Immunogold Detection of L-glutamate and D-serine in Small Synaptic-Like Microvesicles in Adult Hippocampal Astrocytes.

Glutamate and the N-methyl-D-aspartate receptor ligand D-serine are putative gliotransmitters. Here, we show by immunogold cytochemistry of the adult hippocampus that glutamate and D-serine accumulate in synaptic-like microvesicles (SLMVs) in the perisynaptic processes of astrocytes. The estimated concentration of fixed glutamate in the astrocytic SLMVs is comparable to that in synaptic vesicles of excitatory nerve terminals (∼45 and ∼55 mM, respectively), whereas the D-serine level is about 6 mM. The vesicles are organized in small spaced clusters located near the astrocytic plasma membrane. Endoplasmic reticulum is regularly found in close vicinity to SLMVs, suggesting that astrocytes contain functional nanodomains, where a local Ca(2+) increase can trigger release of glutamate and/or D-serine.

c-Jun N-terminal kinase has a key role in Alzheimer disease synaptic dysfunction in vivo.

Altered synaptic function is considered one of the first features of Alzheimer disease (AD). Currently, no treatment is available to prevent the dysfunction of excitatory synapses in AD. Identification of the key modulators of synaptopathy is of particular significance in the treatment of AD. We here characterized the pathways leading to synaptopathy in TgCRND8 mice and showed that c-Jun N-terminal kinase (JNK) is activated at the spine prior to the onset of cognitive impairment. The specific inhibition of JNK, with its specific inhibiting peptide D-JNKI1, prevented synaptic dysfunction in TgCRND8 mice. D-JNKI1 avoided both the loss of postsynaptic proteins and glutamate receptors from the postsynaptic density and the reduction in size of excitatory synapses, reverting their dysfunction. This set of data reveals that JNK is a key signaling pathway in AD synaptic injury and that its specific inhibition offers an innovative therapeutic strategy to prevent spine degeneration in AD.

Discharge properties of single neurons in the dorsal nucleus of the lateral lemniscus of the rat.

The aim of the present study was to characterize the discharge properties of single neurons in the dorsal nucleus of the lateral lemniscus (DNLL) of the rat. In the absence of acoustic stimulation, two types of spontaneous discharge patterns were observed: units tended to fire in a bursting or in a nonbursting mode. The distribution of units in the DNLL based on spontaneous firing rate followed a rostrocaudal gradient: units with high spontaneous rates were most commonly located in the rostral part of the DNLL, whereas in the caudal part units had lower spontaneous discharge rates. The most common response pattern of DNLL units to 200 ms binaural noise bursts contained a prominent onset response followed by a lower but steady-state response and an inhibitory response in the early-off period. Thresholds of response to noise bursts were on average higher for DNLL units than for units recorded in the inferior colliculus under the same experimental conditions. The DNLL units were arranged according to a mediolateral sensitivity gradient with the lowest threshold units in the most lateral part of the nucleus. In the rat, as in other mammals, the most common DNLL binaural input type was an excitatory response to contralateral ear stimulation and inhibitory response to ipsilateral ear stimulation (EI type). Pure tone bursts were in general a more effective stimulus compared to noise bursts. Best frequency (BF) was established for 97 DNLL units and plotted according to their spatial location. The DNLL exhibits a loose tonotopic organization, where there is a concentric pattern with high BF units located in the most dorsal and ventral parts of the DNLL and lower BF units in the middle part of the nucleus.

