials / Q000502:physiology*; D000818:Animals; D002478:Cells, Cultured; D005260:Female; D008297:Male; D009415:Nerve Net / Q000166:cytology* / Q000502:physiology*; D009474:Neurons / Q000502:physiology*; D011493:Protein Kinase C / Q000502:physiology; D051381:Rats; D017208:Rats, Wistar; D009435:Synaptic Transmission / Q000502:physiology
chemical_list: D011493:Protein Kinase C
keywords: clustering; network structure; neuronal networks; protein kinase C; spatiotemporal pattern; spontaneous activity