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Intrinsic excitability measures track antiepileptic drug action and uncover increasing/decreasing excitability over the wake/sleep cycle.

ABSTRACT: Pathological changes in excitability of cortical tissue commonly underlie the initiation and spread of seizure activity in patients suffering from epilepsy. Accordingly, monitoring excitability and controlling its degree using antiepileptic drugs (AEDs) is of prime importance for clinical care and treatment. To date, adequate measures of excitability and action of AEDs have been difficult to identify. Recent insights into ongoing cortical activity have identified global levels of phase synchronization as measures that characterize normal levels of excitability and quantify any deviation therefrom. Here, we explore the usefulness of these intrinsic measures to quantify cortical excitability in humans. First, we observe a correlation of such markers with stimulation-evoked responses suggesting them to be viable excitability measures based on ongoing activity. Second, we report a significant covariation with the level of AED load and a wake-dependent modulation. Our results indicate that excitability in epileptic networks is effectively reduced by AEDs and suggest the proposed markers as useful candidates to quantify excitability in routine clinical conditions overcoming the limitations of electrical or magnetic stimulation. The wake-dependent time course of these metrics suggests a homeostatic role of sleep, to rebalance cortical excitability.

SUBMITTER: Meisel C

PROVIDER: S-EPMC4664307 | biostudies-other | 2015 Nov

REPOSITORIES: biostudies-other

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Sleep interacts with a? to modulate intrinsic neuronal excitability.

Project description:Emerging data suggest an important relationship between sleep and Alzheimer's disease (AD), but how poor sleep promotes the development of AD remains unclear.Here, using a Drosophila model of AD, we provide evidence suggesting that changes in neuronal excitability underlie the effects of sleep loss on AD pathogenesis. ?-amyloid (A?) accumulation leads to reduced and fragmented sleep, while chronic sleep deprivation increases A? burden. Moreover, enhancing sleep reduces A? deposition. Increasing neuronal excitability phenocopies the effects of reducing sleep on A?, and decreasing neuronal activity blocks the elevated A? accumulation induced by sleep deprivation. At the single neuron level, we find that chronic sleep deprivation, as well as A? expression, enhances intrinsic neuronal excitability. Importantly, these data reveal that sleep loss exacerbates A?-induced hyperexcitability and suggest that defects in specific K(+) currents underlie the hyperexcitability caused by sleep loss and A? expression. Finally, we show that feeding levetiracetam, an anti-epileptic medication, to A?-expressing flies suppresses neuronal excitability and significantly prolongs their lifespan.Our findings directly link sleep loss to changes in neuronal excitability and A? accumulation and further suggest that neuronal hyperexcitability is an important mediator of A? toxicity. Taken together, these data provide a mechanistic framework for a positive feedback loop, whereby sleep loss and neuronal excitation accelerate the accumulation of A?, a key pathogenic step in the development of AD.

| S-EPMC4366315 | biostudies-literature

Clinical Practice Guideline for the Treatment of Intrinsic Circadian Rhythm Sleep-Wake Disorders: Advanced Sleep-Wake Phase Disorder (ASWPD), Delayed Sleep-Wake Phase Disorder (DSWPD), Non-24-Hour Sleep-Wake Rhythm Disorder (N24SWD), and Irregular Sleep-Wake Rhythm Disorder (ISWRD). An Update for 2015: An American Academy of Sleep Medicine Clinical Practice Guideline.

Project description:A systematic literature review and meta-analyses (where appropriate) were performed and the GRADE approach was used to update the previous American Academy of Sleep Medicine Practice Parameters on the treatment of intrinsic circadian rhythm sleep-wake disorders. Available data allowed for positive endorsement (at a second-tier degree of confidence) of strategically timed melatonin (for the treatment of DSWPD, blind adults with N24SWD, and children/ adolescents with ISWRD and comorbid neurological disorders), and light therapy with or without accompanying behavioral interventions (adults with ASWPD, children/adolescents with DSWPD, and elderly with dementia). Recommendations against the use of melatonin and discrete sleep-promoting medications are provided for demented elderly patients, at a second- and first-tier degree of confidence, respectively. No recommendations were provided for remaining treatments/ populations, due to either insufficient or absent data. Areas where further research is needed are discussed.

| S-EPMC4582061 | biostudies-literature

Conventional measures of intrinsic excitability are poor estimators of neuronal activity under realistic synaptic inputs.