A numerical solver for a nonlinear Fokker-Planck equation representation of neuronal network dynamics

To describe the collective behavior of large ensembles of neurons in neuronal network, a kinetic theory description was developed in [13, 12], where a macroscopic representation of the network dynamics was directly derived from the microscopic dynamics of individual neurons, which are modeled by conductance-based, linear, integrate-and-fire point neurons. A diffusion approximation then led to a nonlinear Fokker-Planck equation for the probability density function of neuronal membrane potentials and synaptic conductances. In this work, we propose a deterministic numerical scheme for a Fokker-Planck model of an excitatory-only network. Our numerical solver allows us to obtain the time evolution of probability distribution functions, and thus, the evolution of all possible macroscopic quantities that are given by suitable moments of the probability density function. We show that this deterministic scheme is capable of capturing the bistability of stationary states observed in Monte Carlo simulations. Moreover, the transient behavior of the firing rates computed from the Fokker-Planck equation is analyzed in this bistable situation, where a bifurcation scenario, of asynchronous convergence towards stationary states, periodic synchronous solutions or damped oscillatory convergence towards stationary states, can be uncovered by increasing the strength of the excitatory coupling. Finally, the computation of moments of the probability distribution allows us to validate the applicability of a moment closure assumption used in [13] to further simplify the kinetic theory.

Glioprotective impact of cell-permeable peptides in preclinical models of amyotrophic lateral sclerosis

Amyotrophic Lateral Sclerosis (ALS) is a neurodegenerative disorder characterized by progressive degeneration of upper and lower motor neurons. It is mostly sporadic, but about 2% of cases are associated with mutations in the gene encoding the enzyme superoxide dismutase 1 (SOD1). A major constraint to the comprehension of the pathogenesis of ALS has been long represented by the conviction that this disorder selectively affects motor neurons in a cell-autonomous manner. However, the failure to identify the events underlying the neurodegenerative process and the increased knowledge of the complex cellular interactions necessary for the correct functioning of the CNS has recently focused the attention on the contribution to neurodegeneration of glial cells, including astrocytes. Astrocytes can hurt motor neurons directly by secreting neurotoxic factors, but they can also play a deleterious role indirectly by losing functions that are supportive for neurons. Recently, we reported that a subpopulation of astrocytes degenerates in the spinal cord of hSOD1G93A transgenic mouse model of ALS. Mechanistic studies in cultured astrocytes revealed that such effect is mediated by the excitatory amino acid glutamate.On the bsis of these observations, we next used the established cell culture model as a tool to screen the glioprotective effect of innovative drugs, namely cell-permeable therapeutics. These consist of peptidic effector moieties coupled to the selective intracellular peptide transporter TAT protein. We initially validated the usefulness of these molecules demonstrating that a control fluorescent peptide enters astrocytes in culture and is retained within the cells up to 24-48 h, according to the timing of our cytotoxicity experiments. We then tested the impact of specific intracellular peptides with antiapoptotic properties on glutamate-treated hSOD1G93A- expressing astrocytes and we identified one molecule that protects the cells from death. Chronic treatment of ALS mice with this peptide had a positive impact on the outcome of the disease.

Analysis of nonlinear noisy integrate & fire neuron models: blow-up and steady states

Nonlinear Noisy Leaky Integrate and Fire (NNLIF) models for neurons networks can be written as Fokker-Planck-Kolmogorov equations on the probability density of neurons, the main parameters in the model being the connectivity of the network and the noise. We analyse several aspects of the NNLIF model: the number of steady states, a priori estimates, blow-up issues and convergence toward equilibrium in the linear case. In particular, for excitatory networks, blow-up always occurs for initial data concentrated close to the firing potential. These results show how critical is the balance between noise and excitatory/inhibitory interactions to the connectivity parameter.

Glutamate Transport Decreases Mitochondrial pH and Modulates Oxidative Metabolism in Astrocytes.

During synaptic activity, the clearance of neuronally released glutamate leads to an intracellular sodium concentration increase in astrocytes that is associated with significant metabolic cost. The proximity of mitochondria at glutamate uptake sites in astrocytes raises the question of the ability of mitochondria to respond to these energy demands. We used dynamic fluorescence imaging to investigate the impact of glutamatergic transmission on mitochondria in intact astrocytes. Neuronal release of glutamate induced an intracellular acidification in astrocytes, via glutamate transporters, that spread over the mitochondrial matrix. The glutamate-induced mitochondrial matrix acidification exceeded cytosolic acidification and abrogated cytosol-to-mitochondrial matrix pH gradient. By decoupling glutamate uptake from cellular acidification, we found that glutamate induced a pH-mediated decrease in mitochondrial metabolism that surpasses the Ca(2+)-mediated stimulatory effects. These findings suggest a model in which excitatory neurotransmission dynamically regulates astrocyte energy metabolism by limiting the contribution of mitochondria to the metabolic response, thereby increasing the local oxygen availability and preventing excessive mitochondrial reactive oxygen species production.

