The development of bursting networks following chemical long term potentiation
Niedringhaus, Mark Stephen
Collective rhythmic dynamics from neurons are vital for cognitive functions but how neurons self-organize to produce such activity is not well understood. Attractor-based computational models are a theoretical framework for memory storage in networks of neurons. Additionally, activity-dependent modification of synaptic transmission is thought to be the physiological basis of learning and memory referred to as long term potentiation (LTP). The goal of this study is to demonstrate that using a pharmacological treatment, which has been shown to increase synaptic strength, on in vitro networks of hippocampal neurons, follows the dynamical postulates theorized by attractor models. I use a grid of extracellular electrodes to study changes in network activity during this perturbation (induction phase of LTP) and then monitor the evolving network activity following the removal of the treatment (maintenance phase of LTP). Following a chemically-induced LTP (cLTP) there was an initial increase in activity. Phase plots indicated a conserved activity pattern suggesting that the network was initially operating in a stable dynamical state. This attractor state was not preserved during later time points, with an induction of superbursting and an incidence of theta frequency activity. Finally, activity 5 days post-treatment suggested a homeostatic mechanism to prevent runaway excitation.Next I hypothesized that matrix metalloproteinases (MMPs), zinc-dependent endopeptidases that are released from neurons in an activity dependent manner, drive these changes in the attractor state. These changes may be associated with increased synaptic glutamate receptor incorporation, and an increased amplitude and/or frequency of alpha-amino-3-hydroxyl-5-methyl-4-isoxazole-propionate (AMPA) mini excitatory post-synaptic currents (EPSCs). While the mechanism(s) by which MMPs may influence synaptic structure and function are not completely understood, MMP dependent shedding of specific cell adhesion molecules (CAMs) could play an important role. In this study, cLTP evoked changes in activity and spatiotemporal dynamics were altered by MMP inhibition. These changes were also dependent on beta1 integrin. I also showed that the ectodomain of ICAM-5 can stimulate beta1 integrin dependent increases in spike counts and burst number. These results support the possibility that MMP dependent shedding of specific synaptic CAMs can contribute to these effects.
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