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PhD Neurosciences, axe de recherche Physiologie des Assemblées Neuronales (Equipe A. Frick)

Expertise: hippocampus, electrophysiology, oscillations, neural networks

30 publication(s) since Juillet 1994:

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The indicated IF have been collected by the Web of Sciences in

19/07/2017 | Neuropsychopharmacology   IF 7.2
Potential Involvement of Impaired BKCa Channel Function in Sensory Defensiveness and Some Behavioral Disturbances Induced by Unfamiliar Environment in a Mouse Model of Fragile X Syndrome.
Carreno-Munoz MI, Martins F, Medrano MC, Aloisi E, Pietropaolo S, Dechaud C, Subashi E, Bony G, Ginger M, Moujahid A, Frick A, Leinekugel X

In fragile X syndrome (FXS), sensory hypersensitivity and impaired habituation is thought to result in attention overload and various behavioral abnormalities in reaction to the excessive and remanent salience of environment features that would normally be ignored. This phenomenon, termed sensory defensiveness, has been proposed as the potential cause of hyperactivity, hyperarousal, and negative reactions to changes in routine that are often deleterious for FXS patients. However, the lack of tools for manipulating sensory hypersensitivity has not allowed the experimental testing required to evaluate the relevance of this hypothesis. Recent work has shown that BMS-204352, a BKCa channel agonist, was efficient to reverse cortical hyperexcitability and related sensory hypersensitivity in the Fmr1-KO mouse model of FXS. In the present study, we report that exposing Fmr1-KO mice to novel or unfamiliar environments resulted in multiple behavioral perturbations, such as hyperactivity, impaired nest building and excessive grooming of the back. Reversing sensory hypersensitivity with the BKCa channel agonist BMS-204352 prevented these behavioral abnormalities in Fmr1-KO mice. These results are in support of the sensory defensiveness hypothesis, and confirm BKCa as a potentially relevant molecular target for the development of drug medication against FXS/ASD.Neuropsychopharmacology advance online publication, 16 August 2017; doi:10.1038/npp.2017.149.

The possible effects on cognitive processes of external electric fields, such as those generated by power line pillars and household appliances are of increasing public concern. They are difficult to study experimentally, and the relatively scarce and contradictory evidence make it difficult to clearly assess these effects. In this study, we investigate how, why and to what extent external perturbations of the intrinsic neuronal activity, such as those that can be caused by generation, transmission and use of electrical energy can affect neuronal activity during cognitive processes. For this purpose, we used a morphologically and biophysically realistic three-dimensional model of CA1 pyramidal neurons. The simulation findings suggest that an electric field oscillating at power lines frequency, and environmentally measured strength, can significantly alter both the average firing rate and temporal spike distribution properties of a hippocampal CA1 pyramidal neuron. This effect strongly depends on the specific and instantaneous relative spatial location of the neuron with respect to the field, and on the synaptic input properties. The model makes experimentally testable predictions on the possible functional consequences for normal hippocampal functions such as object recognition and spatial navigation. The results suggest that, although EF effects on cognitive processes may be difficult to occur in everyday life, their functional consequences deserve some consideration, especially when they constitute a systematic presence in living environments.

09/2015 | brain behav   IF 2.1
Genetic deletion of the Histone Deacetylase 6 exacerbates selected behavioral deficits in the R6/1 mouse model for Huntington's disease.
Ragot A, Pietropaolo S, Vincent J, Delage P, Zhang H, Allinquant B, Leinekugel X, Fischer A, Cho YH

INTRODUCTION: The inhibition of the Histone Deacetylase 6 (HDAC6) increases tubulin acetylation, thus stimulating intracellular vesicle trafficking and brain-derived neurotrophic factor (BDNF) release, that is, cellular processes markedly reduced in Huntington's disease (HD). METHODS: We therefore tested that reducing HDAC6 levels by genetic manipulation would attenuate early cognitive and behavioral deficits in R6/1 mice, a mouse model which develops progressive HD-related phenotypes. RESULTS: In contrast to our initial hypothesis, the genetic deletion of HDAC6 did not reduce the weight loss or the deficits in cognitive abilities and nest-building behavior shown by R6/1 mice, and even worsened their social impairments, hypolocomotion in the Y-maze, and reduced ultrasonic vocalizations. CONCLUSIONS: These results weaken the validity of HDAC6 reduction as a possible therapeutic strategy for HD. The data are discussed in terms of additional cellular consequences and anatomical specificity of HDAC6 that could explain these unexpected effects.