Intracortical connectivity of layer VI pyramidal cells in the barrel cortex of mice

ABSTRACT : The whisker-to-barrel pathway of rodents is formed by a series of somatotopic projections from the mystacial whisker follicles to the layer IV of the primary somatosensory cortex such that each follicle corresponds to a cluster of cortical neurons called barrel. Barrels are present in layer IV but form part of functional columns that comprise the entire depth of the somatosensory cortex. Interestingly, the cortex of the barrelless mouse strain (BRL) is organized such a manner that thalamocortical afferents do not remodel their projections in layer IV and barrels fail to appear. Nevertheless, functionally, a columnar organization persists, indicating that functional columns are not only provided by thalamocortical projections and layer IV cells. Since in the visual cortex of cats, layer VI cells contribute to the response properties of layer IV neurons, we wonder whether layer VI pyramidal cells could contribute to the columnar organization of the primary somatosensory cortex of mice. To address -this question, we morphologically analyzed the distribution of intracortical axon collaterals of layer VI neurons after in-vivo juxtacellular injections of biocytin in the C2 barrel column. Injected hemispheres were tangentially serial cut and intracortical collaterals of individual layer VI neurons were reconstructed at the light microscopic level. The position of axonal boutons was recorded to evaluate the distribution of presumed synaptic contacts. In normal (NOR) mice, cluster analysis shows that layer VI pyramidal cells can be classified in four statistically different clusters of neurons. Moreover, we assume that two classes are formed by cortico-cortical neurons and two classes are formed by cortico-thalamic neurons. Looking at the direction of the main axon in the white matter, we noticed that its orientation correlates perfectly with the type of neuron: cortico-cortical neurons send main axon medially whereas cortico-thalamic neurons send main axon laterally. Performing the same study in the BRL strain, we showed that the BRL mutation affects layer VI pyramidal cells tangentially and radially: the effects of the mutation are illustrated by a significant decrease of the index of colurnnarization and a significant decrease of percentage of boutons in granular and supragranular layers comparing to NOR neurons. In spite of these differences, the same four classes of layer VI neurons have been found in BRL mice. Using a tangential analysis of the boutons distribution, we showed that putative synapses are distributed mainly in the C2 barrel column. This was observed for each layer, type of neuron, cluster or strain, indicating that layer VI pyramidal cells could participate to the functional columnar organization of the barrel cortex. To determine post-synaptic partners of layer VI neurons in layer IV, we conducted an ultrastructural analysis of layer VI-to-IV contacts. We showed that synapses principally occur on spines and spiny dendritic shafts, supposed to belong to excitatory neurons. We furthermore showed that pre-synaptic elements are significantly different between en passant and terminaux contacts, which support hypothesis that terminaux boutons should show longer duration of facilitation than en passant boutons. RÉSUMÉ : Le «whisker-to-barrel pathway» des rongeurs est caractérisé par une série de projections somatotopiques depuis les follicules des moustaches ('whiskers') jusqu'à la couche IV de l'aire somatosensorielle primaire, de telle façon que chaque follicule corresponde à un groupe de neurones corticaux appelés tonneaux (`barrels'). Les tonneaux sont seulement présents en couche IV mais font partie de colonnes fonctionnelles qui s'étendent sur toute la profondeur du cortex somatosensoriel. Chez les souris mutantes barrelless (BRL), le cortex somatosensoriel est organisé de façon telle que lés afférences thalamocorticales ne remodellent pas leurs projections en couche IV et que les tonneaux n'apparaissent pas. Fonctionnellement, pourtant, une organisation en colonnes persiste, ce qui indique que les colonnes fonctionnelles ne sont pas uniquement produites par les projections thalamocorticales et par les cellules de la couche IV. Puisque les cellules de la couche VI contribuent à influencer les réponses des cellules de la couche IV dans le cortex visuel du chat, nous nous sommes demandé si ces cellules ne pourraient pas aussi contribuer à l'organisation en colonnes du cortex somatosensoriel primaire de la souris. Pour répondre à cette question, nous avons analysé de façon morphologique la distribution intracorticale des collatéraux axonaux de neurones de la couche VI. Suite à des injections juxtacellulaires de biocytine in-vivo dans la colonne C2, les hémisphères cérébraux ont été tangentiellement coupés en série et les collatéraux intracorticaux des neurones de la couche VI ont été reconstruits en microscopie optique. La position des boutons axonaux a aussi été enregistrée pour évaluer la distribution des contacts synpptiques potentiels. Chez les souris NOR, une analyse multivariée montre que les cellules pyramidales de la couche VI sont distribuées en quatre classes. Deux de ces classes sont probablement formées de neurons cortico-corticaux, alors que les deux autres sont probablement formées de neurones corticothalamiques. En observant la direction de l'axone principal dans la matière blanche, nous avons noté que son orientation est parfaitement corrélée avec le type supposé de neurone : les neurones corticocorticaux envoient leurs axones principaux médiallement, alors que les neurons cortico-thalamiques envoient leurs axones principaux latéralement. En menant la même étude chez les souris BRL, nous avons montré que la mutation affecte les cellules pyramidales de la couche VI de façon tangentielle, mais aussi radiaire : les effets de 1a mutation se traduisent par une diminution significative de l'index de « columnarization » et de la connectivité en couches granulaire et supragranulaire. Malgré ces différences, les quatre mêmes classes de neurones ont été retrouvées. En utilisant une analyse tangentielle de la distribution des boutons, nous avons montré que les synapses potentielles sont distribuées principalement dans la colonne C2. Cette observation a été faite dans chaque couche, chaque type de neurones, chaque classe de neurones et chaque souche de souris, indicant que les cellules de la couche VI participent certainement à l'organisation en colonne du cortex somatosensoriel. Pour déterminer les partenaires post-synaptiques des cellules de la couche VI en couche IV, nous avons conduit une analyse ultrastructurelle de ces contacts. Nous avons montré que les synapses interviennent principalement sur les épines et sur les dendrites supposés appartenir à des cellules excitatrices. Nous avons aussi montré que les éléments pré-synaptiques de ces synapses sont significativement differents selon le type de bouton, en passant ou terminal, ce qui supporte l'hypothèse que les boutons terminaux seraient capables d'une plus longue facilitation.

