Papers by Yehezkel Ben-Ari
Pediatric Research, Mar 1, 2001
The following article is the second in our series on the developmental biology of the nervous sys... more The following article is the second in our series on the developmental biology of the nervous system and its relation to diseases and disorders that are found in newborn infants and children. This article, by Gregory Holmes and Yehezkiel Ben-Ari, discusses the pathophysiology of epileptic seizures in the developing brain and the long-term consequences that may result from seizures that occur in the immature brain.
Neural Plasticity, 2019
Autism spectrum disorders (ASD) are neurodevelopmental disorders induced by genetic and environme... more Autism spectrum disorders (ASD) are neurodevelopmental disorders induced by genetic and environmental factors. In our recent studies, we showed that the GABA developmental shifts during delivery and the second postnatal week are abolished in two rodent models of ASD. Maternal treatment around birth with bumetanide restored the GABA developmental sequence and attenuated the autism pathogenesis in offspring. Clinical trials conducted in parallel confirmed the usefulness of bumetanide treatment to attenuate the symptoms in children with ASD. Collectively, these observations suggest that an alteration of the GABA developmental sequence is a hallmark of ASD. Here, we investigated whether similar alterations occur in the Shank3 mouse model of ASD. We report that in CA3 pyramidal neurons, the driving force and inhibitory action of GABA are not different in naĆÆve and Shank3-mutant age-matched animals at birth and during the second postnatal week. In contrast, the frequency of spontaneous ex...
The Journal of Neuroscience, 1998
The Journal of Neuroscience, 2001
Morphological studies suggest that the primate hippocampus develops extensively before birth, but... more Morphological studies suggest that the primate hippocampus develops extensively before birth, but little is known about its functional development. Patch-clamp recordings of hippocampal neurons and reconstruction of biocytin-filled pyramidal cells were performed in slices of macaque cynomolgus fetuses delivered by cesarean section. We found that during the second half of gestation, axons and dendrites of pyramidal cells grow intensively by hundreds of micrometers per day to attain a high level of maturity near term. Synaptic currents appear around midgestation and are correlated with the level of morphological differentiation of pyramidal cells: the first synapses are GABAergic, and their emergence correlates with the growth of apical dendrite into stratum radiatum. A later occurrence of glutamatergic synaptic currents correlates with a further differentiation of the axodendritic tree and the appearance of spines. Relying on the number of dendritic spines, we estimated that hundreds...
The Journal of Neuroscience, 1999
We have performed a morphofunctional analysis of CA1 pyramidal neurons at birth to examine the se... more We have performed a morphofunctional analysis of CA1 pyramidal neurons at birth to examine the sequence of formation of GABAergic and glutamatergic postsynaptic currents (PSCs) and to determine their relation to the dendritic arborization of pyramidal neurons. We report that at birth pyramidal neurons are heterogeneous. Three stages of development can be identified: (1) the majority of the neurons (80%) have small somata, an anlage of apical dendrite, and neither spontaneous nor evoked PSCs; (2) 10% of the neurons have a small apical dendrite restricted to the stratum radiatum and PSCs mediated only by GABAAreceptors; and (3) 10% of the neurons have an apical dendrite that reaches the stratum lacunosum moleculare and PSCs mediated both by GABAAand glutamate receptors. These three groups of pyramidal neurons can be differentiated by their capacitance (Cm= 17.9 Ā± 0.8; 30.2 Ā± 1.6; 43.2 Ā± 3.0 pF, respectively). At birth, the synaptic markers synapsin-1 and synaptophysin labeling are pre...
