Temporal correlations in the brain are thought to have very dichotomic roles. On one hand they are ubiquitously present in the healthy brain and are thought to underlie feature binding during information processing. On the other hand large scale synchronization is an underlying mechanism of epileptic seizures. In this paper we show a possible mechanism of transition to pathological coherence underlying seizure generation. We show that properties of phase synchronization in the 2-D lattice of non-identical coupled Hindmarsh-Rose neurons change radically depending on the connectivity structure. We modify the connectivity using the small world network paradigm and measure properties of phase synchronization using previously developed measure based on assessment of the distributions of relative interspike intervals [1]. We show that the phase synchronization undergoes a dramatic change as a function of locality of network connections from local coherence strongly dependent on the distance between two neurons to global coherence exhibiting stronger phase locking and spanning the whole network. Epilepsy is one of the most common neurological disorders, with underlying seizures generated by indiscriminate, synchronized bursting of multiple cells in the brain [2], leading to the increased level of coherence in the recorded signal between individual neurons as well as whole networks [3,4]. There is a wide range of molecular and cellular mechanisms underlying seizure generation; however, they are often linked to increased excitatory transmission mediated by NMDA, AMPA or metabotropic glutamate receptors, and a decrease in inhibitory (GABAergic) transmission, causing an imbalance between excitation and inhibition in the system [5]. One of the mechanisms generating the changes of the excitatory transmission under pathological conditions is axonal sprouting [6,7]. This mechanism involves excessive growth of excitatory processes within an area that was exposed to ischemia or physical trauma, causing (in time) generation of seizures. We hypothesize that hyperexcitability induced by sprouting could be only one of the causes of seizures and show that alteration of network structure through introduction of random long-range connectivity in the network produces relatively abrupt transition in phase coherence in the 2-D small world network (SWN) lattice of non-identical Hindmarsh-Rose models of thalamocortical neurons [8].Emergence of the concept of small-world networks [9] has allowed for rigorous study of the properties of intermediate structured network where the connectivities are neither entirely regular not entirely random. Networks exhibiting such structure have been identified in social as well as biological systems [9,10]. Most studies have concentrated on their static properties [11,12,13]. However, recent work has also focused on the dynamic properties of SWN, including synchronization. It has been shown that the linear stability of the synchronous state is linked to the algebraic condition of the Laplacian matrix defini...

Epileptiform discharges recorded in the 4-aminopyridine (4-AP) in vitro epilepsy model are mediated by glutamatergic and GABAergic signaling. Using a 60-channel perforated multielectrode array (pMEA) on corticohippocampal slices from 2 to 3 week old mice we recorded interictal-and ictal-like events. When glutamatergic transmission was blocked, interictal-like events events no longer initiated in the hilus or CA3/CA1 pyramidal layers but originated from the dentate gyrus granule and molecular layers. Furthermore, frequencies of interictal-like events were reduced and durations were increased in these regions while cortical discharges were completely blocked. Following GABA A receptor blockade interictal-like events no longer propagated to the dentate gyrus while their frequency in CA3 increased; in addition, ictal-like cortical events became shorter while increasing in frequency. Lastly, drugs that affect tonic and synaptic GABAergic conductance modulate the frequency, duration, initiation and propagation of interictal-like events. These findings confirm and expand on previous studies indicating that multiple synaptic mechanisms contribute to synchronize neuronal network activity in forebrain structures.

Matrix metalloproteinases (MMPs) are zinc-dependent endopeptidases that are released from neurons in an activity dependent manner. Published studies suggest their activity is important to varied forms of learning and memory. At least one MMP can stimulate an increase in the size of dendritic spines, structures which represent the post synaptic component for a large number of glutamatergic synapses. This change may be associated with increased synaptic glutamate receptor incorporation, and an increased amplitude and/or frequency of α-amino-3-hydroxyl-5-methyl-4-isoxazole-propionate (AMPA) mini excitatory post-synaptic currents (EPSCs). An associated increase in the probability of action potential occurrence would be expected. 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. CAMs are ideally positioned to be cleaved by synaptically released MMPs, and shed N terminal domains could potentially interact with previously unengaged integrins to stimulate dendritic actin polymerization with spine expansion. In the present study, we have used multielectrode arrays (MEAs) to investigate MMP and soluble CAM dependent changes in neuronal activity recorded from hippocampal cultures. We have focused on intercellular adhesion molecule-5 (ICAM-5) in particular, as this CAM is expressed on glutamatergic dendrites and shed in an MMP dependent manner. We show that chemical long-term potentiation (cLTP) evoked changes in recorded activity, and the dynamics of action potential bursts in particular, are altered by MMP inhibition. A blocking antibody to β1 integrins has a similar effect. We also show that the ectodomain of ICAM-5 can stimulate β1 integrin dependent increases in spike counts and burst number. These results support a growing body of literature suggesting that MMPs have important effects on neuronal excitability. They also support the possibility that MMP dependent shedding of specific synaptic CAMs can contribute to these effects.

Complexity in the temporal organization of neural systems may be a reflection of the diversity of their neural constituents. These constituents, excitatory and inhibitory neurons, comprise a well-defined ratio in vivo and form the substrate for rhythmic oscillatory activity. To begin to elucidate the dynamical implications that underlie this balance, we construct novel neural circuits not ordinarily found in nature and study the resulting temporal patterns. We culture several networks of neurons composed of varying fractions of excitatory and inhibitory cells and use a multi-electrode array to study their temporal dynamics as this balance is modulated. We use the electrode burst as the temporal imprimatur to signify the presence of network activity. Burst durations, inter-burst intervals, and the number of spikes participating within a burst are used to illustrate the vivid differences in the temporal organization between the various cultured networks. When the network consists largely of excitatory neurons, no network temporal structure is apparent. However, the addition of inhibitory neurons evokes a temporal order. Calculation of the temporal autocorrelation shows that when the number of inhibitory neurons is a major fraction of the network, a striking network pattern materializes when none was previously present.