Project description:Activity-dependent regulation of intrinsic excitability has been shown to greatly contribute to the overall plasticity of neuronal circuits. Such neuroadaptations are commonly investigated in patch clamp experiments using current step stimulation and the resulting input-output functions are analyzed to quantify alterations in intrinsic excitability. However, it is rarely addressed, how such changes translate to the function of neurons when they operate under natural synaptic inputs. Still, it is reasonable to expect that a strong correlation and near proportional relationship exist between static firing responses and those evoked by synaptic drive. We challenge this view by performing a high-yield electrophysiological analysis of cultured mouse hippocampal neurons using both standard protocols and simulated synaptic inputs via dynamic clamp. We find that under these conditions the neurons exhibit vastly different firing responses with surprisingly weak correlation between static and dynamic firing intensities. These contrasting responses are regulated by two intrinsic K-currents mediated by Kv1 and Kir channels, respectively. Pharmacological manipulation of the K-currents produces differential regulation of the firing output of neurons. Static firing responses are greatly increased in stuttering type neurons under blocking their Kv1 channels, while the synaptic responses of the same neurons are less affected. Pharmacological blocking of Kir-channels in delayed firing type neurons, on the other hand, exhibit the opposite effects. Our subsequent computational model simulations confirm the findings in the electrophysiological experiments and also show that adaptive changes in the kinetic properties of such currents can even produce paradoxical regulation of the firing output.

| S-EPMC8478185 | biostudies-literature

Measures of Sleep-Wake Patterns and Risk of Mild Cognitive Impairment or Dementia in Older Women.

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| S-EPMC4807599 | biostudies-literature

Sleep-wake cycles drive daily dynamics of synaptic phosphorylation

Project description:The circadian clock drives daily changes of physiology, including sleep-wake cycles, by regulating transcription, protein abundance and function. Circadian phosphorylation controls cellular processes in peripheral organs, but little is known about its role in brain function and synaptic activity. We applied advanced quantitative phosphoproteomics to mouse forebrain synaptoneurosomes isolated across 24h, accurately quantifying almost 8,000 phosphopeptides. Remarkably, half of the synaptic phosphoproteins, including numerous kinases, had large-amplitude rhythms peaking at rest-activity and activity-rest transitions. Bioinformatic analyses revealed global temporal control of synaptic function via phosphorylation, including synaptic transmission, cytoskeleton reorganization and excitatory/inhibitory balance. Remarkably, sleep deprivation abolished 98% of all phosphorylation cycles in synaptoneurosomes, indicating that sleep-wake cycles rather than circadian signals are main drivers of synaptic phosphorylation, responding to both sleep and wake pressures.

2019-10-14 | PXD010697 | Pride

REM sleep reorganizes hippocampal excitability.

Project description:Sleep is composed of an alternating sequence of REM and non-REM episodes, but their respective roles are not known. We found that the overall firing rates of hippocampal CA1 neurons decreased across sleep concurrent with an increase in the recruitment of neuronal spiking to brief "ripple" episodes, resulting in a net increase in neural synchrony. Unexpectedly, within non-REM episodes, overall firing rates gradually increased together with a decrease in the recruitment of spiking to ripples. The rate increase within non-REM episodes was counteracted by a larger and more rapid decrease of discharge frequency within the interleaved REM episodes. Both the decrease in firing rates and the increase in synchrony during the course of sleep were correlated with the power of theta activity during REM episodes. These findings assign a prominent role of REM sleep in sleep-related neuronal plasticity.

| S-EPMC3608095 | biostudies-literature

Dietary modulation of Drosophila sleep-wake behaviour.

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| S-EPMC2919389 | biostudies-literature

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| S-EPMC3465396 | biostudies-other

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