Glutamatergic regulation of mitochondrial ion dynamics in astrocytes

Résumé grand public :Le cerveau se compose de cellules nerveuses appelées neurones et de cellules gliales dont font partie les astrocytes. Les neurones communiquent entre eux par signaux électriques et en libérant des molécules de signalisation comme le glutamate. Les astrocytes ont eux pour charge de capter le glucose depuis le sang circulant dans les vaisseaux sanguins, de le transformer et de le transmettre aux neurones pour qu'ils puissent l'utiliser comme source d'énergie. L'astrocyte peut ensuite utiliser ce glucose de deux façons différentes pour produire de l'énergie : la première s'opère dans des structures appelées mitochondries qui sont capables de produire plus de trente molécules riches en énergie (ATP) à partir d'une seule molécule de glucose ; la seconde possibilité appelée glycolyse peut produire deux molécules d'ATP et un dérivé du glucose appelé lactate. Une théorie couramment débattue propose que lorsque les astrocytes capturent le glutamate libéré par les neurones, ils libèrent en réponse du lactate qui servirait de base énergétique aux neurones. Cependant, ce mécanisme n'envisage pas une augmentation de l'activité des mitochondries des astrocytes, ce qui serait pourtant bien plus efficace pour produire de l'énergie.En utilisant la microscopie par fluorescence, nous avons pu mesurer les changements de concentrations ioniques dans les mitochondries d'astrocytes soumis à une stimulation glutamatergique. Nous avons démontré que les mitochondries des astrocytes manifestent des augmentations spontanées et transitoires de leur concentrations ioniques, dont la fréquence était diminuée au cours d'une stimulation avec du glutamate. Nous avons ensuite montré que la capture de glutamate augmentait la concentration en sodium et acidifiait les mitochondries des astrocytes. En approfondissant ces mécanismes, plusieurs éléments ont suggéré que l'acidification induite diminuerait le potentiel de synthèse d'énergie d'origine mitochondriale et la consommation d'oxygène dans les astrocytes. En résumé, l'ensemble de ces travaux suggère que la signalisation neuronale impliquant le glutamate dicte aux astrocytes de sacrifier temporairement l'efficacité de leur métabolisme énergétique, en diminuant l'activité de leurs mitochondries, afin d'augmenter la disponibilité des ressources énergétiques utiles aux neurones.Résumé :La remarquable efficacité du cerveau à compiler et propager des informations coûte au corps humain 20% de son budget énergétique total. Par conséquent, les mécanismes cellulaires responsables du métabolisme énergétique cérébral se sont adéquatement développés pour répondre aux besoins énergétiques du cerveau. Les dernières découvertes en neuroénergétique tendent à démontrer que le site principal de consommation d'énergie dans le cerveau est situé dans les processus astrocytaires qui entourent les synapses excitatrices. Un nombre croissant de preuves scientifiques a maintenant montré que le transport astrocytaire de glutamate est responsable d'un coût métabolique important qui est majoritairement pris en charge par une augmentation de l'activité glycolytique. Cependant, les astrocytes possèdent également un important métabolisme énergétique de type mitochondrial. Par conséquent, la localisation spatiale des mitochondries à proximité des transporteurs de glutamate suggère l'existence d'un mécanisme régulant le métabolisme énergétique astrocytaire, en particulier le métabolisme mitochondrial.Afin de fournir une explication à ce paradoxe énergétique, nous avons utilisé des techniques d'imagerie par fluorescence pour mesurer les modifications de concentrations