Network Burst Activity in Hippocampal Neuronal Cultures: The Role of Synaptic and Intrinsic Currents

The goal of this work is to define the contributions of intrinsic and synaptic mechanisms towards 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 PTX, CNQX and CPP to selectively block GABA_A, AMPA and NMDA receptors and riluzole to selectively block Na_p channels. We systematically compared intracellular activity (recorded using patch-clamp) and network-activity (recorded using multi-electrode arrays), in eight different synaptic-connectivity conditions: GABA_A+NMDA+AMPA, NMDA+AMPA, GABA_A+AMPA, GABA_A+NMDA, AMPA, NMDA, GABA_A, and all receptors blocked. Furthermore, we used mixed-effects modeling to quantify aforementioned independent and interactive synaptic-receptor contributions towards 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 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.

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