Francois David - Academia.edu (original) (raw)

Papers by Francois David

Regulators of chromatin dynamics and transcription are increasingly implicated in the aetiology o... more Regulators of chromatin dynamics and transcription are increasingly implicated in the aetiology of neurodevelopmental disorders (NDDs). Haploinsufficiency of EHMT1, encoding a histone methyl-transferase, is associated with several NDDs, including Kleefstra syndrome, developmental delay and autism spectrum disorder. Using a mouse model of Ehmt1 haploinsufficiency (Ehmt1D6Cre/+), we examined a number of brain and behavioural endophenotypes of relevance to NDDs. Specifically, we show that Ehmt1D6Cre/+ mice have deficits in information processing, evidenced by abnormal sensory-motor gating, a complete absence of object recognition memory and a reduced magnitude of auditory evoked potentials in both paired-pulse inhibition and mismatch negativity (MMN). The electrophysiological experiments show that differences in magnitude response to auditory stimulus were associated with marked reductions in total and evoked beta- and gamma-band oscillatory activity, as well as significant reductions ...

It is an uninformative truism to state that the brain operates at multiple spatial and temporal s... more It is an uninformative truism to state that the brain operates at multiple spatial and temporal scales, each with each own set of emergent phenomena. More worthy of attention is the point that our current understanding of it cannot clearly indicate which of these phenomenological scales are the significant contributors to the brain’s function and primary output (i.e. behaviour). Apart from the sheer complexity of the problem, a major contributing factor to this state of affairs is the lack of instrumentation that can simultaneously address these multiple scales without causing function altering damages to the underlying tissue. One important facet of this problem is that standard neural recording devices normally require one output connection per electrode. This limits the number of electrodes that can fit along the thin shafts of implantable probes generating a limiting balance between density and spread. Sharing a single output connection between multiple electrodes relaxes this c...

The Journal of neuroscience : the official journal of the Society for Neuroscience, Jan 20, 2018

Hyperpolarization-activated cyclic nucleotide-gated (HCN) Hyperpolarization-activated cyclic nucl... more Hyperpolarization-activated cyclic nucleotide-gated (HCN) Hyperpolarization-activated cyclic nucleotide-gated (HCN) channels play critical roles in the fine tuning of cellular and network excitability and have been suggested to be a key element of the pathophysiological mechanism underlying absence seizures. However, the precise contribution of HCN channels in neocortical and thalamic neuronal populations to these non-convulsive seizures is still controversial. In the present study, pharmacological block and genetic suppression of HCN channels in thalamocortical neurons in the ventrobasal thalamic nucleus leads to a marked reduction of absence seizures in one pharmacological and two genetic rodent models of absence seizures. These results provide the first evidence that block of TC neuron HCN channels prevents ASs.

Nature reviews. Neuroscience, 2018

During inattentive wakefulness and non-rapid eye movement (NREM) sleep, the neocortex and thalamu... more During inattentive wakefulness and non-rapid eye movement (NREM) sleep, the neocortex and thalamus cooperatively engage in rhythmic activities that are exquisitely reflected in the electroencephalogram as distinctive rhythms spanning a range of frequencies from <1 Hz slow waves to 13 Hz alpha waves. In the thalamus, these diverse activities emerge through the interaction of cell-intrinsic mechanisms and local and long-range synaptic inputs. One crucial feature, however, unifies thalamic oscillations of different frequencies: repetitive burst firing driven by voltage-dependent Caspikes. Recent evidence reveals that thalamic Caspikes are inextricably linked to global somatodendritic Catransients and are essential for several forms of thalamic plasticity. Thus, we propose herein that alongside their rhythm-regulation function, thalamic oscillations of low-vigilance states have a plasticity function that, through modifications of synaptic strength and cellular excitability in local n...

Biomedical microdevices, 2017

This article reports on the development, i.e., the design, fabrication, and validation of an impl... more This article reports on the development, i.e., the design, fabrication, and validation of an implantable optical neural probes designed for in vivo experiments relying on optogenetics. The probes comprise an array of ten bare light-emitting diode (LED) chips emitting at a wavelength of 460 nm and integrated along a flexible polyimide-based substrate stiffened using a micromachined ladder-like silicon structure. The resulting mechanical stiffness of the slender, 250-μm-wide, 65-μm-thick, and 5- and 8-mm-long probe shank facilitates its implantation into neural tissue. The LEDs are encapsulated by a fluropolymer coating protecting the implant against the physiological conditions in the brain. The electrical interface to the external control unit is provided by 10-μm-thick, highly flexible polyimide cables making the probes suitable for both acute and chronic in vivo experiments. Optical and electrical properties of the probes are reported, as well as their in vivo validation in acute ...