dence from several brain regions suggests ā„-aminobutyric acid (GABA) can exert a trophic influenc... more dence from several brain regions suggests ā„-aminobutyric acid (GABA) can exert a trophic influence during development, expanding the role of this amino acid beyond its function as an inhibitory neurotransmitter. Proliferating precursor cells in the neocortical ventricular zone (VZ) express functional GABA A receptors as do immature postmigratory neurons in the developing cortical plate (CP); however, GABA A receptor properties in these distinct cell populations have not been compared. Using electrophysiological techniques in embryonic and early postnatal neocortex, we find that GABA A receptors expressed by VZ cells have a higher apparent affinity for GABA and are relatively insensitive to receptor desensitization compared with neurons in the CP. GABA-induced current magnitude increases with maturation with the smallest responses found in recordings from precursor cells in the VZ. No evidence was found that GABA A receptors on VZ cells are activated synaptically, consistent with previous data suggesting that these receptors are activated in a paracrine fashion by nonsynaptically released ligand. After neurons are born and migrate to the CP, they begin to demonstrate spontaneous synaptic activity, the majority of which is GABA A mediated. These spontaneous GABA A postsynaptic currents (sPSCs) first were detected at embryonic day 18 (E18). At birth, Ļ³50% of recordings from cortical neurons demonstrated GABA A -mediated sPSCs, and this value increased with age. GABA A -mediated sPSCs were action potential dependent and arose from local GABAergic interneurons. GABA application could evoke action potential-dependent PSCs in neonatal cortical neurons, suggesting that during the first few postnatal days, GABA can act as an excitatory neurotransmitter. Finally, N-methyl-D-aspartate (NMDA)-but not non-NMDA-mediated sPSCs were also present in early postnatal neurons. These events were not observed in cells voltage clamped at negative holding potentials (ĻŖ60 to ĻŖ70 mV) but were evident when the holding potential was set at positive values (Ļ©30 to Ļ©60 mV). Together these results provide evidence for the early maturation of GABAergic communication in the neocortex and a functional change in GABA A -receptor properties between precursor cells and early postmitotic neurons. The change in GABA A -receptor properties may reflect the shift from paracrine to synaptic receptor activation.
Epilepsy currents / American Epilepsy Society
PURPOSE: Infantile spasms is one of the most severe epileptic syndromes of infancy and early chil... more PURPOSE: Infantile spasms is one of the most severe epileptic syndromes of infancy and early childhood. Progress toward understanding the pathophysiology of this disorder and the development of effective therapies has been hindered by the lack of a relevant animal model. We report here the creation of such a model. METHODS: The sodium channel blocker, tetrodotoxin (TTX), was chronically infused into the developing neocortex or hippocampus of infant rats by way of an osmotic minipump starting on postnatal day 10-12. RESULTS: After a minimum of 10 days of infusion, approximately one-third of these rats began to display very brief (1-2 s) spasms, which consisted of symmetric or asymmetric flexion or extension of the trunk and sometimes involvement of one or both forelimbs. The typical ictal EEG pattern associated with the behavioral spasms consisted of an initial generalized, high amplitude, slow wave followed by an electrodecrement with superimposed fast activity. The interictal EEG revealed multifocal spikes and sharp waves, and in most animals that had spasms a hypsarrhythmic pattern was seen, at least intermittently, during NREM sleep. Like in humans, the spasms in the rat often occurred in clusters especially during sleep-wake transitions. Comparison of the ictal and interictal EEGs recorded in this model and those from humans with infantile spasms revealed that the patterns and the frequency components of both the ictal events and hypsarrhythmia were very similar. DISCUSSION: The TTX model of infantile spasms should be of value in furthering an understanding of the pathophysiology of this seizure disorder.
Trends in Neurosciences, 2005
During brain development, transmitter-gated receptors are operative before synapse formation, sug... more During brain development, transmitter-gated receptors are operative before synapse formation, suggesting that their action is not restricted to synaptic transmission. GABA, which is the principal excitatory transmitter in the developing brain, acts as an epigenetic factor to control processes including cell proliferation, neuroblast migration and dendritic maturation. These effects appear to be mediated through a paracrine, diffuse, non-synaptic mode of action that precedes the more focused, rapid mode of operation characteristic of synaptic connections. This sequential operation implies that GABA is used as an informative agent but in a unique context at an early developmental stage. This sequence also implies that by altering these effects, drugs acting on the GABA system could be pathogenic during pregnancy.
