AK, Marks JD, van Drongelen W. Network burst activity in hippocampal neuronal cultures: the role of synaptic and intrinsic currents. J Neurophysiol 115: 3073-3089, 2016. First published March 16, 2016 doi:10.1152/jn.00995.2015.-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 shorttimescale synaptic processes modulate spectro-temporal intraburst properties and network-wide burst propagation, much longer timescales of intrinsic membrane properties such as persistent sodium (Na p ) 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 GABA A , AMPA, and NMDA receptors and riluzole to selectively block Na p channels. We systematically compared intracellular activity (recorded with patch clamp) and network activity (recorded with multielectrode arrays) in eight different synaptic connectivity conditions: GABA A ϩ NMDA ϩ AMPA, NMDA ϩ AMPA, GABA A ϩ AMPA, GABA A ϩ NMDA, AMPA, NMDA, GABA A , 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 Na p 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. epilepsy; multielectrode arrays; network bursting; pharmacology; synaptic mechanisms SPONTANEOUS NETWORK-WIDE SYNCHRONIZED bursting activity appears to play an important role in several aspects of the nervous system including development (Gu and Spitzer 1995;Meister et al. 1991;Shatz 1990;Yuste et al. 1992) and integration in the sensory system (Engel et al. 1992) but also in the initiation of pathological activity such as epileptic seizures (Gutnick et al. 1982;Miles and Wong 1983). Therefore, clarifying how the underlying synaptic and intrinsic neuronal properties modulate and cause this network behavior is likely to provide valuable under...

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