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Tuning of excitability and synaptic efficacy switches among physiological and epileptic dynamics
Attila I. Gulyás, Rita Karlócai, Zsolt Kohus, Dániel Schlingloff, Tamás F. Freund, Norbert Hájos, Szabolcs Káli
Institute of Experimental Medicine, Hungarian Academy of Sciences, H-1083, Budapest, Hungary

Brain states are characterized by behaviour-associated coordinated alternation of distinct EEG patterns in different cortical regions and are assumed to be the manifestation of distinct modes of cortical information processing, controlled by subcortical modulatory inputs. Various physiological cortical network states, such as the up and down states of the slow cortical oscillation, cortical and hippocampal theta phase-modulated gamma oscillations and hippocampal irregular activity with associated sharp wave-ripples, are characterized by recurring low and high activity phases. Different forms of epileptic activities can be considered similar transitions among low and pathologically high activity phases. This suggests that the generation of recurring transient high activity events (THAEs) is an inherent and general property of healthy and pathological cortical networks.

The questions are: How are these different activity patterns generated? And whether they can be fitted into a common framework. In particular, how can the same network switch between distinct types of dynamics and what are the generating mechanisms?

To address this issue, we investigated the network dynamics generated intrinsically in the CA3 region of thick (450-600um) mouse hippocampal slices. The CA3 network generates irregularly recurring sharp wave-ripples (SWRs) in its default state, and using pharmacological agents its activity can be quickly and reversibly switched either into pathological epileptic activity or to gamma oscillation (as a result of cholinergic receptor activation). SWRs are initiated in a stochastic way in the recurrent excitatory pyramidal cell network. This tonic excitation start to drive the reciprocally connected inhibitory network of parvalbumin-positive basket cells to fire at ripple frequency (~160-180Hz) and phase lock pyramidal cell firing. In the epileptic state excitatory transmission and cellular excitability is enhanced, while inhibiton is compromised at several points. The stochastically initiated excitatory buildup will not be controlled by inhibition. The excess excitation drives parvalbumin-positive basket cells into depolarization block and at this point pyramidal cells will start a pseudo-synchronous burst firing, that is manifested as pathological high-frequency oscillation. The SWR to gamma transition is also the consequence of concurrent changes in cellular excitability (increased) and in the efficacy of synaptic interactions (both excitation and inhibition decreased).

We propose that the cellular and network parameter changes modify the initiation and propagation of THAEs in the network. The distinct dynamics possibly implement different modes of information processing and can explain the genesis of pathological events. A sharp wave-ripple can be considered as archetypical THAE and epileptic events are pathological, degenerate forms of a THAE.

Support: OTKA K83251, 77793 NNF 85659, 78917, 81357, ERC, ERC-2011-ADG-294313 (SERRACO)