The Journal of Physiology, 2005
The development of GABAergic synapses is associated with an excitatory to inhibitory shift of the... more The development of GABAergic synapses is associated with an excitatory to inhibitory shift of the actions of GABA because of a reduction of [Cl -] i . This is due to a delayed postnatal expression of the K + -Cl -cotransporter KCC2, which has low levels at birth and peaks during the first few postnatal weeks. Whether the expression of the cotransporter and the excitatory to inhibitory shift have other consequences on the operation of GABA A receptors and synapses is not yet known. We have now expressed KCC2 in immature neurones at an early developmental stage and determined the consequences on the formation of GABA and glutamate synapses. We report that early expression of the cotransporter selectively enhances GABAergic synapses: there is a significant increase of the density of GABA A receptors and synapses and an increase of the frequency of GABAergic miniature postsynaptic currents. The density of glutamate synapses and frequency of AMPA miniature postsynaptic currents are not affected. We conclude that the expression of KCC2 and the reduction of [Cl -] i play a critical role in the construction of GABAergic networks that extends beyond the excitatory to inhibitory shift of the actions of GABA.
The Journal of Neuroscience, 2006
Ischemic strokes are often associated with late-onset epilepsy, but the underlying mechanisms are... more Ischemic strokes are often associated with late-onset epilepsy, but the underlying mechanisms are poorly understood. In the hippocampus, which is one of the regions most sensitive to ischemic challenge, global ischemia induces a complete loss of CA1 pyramidal neurons, whereas the resistant CA3 pyramidal neurons display a long-term hyperexcitability several months after the insult. The mechanisms of this long-term hyperexcitability remain unknown despite its clinical implication. Using chronicin vivoEEG recordings andin vitrofield recordings in slices, we now report spontaneous interictal epileptiform discharges in the CA3 area of the hippocampus from post-ischemic rats several months after the insult. Whole-cell recordings from CA3 pyramidal neurons, revealed a permanent reduction in the frequency of spontaneous and miniature GABAergic IPSCs and a parallel increase in the frequency of spontaneous and miniature glutamatergic postsynaptic currents. Global ischemia also induced a drama...
Neuron, 2002
hippocampal neurons (Valeyev et al., 1993); (5) blockade of NMDA receptors reduces spontaneous IN... more hippocampal neurons (Valeyev et al., 1993); (5) blockade of NMDA receptors reduces spontaneous INSERM U29 Parc Scientifique de Luminy, BP13 Ca 2Ļ© elevation and alters the rate of migration of cerebellum granular cells (Komuro and Rakic, 1993); and (6) 13273 Marseille cedex 09 France blockade of GABA A receptors generates an outward current and produces an enhancement of DNA synthesis in proliferating neuronal precursors of the neocortical ventricular zone (Lo Turco et al., 1995). If transmitters Summary mediate intercellular communication prior to synapse formation, a tonic, spontaneous, and evoked nonsynap-GABA and glutamate receptors are expressed in immature "silent" CA1 pyramidal neurons prior to syn-tic current should be observed in maturing neurons. We have now investigated this issue in CA1 hippo-apse formation, but their function is unknown. We now report the presence of tonic, spontaneous, and evoked campal neurons of embryonic and neonatal slices. This region is particularly suitable since at birth most pyrami-currents in embryonic and neonatal CA1 neurons mediated primarily by the activation of GABA A receptors. dal neurons have just an anlage of apical dendrite and have no synapses and no excitatory or inhibitory post-These currents are mediated by a nonconventional release of transmitters, as they persist in the presence synaptic currents. These cells (synaptically silent cells) have, however, functional GABA and glutamate recep-of calcium channel blockers or botulinium toxin and are observed in Munc18-1-deficient mice in which ve-tors, as they respond to applications of GABA or glutamate (Tyzio et al., 1999). In addition, GABA and gluta-sicular release is abolished. This paracrine communication is modulated by glutamate but not GABA trans-mate fibers are present already in utero and may provide a source of transmitter (Rozenberg et al.,1989; Super porters, which do not operate during this period of life. Thus, a Ca 2Ų -and SNARE-independent release of and Soriano, 1994; Dupuy and Houser, 1996; Diabira et al., 1999). We report that these neurons exhibit a tonic transmitters underlies a paracrine mode of communication before synapse formation. form of GABAergic activation and that the evoked release of GABA and glutamate generates an early slow current (ESC) primarily mediated by the activation of
European Journal of Neuroscience, 2002
During postnatal development of CA1 pyramidal neurons, GABAergic synapses are excitatory and esta... more During postnatal development of CA1 pyramidal neurons, GABAergic synapses are excitatory and established prior to glutamatergic synapses. As interneurons are generated before pyramidal cells, we have tested the hypothesis that the GABAergic interneuronal network is operative before glutamate pyramidal neurons and provides the initial patterns of activity. We patchāclamp recorded interneurons in foetal (69 neurons) and neonatal P0 (162 neurons) hippocampal slices and performed a morphofunctional analysis of biocytināfilled neurons. At P0, three types of interneurons were found: (i) nonāinnervated āsilentā interneurons (5%) with no spontaneous or evoked synaptic currents; (ii) G interneurons (17%) with GABAA synapses only; and (iii) GG interneurons with GABA and glutamatergic synapses (78%). Relying on the neuronal capacitance, cell body size and arborization of dendrites and axons, the three types of interneurons correspond to three stages of development with nonāinnervated neurons a...