2013 | PLoS ONE   IF 2.8
Recruitment of Perisomatic Inhibition during Spontaneous Hippocampal Activity
Beyeler A, Retailleau A, Molter C, Mehidi A, Szabadics J, Leinekugel X

It was recently shown that perisomatic GABAergic inhibitory postsynaptic potentials (IPSPs) originating from basket and chandelier cells can be recorded as population IPSPs from the hippocampal pyramidal layer using extracellular electrodes (eIPSPs). Taking advantage of this approach, we have investigated the recruitment of perisomatic inhibition during spontaneous hippocampal activity in vitro. Combining intracellular and extracellular recordings from pyramidal cells and interneurons, we confirm that inhibitory signals generated by basket cells can be recorded extracellularly, but our results suggest that, during spontaneous activity, eIPSPs are mostly confined to the CA3 rather than CA1 region. CA3 eIPSPs produced the powerful time-locked inhibition of multi-unit activity expected from perisomatic inhibition. Analysis of the temporal dynamics of spike discharges relative to eIPSPs suggests significant but moderate recruitment of excitatory and inhibitory neurons within the CA3 network on a 10 ms time scale, within which neurons recruit each other through recurrent collaterals and trigger powerful feedback inhibition. Such quantified parameters of neuronal interactions in the hippocampal network may serve as a basis for future characterisation of pathological conditions potentially affecting the interactions between excitation and inhibition in this circuit.

2013 | front comput neurosci   IF 2.3
Computational modeling of the effects of amyloid-beta on release probability at hippocampal synapses.
Romani A, Marchetti C, Bianchi D, Leinekugel X, Poirazi P, Migliore M, Marie H

The role of amyloid beta (Abeta) in brain function and in the pathogenesis of Alzheimer's disease (AD) remains elusive. Recent publications reported that an increase in Abeta concentration perturbs pre-synaptic release in hippocampal neurons. In particular, it was shown in vitro that Abeta is an endogenous regulator of synaptic transmission at the CA3-CA1 synapse, enhancing its release probability. How this synaptic modulator influences neuronal output during physiological stimulation patterns, such as those elicited in vivo, is still unknown. Using a realistic model of hippocampal CA1 pyramidal neurons, we first implemented this Abeta-induced enhancement of release probability and validated the model by reproducing the experimental findings. We then demonstrated that this synaptic modification can significantly alter synaptic integration properties in a wide range of physiologically relevant input frequencies (from 5 to 200 Hz). Finally, we used natural input patterns, obtained from CA3 pyramidal neurons in vivo during free exploration of rats in an open field, to investigate the effects of enhanced Abeta on synaptic release under physiological conditions. The model shows that the CA1 neuronal response to these natural patterns is altered in the increased-Abeta condition, especially for frequencies in the theta and gamma ranges. These results suggest that the perturbation of release probability induced by increased Abeta can significantly alter the spike probability of CA1 pyramidal neurons and thus contribute to abnormal hippocampal function during AD.