ioniques spontanées et évoquées par une stimulation glutamatergique dans des astrocytes corticaux de souris. Nous avons montré que les mitochondries d'astrocytes au repos manifestaient des changements individuels, spontanés et sélectifs de leur potentiel électrique, de leur pH et de leur concentration en sodium. Nous avons trouvé que le glutamate diminuait la fréquence des augmentations spontanées de sodium en diminuant le niveau cellulaire d'ATP. Nous avons ensuite étudié la possibilité d'une régulation du métabolisme mitochondrial astrocytaire par le glutamate. Nous avons montré que le glutamate initie dans la population mitochondriale une augmentation rapide de la concentration en sodium due à l'augmentation cytosolique de sodium. Nous avons également montré que le relâchement neuronal de glutamate induit une acidification mitochondriale dans les astrocytes. Nos résultats ont indiqué que l'acidification induite par le glutamate induit une diminution de la production de radicaux libres et de la consommation d'oxygène par les astrocytes. Ces études ont montré que les mitochondries des astrocytes sont régulées individuellement et adaptent leur activité selon l'environnement intracellulaire. L'adaptation dynamique du métabolisme énergétique mitochondrial opéré par le glutamate permet d'augmenter la quantité d'oxygène disponible et amène au relâchement de lactate, tous deux bénéfiques pour les neurones.Abstract :The remarkable efficiency of the brain to compute and communicate information costs the body 20% of its total energy budget. Therefore, the cellular mechanisms responsible for brain energy metabolism developed adequately to face the energy needs. Recent advances in neuroenergetics tend to indicate that the main site of energy consumption in the brain is the astroglial process ensheating activated excitatory synapses. A large body of evidence has now shown that glutamate uptake by astrocytes surrounding synapses is responsible for a significant metabolic cost, whose metabolic response is apparently mainly glycolytic. However, astrocytes have also a significant mitochondrial oxidative metabolism. Therefore, the location of mitochondria close to glutamate transporters raises the question of the existence of mechanisms for tuning their energy metabolism, in particular their mitochondrial metabolism.To tackle these issues, we used real time imaging techniques to study mitochondrial ionic alterations occurring at resting state and during glutamatergic stimulation of mouse cortical astrocytes. We showed that mitochondria of intact resting astrocytes exhibited individual spontaneous and selective alterations of their electrical potential, pH and Na+ concentration. We found that glutamate decreased the frequency of mitochondrial Na+ transient activity by decreasing the cellular level of ATP. We then investigated a possible link between glutamatergic transmission and mitochondrial metabolism in astrocytes. We showed that glutamate triggered a rapid Na+ concentration increase in the mitochondrial population as a result of plasma-membrane Na+-dependent uptake. We then demonstrated that neuronally released glutamate also induced a mitochondrial acidification in astrocytes. Glutamate induced a pH-mediated and cytoprotective decrease of mitochondrial metabolism that diminished oxygen consumption. Taken together, these studies showed that astrocytes contain mitochondria that are individually regulated and sense the intracellular environment to modulate their own activity. The dynamic regulation of astrocyte mitochondrial energy output operated by glutamate allows increasing oxygen availability and lactate production both being beneficial for neurons.