Epilepsy Research, 1998
One axiom at the basis of epilepsy research is that there exists an imbalance between excitation ... more One axiom at the basis of epilepsy research is that there exists an imbalance between excitation and inhibition. This abnormality can be achieved by an increase of excitation on principal cells, a decreased inhibition (i.e. disinhibition) or both. This review focuses on dysfunction of inhibition, and in particular on the 'dormant basket cell hypothesis'. This hypothesis states that, (1) interneurones are functionally disconnected from excitatory afferents, resulting in hyperexcitability of principal neurones and loss of paired pulse inhibition, (2) when properly activated, interneurones can still perform their task, i.e. suppress epileptiform activity and restore paired pulse inhibition. The aim of this review is to discuss the evidence in support of the 'dormant basket cell hypothesis'. We will first discuss the rationale underlying the hypothesis and the criteria needed to validate the hypothesis. We will then show that, (1) the key experimental data offered in support of the hypothesis (Bekenstein and Lothman, 1993. Dormancy of inhibitory interneurones in a model of temporal lobe epilepsy. Science 259, 97 -100; Sloviter, 1991. Permanently altered hippocampal structure, excitability, and inhibition after experimental status epilepticus in the rat: the 'dormant basket cell' hypothesis and its relevance to temporal lobe epilepsy. Hippocampus 1, 41 -66) are difficult to interpret, and (2) recent recordings from interneurones in epileptic tissue argue against the hypothesis. The 'dormant basket cell hypothesis' is then discussed in the broader context of disinhibition.
Cerebral Cortex, 2008
N-methyl-D-aspartate (NMDA) type of glutamate receptors play an important role in activity-depend... more N-methyl-D-aspartate (NMDA) type of glutamate receptors play an important role in activity-dependent plasticity in the developing cortex. However, the physiological patterns of cortical activity that activate NMDA receptors in vivo remain largely unknown. We performed full-band recordings from the barrel cortex of neonatal rats in vivo and found that the dominant pattern of the early activity, network driven spindle bursts, are associated with large amplitude NMDA receptor--dependent delta waves. The major sink of delta waves was in the dense cortical plate, which coincided with the sinks of sensory-evoked responses as well as fast spindle-burst oscillations. Pharmacological analysis revealed major contributions from NMDA and alpha-aminopropionate (AMPA) type of glutamate receptors in the generation of delta waves, whereas fast oscillations primarily involved only AMPA receptors. Our results suggest that the 2 component spindle burst is generated by rhythmic, presumably thalamocortical, synaptic input which entrains an AMPA receptor-mediated fast oscillation and who's summation generates an NMDA and AMPA receptor mediated delta wave. The massive summation of thalamocortical activity during the spindle bursts thus provides a long time window for co-incident activation of cortical neurons by the thalamocortical cells which may contribute to the formation of thalamocortical synapses in the barrel cortex during the critical period of developmental plasticity.