Neuropharmacology, Sep 13, 2016

Absence seizures (ASs) are the hallmark of childhood/juvenile absence epilepsy. Monotherapy with ... more Absence seizures (ASs) are the hallmark of childhood/juvenile absence epilepsy. Monotherapy with first-line anti-absence drugs only controls ASs in 50% of patients, indicating the need for novel therapeutic targets. Since serotonin family-2 receptors (5-HT2Rs) are known to modulate neuronal activity in the cortico-thalamo-cortical loop, the main network involved in AS generation, we investigated the effect of selective 5-HT2AR and 5-HT2CR ligands on ASs in the Genetic Absence Epilepsy Rats from Strasbourg (GAERS), a well established polygenic rat model of these non-convulsive seizures. GAERS rats were implanted with fronto-parietal EEG electrodes under general anesthesia, and their ASs were later recorded under freely moving conditions before and after intraperitoneal administration of various 5-HT2AR and 5-HT2CR ligands. The 5-HT2A agonist TCB-2 dose-dependently decreased the total time spent in ASs, an effect that was blocked by the selective 5-HT2A antagonist MDL11,939. Both MDL1...

Frontiers in neural circuits, 2016

During non-REM sleep the EEG shows characteristics waves that are generated by the dynamic intera... more During non-REM sleep the EEG shows characteristics waves that are generated by the dynamic interactions between cortical and thalamic oscillators. In thalamic neurons, low-threshold T-type Ca(2+) channels play a pivotal role in almost every type of neuronal oscillations, including slow (< 1 Hz) waves, sleep spindles and delta waves. The transient opening of T channels gives rise to the low threshold spikes (LTSs), and associated high frequency bursts of action potentials, that are characteristically present during sleep spindles and delta waves, whereas the persistent opening of a small fraction of T channels, (i.e., ITwindow) is responsible for the membrane potential bistability underlying sleep slow oscillations. Surprisingly thalamocortical (TC) neurons express a very high density of T channels that largely exceed the amount required to generate LTSs and therefore, to support certain, if not all, sleep oscillations. Here, to clarify the relationship between T current density a...

Local field potential (LFP) oscillations are often accompanied by synchronization of activity wit... more Local field potential (LFP) oscillations are often accompanied by synchronization of activity within a widespread cerebral area. Thus, the LFP and neuronal coherence appear to be the result of a common mechanism that underlies neuronal assembly formation. We used the olfactory bulb as a model to investigate: (1) the extent to which unitary dynamics and LFP oscillations can be correlated and (2) the precision with which a model of the hypothesized underlying mechanisms can accurately explain the experimental data. For this purpose, we analyzed simultaneous recordings of mitral cell (MC) activity and LFPs in anesthetized and freely breathing rats in response to odorant stimulation. Spike trains were found to be phaselocked to the gamma oscillation at specific firing rates and to form odor-specific temporal patterns. The use of a conductance-based MC model driven by an approximately balanced excitatory-inhibitory input conductance and a relatively small inhibitory conductance that oscillated at the gamma frequency allowed us to provide one explanation of the experimental data via a mode-locking mechanism. This work sheds light on the way network and intrinsic MC properties participate in the locking of MCs to the gamma oscillation in a realistic physiological context and may result in a particular time-locked assembly. Finally, we discuss how a self-synchronization process with such entrainment properties can explain, under experimental conditions: (1) why the gamma bursts emerge transiently with a maximal amplitude position relative to the stimulus time course; (2) why the oscillations are prominent at a specific gamma frequency; and (3) why the oscillation amplitude depends on specific stimulus properties. We also discuss information processing and functional consequences derived from this mechanism.

Editor's Note: These short, critical reviews of recent papers in the Journal, written exclusively... more Editor's Note: These short, critical reviews of recent papers in the Journal, written exclusively by graduate students or postdoctoral fellows, are intended to summarize the important findings of the paper and provide additional insight and commentary. For more information on the format and purpose of the Journal Club, please see http://www.jneurosci.org/misc/ifa_features.shtml.

h i g h l i g h t s • Optogenetics and microdialysis can be successfully combined. • How to manip... more h i g h l i g h t s • Optogenetics and microdialysis can be successfully combined. • How to manipulate circuits of spontaneous and evoked activities with drugs and lights? • Thalamic control of delta waves and sleep spindles.

The Journal of Physiology, 2011

Non-technical summary Voltage-dependant calcium channels constitute a heterogeneous group playing... more Non-technical summary Voltage-dependant calcium channels constitute a heterogeneous group playing ubiquitous roles in excitable cells. Among them the low-voltage activated T-type channels generate a family of currents that differ in their biophysical properties reflecting structural or neuromodulatory diversity. These T-type calcium channels are highly expressed in neurons located in the thalamus, a brain structure considered as the gateway to the cortex. Thalamic T-type calcium channels are critically involved in oscillatory neuronal activities associated with sleep or epilepsy and may contribute to sensory processing. Using injections of computer-simulated T-type conductances (a real time mimicry of ionic currents) in biological thalamic neurons, we dissect how the diversity in T-type currents impact on the output of thalamic neurons. We show that very subtle modifications in the properties of the T current that were overlooked so far affect drastically the physiological output of the thalamic neurons and therefore condition the dynamics of thalamo-cortical information integration.