06/09/2012 | Neuron   IF 14.4
Rhythmic modulation of theta oscillations supports encoding of spatial and behavioral information in the rat hippocampus.
Molter C, O'Neill J, Yamaguchi Y, Hirase H, Leinekugel X

Oscillatory patterns of activity in various frequency ranges are ubiquitously expressed in cortical circuits. While recent studies in humans emphasized rhythmic modulations of neuronal oscillations ('second-order' rhythms), their potential involvement in information coding remains an open question. Here, we show that a rhythmic (~0.7 Hz) modulation of hippocampal theta power, unraveled by second-order spectral analysis, supports encoding of spatial and behavioral information. The phase preference of neuronal discharge within this slow rhythm significantly increases the amount of information carried by action potentials in various motor/cognitive behaviors by (1) distinguishing between the spikes fired within versus outside the place field of hippocampal place cells, (2) disambiguating place firing of neurons having multiple place fields, and (3) predicting between alternative future spatial trajectories. This finding demonstrates the relevance of second-order spectral components of brain rhythms for decoding neuronal information.

05/2012 | J Physiol Paris   IF 2.7
Neural circuits underlying the generation of theta oscillations.
Pignatelli M, Beyeler A, Leinekugel X

Theta oscillations represent the neural network configuration underlying active awake behavior and paradoxical sleep. This major EEG pattern has been extensively studied, from physiological to anatomical levels, for more than half a century. Nevertheless the cellular and network mechanisms accountable for the theta generation are still not fully understood. This review synthesizes the current knowledge on the circuitry involved in the generation of theta oscillations, from the hippocampus to extra hippocampal structures such as septal complex, entorhinal cortex and pedunculopontine tegmentum, a main trigger of theta state through direct and indirect projections to the septal complex. We conclude with a short overview of the perspectives offered by technical advances for deciphering more precisely the different neural components underlying the emergence of theta oscillations.

01/10/2005 | J Physiol   IF 5
The birth (and adolescence) of LTP.
Miles R, Poncer JC, Fricker D, Leinekugel X


09/12/2004 | Nature   IF 43.1
Early motor activity drives spindle bursts in the developing somatosensory cortex.
Khazipov R, Sirota A, Leinekugel X, Holmes GL, Ben-Ari Y, Buzsaki G

Sensorimotor coordination emerges early in development. The maturation period is characterized by the establishment of somatotopic cortical maps, the emergence of long-range cortical connections, heightened experience-dependent plasticity and spontaneous uncoordinated skeletal movement. How these various processes cooperate to allow the somatosensory system to form a three-dimensional representation of the body is not known. In the visual system, interactions between spontaneous network patterns and afferent activity have been suggested to be vital for normal development. Although several intrinsic cortical patterns of correlated neuronal activity have been described in developing somatosensory cortex in vitro, the in vivo patterns in the critical developmental period and the influence of physiological sensory inputs on these patterns remain unknown. We report here that in the intact somatosensory cortex of the newborn rat in vivo, spatially confined spindle bursts represent the first and only organized network pattern. The localized spindles are selectively triggered in a somatotopic manner by spontaneous muscle twitches, motor patterns analogous to human fetal movements. We suggest that the interaction between movement-triggered sensory feedback signals and self-organized spindle oscillations shapes the formation of cortical connections required for sensorimotor coordination.

01/2003 | J Physiol Paris   IF 2.7
Developmental patterns and plasticities: the hippocampal model.
Leinekugel X

Because developmental activity-dependent synaptic plasticity has been hypothesized to participate in network refinement, leading to the precise mapping of synaptic contacts constituting a functional brain, it is important to investigate the spatio-temporal structure of immature network activities. This article is briefly reviewing 15 years of studies on the immature rat hippocampus which, together with recent results obtained from awake rat pups, represent an important step toward the understanding of spontaneous patterns of activity and their potential implication in network maturation. Due to synergistic excitatory actions of GABA and glutamate receptor mediated signals during early postnatal life, spontaneous patterns of hippocampal activity that have been characterized both in vitro and in vivo are likely to provide hebbian modulation of developing glutamatergic and GABAergic synapses. Together with studies on trophic actions of these transmitters, study of the immature hippocampal network patterns and plasticities allows for multiple technical and conceptual approaches and represents an interesting experimental model for development studies.