Brain Research, 2001
Rat perinatal (E20-P0) CA1 pyramidal neurons were either synaptically active or silent. We show h... more Rat perinatal (E20-P0) CA1 pyramidal neurons were either synaptically active or silent. We show here that, during this developmental period, active but not silent cells form recurrent axon-collaterals that invade the radiatum and the lacunosum moleculare strata. These recurrents were never observed in adult rats. We propose that these transient recurrent axons may participate in the activity-dependent modulation of the synaptogenesis
Neuron, 2005
GABA excites immature neurons and inhibits adult ones, but whether this contributes to seizures i... more GABA excites immature neurons and inhibits adult ones, but whether this contributes to seizures in the developing brain is not known. We now report that in the developing, but not the adult, hippocampus, seizures beget seizures only if GABAergic synapses are functional. In the immature hippocampus, seizures generated with functional GABAergic synapses include fast oscillations that are required to transform a naive network to an epileptic one: blocking GABA receptors prevents the long-lasting sequels of seizures. In contrast, in adult neurons, full blockade of GABA(A) receptors generates epileptogenic high-frequency seizures. Therefore, purely glutamatergic seizures are not epileptogenic in the developing hippocampus. We suggest that the density of glutamatergic synapses is not sufficient for epileptogenesis in immature neurons; excitatory GABAergic synapses are required for that purpose. We suggest that the synergistic actions of GABA and NMDA receptors trigger the cascades involved in epileptogenesis in the developing hippocampus.
Although several investigations have shown that the local GABAergic circuit in the rat hippocampu... more Although several investigations have shown that the local GABAergic circuit in the rat hippocampus is functional very early in development, this result has not been yet completed by the investigation of the full dendritic and axonal arborization of the neonatal interneurones. In the present study, intracellular injection of biocytin was used to assess the branching pattern of interneurones in the hippocampal CA3 region of rat between 2 and 6 days of age. Based on their dendritic morphology, the biocytin-filled interneurones were divided into four classes: bipolar, stellate, pyramidal-like and fusiform interneurones. About half of the biocytin-filled neonatal interneurones exhibited dendritic or somatic filopodial processes. The axonal arbors of the filled-interneurones were widely spread into the CA3 region, and in four out of nine cases extended beyond the CA3 region to branch into the CA1 region. These results show that, despite immature features, the filopodial processes, the hippocampal interneurones are well developed early in development at a time when their target cells, the pyramidal neurones, are still developing. These observations are consistent with a trophic role that GABA may play early in development.
During development, when synapses start to be established, a primitive form of
network-driven act... more During development, when synapses start to be established, a primitive form of
network-driven activity provides most of the synaptic activity. This pattern
enables a high degree of synchrony in immature neurons in spite of the small
number of functional synapses and could participate in activity-dependent
growth and synapse formation. Relying on the giant depolarizing potentials
that provide most of the synaptic activity in the developing hippocampus, this
article reviews the common properties and generating mechanisms of these
patterns, and particularly the role of the early depolarizing action of GABAA and
glycine receptors and the sequential expression of GABA and glutamate
synapses. Patterns similar to giant depolarizing potentials have been observed
in a wide range of structures and species suggesting that there is a temporal
template throughout evolution that constitutes an essential step in the
formation of functional networks
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Papers by Yehezkel Ben-Ari
network-driven activity provides most of the synaptic activity. This pattern
enables a high degree of synchrony in immature neurons in spite of the small
number of functional synapses and could participate in activity-dependent
growth and synapse formation. Relying on the giant depolarizing potentials
that provide most of the synaptic activity in the developing hippocampus, this
article reviews the common properties and generating mechanisms of these
patterns, and particularly the role of the early depolarizing action of GABAA and
glycine receptors and the sequential expression of GABA and glutamate
synapses. Patterns similar to giant depolarizing potentials have been observed
in a wide range of structures and species suggesting that there is a temporal
template throughout evolution that constitutes an essential step in the
formation of functional networks
network-driven activity provides most of the synaptic activity. This pattern
enables a high degree of synchrony in immature neurons in spite of the small
number of functional synapses and could participate in activity-dependent
growth and synapse formation. Relying on the giant depolarizing potentials
that provide most of the synaptic activity in the developing hippocampus, this
article reviews the common properties and generating mechanisms of these
patterns, and particularly the role of the early depolarizing action of GABAA and
glycine receptors and the sequential expression of GABA and glutamate
synapses. Patterns similar to giant depolarizing potentials have been observed
in a wide range of structures and species suggesting that there is a temporal
template throughout evolution that constitutes an essential step in the
formation of functional networks