Journal of Neuroscience, 2012

The thalamic output during different behavioral states is strictly controlled by the firing modes... more The thalamic output during different behavioral states is strictly controlled by the firing modes of thalamocortical neurons. During sleep, their hyperpolarized membrane potential allows activation of the T-type calcium channels, promoting rhythmic highfrequency burst firing that reduces sensory information transfer. In contrast, in the waking state thalamic neurons mostly exhibit action potentials at low frequency (i.e., tonic firing), enabling the reliable transfer of incoming sensory inputs to cortex. Because of their nearly complete inactivation at the depolarized potentials that are experienced during the wake state, T-channels are not believed to modulate tonic action potential discharges. Here, we demonstrate using mice brain slices that activation of T-channels in thalamocortical neurons maintained in the depolarized/wake-like state is critical for the reliable expression of tonic firing, securing their excitability over changes in membrane potential that occur in the depolarized state. Our results establish a novel mechanism for the integration of sensory information by thalamocortical neurons and point to an unexpected role for T-channels in the early stage of information processing.

Pflügers Archiv - European Journal of Physiology, 2014

Since their discovery more than thirty years ago, low-threshold T-type Ca 2+ channels (T-channels... more Since their discovery more than thirty years ago, low-threshold T-type Ca 2+ channels (T-channels) have been suggested to play a key role in many EEG waves of non-REM sleep, which has remained exclusively linked to the ability of these channels to generate low-threshold Ca 2+ potentials and associated high-frequency bursts of action potentials. Our present understanding of the biophysics and physiology of T-channels, however, highlights a much more diverse and complex picture of the pivotal contributions that they make to different sleep rhythms. In particular, recent experimental evidence has conclusively demonstrated the essential contribution of thalamic T-channels to the expression of slow waves of natural sleep and the key role played by Ca 2+ entry through these channels in the activation or modulation of other voltage-dependent channels that are important for the generation of both slow waves and sleep spindles. However, the precise contribution to sleep rhythms of T-channels in cortical neurons and other sleep-controlling neuronal networks remains unknown, and a full understanding of the cellular and network mechanisms of sleep delta waves is still lacking.

Journal of Neuroscience, 2013

Slow waves represent one of the prominent EEG signatures of non-rapid eye movement (non-REM) slee... more Slow waves represent one of the prominent EEG signatures of non-rapid eye movement (non-REM) sleep and are thought to play an important role in the cellular and network plasticity that occurs during this behavioral state. These slow waves of natural sleep are currently considered to be exclusively generated by intrinsic and synaptic mechanisms within neocortical territories, although a role for the thalamus in this key physiological rhythm has been suggested but never demonstrated. Combining neuronal ensemble recordings, microdialysis, and optogenetics, here we show that the block of the thalamic output to the neocortex markedly (up to 50%) decreases the frequency of slow waves recorded during non-REM sleep in freely moving, naturally sleeping-waking rats. A smaller volume of thalamic inactivation than during sleep is required for observing similar effects on EEG slow waves recorded during anesthesia, a condition in which both bursts and single action potentials of thalamocortical neurons are almost exclusively dependent on T-type calcium channels. Thalamic inactivation more strongly reduces spindles than slow waves during both anesthesia and natural sleep. Moreover, selective excitation of thalamocortical neurons strongly entrains EEG slow waves in a narrow frequency band (0.75-1.5 Hz) only when thalamic T-type calcium channels are functionally active. These results demonstrate that the thalamus finely tunes the frequency of slow waves during non-REM sleep and anesthesia, and thus provide the first conclusive evidence that a dynamic interplay of the neocortical and thalamic oscillators of slow waves is required for the full expression of this key physiological EEG rhythm.

Current opinion in neurobiology, Jan 15, 2014

During non-REM sleep the EEG is dominated by slow waves which result from synchronized UP and DOW... more During non-REM sleep the EEG is dominated by slow waves which result from synchronized UP and DOWN states in the component neurons of the thalamocortical network. This review focuses on four areas of recent progress in our understanding of these events. Thus, it has now been conclusively demonstrated that the full expression of slow waves, both of natural sleep and anesthesia, requires an essential contribution by the thalamus. Furthermore, the modulatory role of brainstem transmitters, the function of cortical inhibition and the relative contribution of single neocortical neurons to EEG slow waves have started to be carefully investigated. Together, these new data confirm the view that a full understanding of slow waves can only be achieved by considering the thalamocortical network as a single functional and dynamic unit for the generation of this key EEG rhythm.

European Journal …, 2009

A growing body of data suggests that information coding can be achieved not only by varying neuro... more A growing body of data suggests that information coding can be achieved not only by varying neuronal firing rate, but also by varying spike timing relative to network oscillations. In the olfactory bulb (OB) of a freely breathing anaesthetized mammal, odorant stimulation induces ...