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Vulnerability to paroxysmal oscillations in delayed neural networks: a basis for nocturnal frontal lobe epilepsy?

ABSTRACT: Resonance can occur in bistable dynamical systems due to the interplay between noise and delay (τ) in the absence of a periodic input. We investigate resonance in a two-neuron model with mutual time-delayed inhibitory feedback. For appropriate choices of the parameters and inputs three fixed-point attractors co-exist: two are stable and one is unstable. In the absence of noise, delay-induced transient oscillations (referred to herein as DITOs) arise whenever the initial function is tuned sufficiently close to the unstable fixed-point. In the presence of noisy perturbations, DITOs arise spontaneously. Since the correlation time for the stationary dynamics is ∼τ, we approximated a higher order Markov process by a three-state Markov chain model by rescaling time as t → 2sτ, identifying the states based on whether the sub-intervals were completely confined to one basin of attraction (the two stable attractors) or straddled the separatrix, and then determining the transition probability matrix empirically. The resultant Markov chain model captured the switching behaviors including the statistical properties of the DITOs. Our observations indicate that time-delayed and noisy bistable dynamical systems are prone to generate DITOs as switches between the two attractors occur. Bistable systems arise transiently in situations when one attractor is gradually replaced by another. This may explain, for example, why seizures in certain epileptic syndromes tend to occur as sleep stages change.

SUBMITTER: Quan A

PROVIDER: S-EPMC3258285 | biostudies-other | 2011 Dec

REPOSITORIES: biostudies-other

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Project description:Previously characterized nicotinic acetylcholine receptor (nAChR) autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE)-associated mutations are found in α2, α4 and β2 subunit transmembrane (TM) domains. They predominantly increase ACh potency and, for β2-subunit mutants, increase macroscopic currents. Two recently-identified mutations, α4(R336H) and β2(V337G), located in the intracellular cytoplasmic loop (C2) have been associated with non-familial NFLE. Effects of these mutations on α4β2-nAChR function and expression were studied for the first time, using two-electrode voltage clamp recordings in Xenopus laevis oocytes. Biased-ratio preparations elucidated the mutations' effects at alternate isoforms: high-sensitivity [HS; (α4)2(β2)3] or low-sensitivity [LS; (α4)3(β2)2] via 1:10 or 30:1 [α4:β2] cRNA injection ratios, respectively. An unbiased (1:1 [α4:β2] cRNA) injection ratio was also used to study potential shifts in isoform expression. α4(R336H)-containing receptors showed significant increases in maximal ACh-induced currents (Imax) in all preparations (140% increase compared to wild type control). β2(V337G)-containing receptors significantly increased Imax in the LS-favoring preparation (20% increase compared to control). Expression of either mutation consistently produced enrichment of HS-isoform expression in all preparations. α4β2-nAChR harboring either NFLE mutant subunit showed unchanged ACh, sazetidine-A, nicotine, cytisine and mecamylamine potency. However, both mutant subunits enhanced partial agonist efficacies in the LS-biased preparation. Using β2-subunit-specific [(125)I]mAb 295 immunolabeling, nAChR cell-surface expression was determined. Antibody binding studies revealed that the β2(V337G) mutation tended to reduce cell-surface expression, and function per receptor was significantly increased by either NFLE mutant subunit in HS-favoring preparations. These findings identify both common and differing features between TM- and C2-domain AD/NFLE-associated mutations. As we discuss, the shared features may be particularly salient to AD/NFLE etiology.

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Vulnerability to paroxysmal oscillations in delayed neural networks: a basis for nocturnal frontal lobe epilepsy?

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