Roles of mGluR5 in synaptic function and plasticity of the mouse thalamocortical pathway.

The group I metabotropic glutamate receptor 5 (mGluR5) has been implicated in the development of cortical sensory maps. However, its precise roles in the synaptic function and plasticity of thalamocortical (TC) connections remain unknown. Here we first show that in mGluR5 knockout (KO) mice bred onto a C57BL6 background cytoarchitectonic differentiation into barrels is missing, but the representations for large whiskers are identifiable as clusters of TC afferents. The altered dendritic morphology of cortical layer IV spiny stellate neurons in mGluR5 KO mice implicates a role for mGluR5 in the dendritic morphogenesis of excitatory neurons. Next, in vivo single-unit recordings of whisker-evoked activity in mGluR5 KO adults demonstrated a preserved topographical organization of the whisker representation, but a significantly diminished temporal discrimination of center to surround whiskers in the responses of individual neurons. To evaluate synaptic function at TC synapses in mGluR5 KO mice, whole-cell voltage-clamp recording was conducted in acute TC brain slices prepared from postnatal day 4-11 mice. At mGluR5 KO TC synapses, N-methyl-D-aspartate (NMDA) currents decayed faster and synaptic strength was more easily reduced, but more difficult to strengthen by Hebbian-type pairing protocols, despite a normal developmental increase in alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR)-mediated currents and presynaptic function. We have therefore demonstrated that mGluR5 is required for synaptic function/plasticity at TC synapses as barrels are forming, and we propose that these functional alterations at the TC synapse are the basis of the abnormal anatomical and functional development of the somatosensory cortex in the mGluR5 KO mouse.

Connexin 30 sets synaptic strength by controlling astroglial synapse invasion.

Astrocytes play active roles in brain physiology by dynamic interactions with neurons. Connexin 30, one of the two main astroglial gap-junction subunits, is thought to be involved in behavioral and basic cognitive processes. However, the underlying cellular and molecular mechanisms are unknown. We show here in mice that connexin 30 controls hippocampal excitatory synaptic transmission through modulation of astroglial glutamate transport, which directly alters synaptic glutamate levels. Unexpectedly, we found that connexin 30 regulated cell adhesion and migration and that connexin 30 modulation of glutamate transport, occurring independently of its channel function, was mediated by morphological changes controlling insertion of astroglial processes into synaptic clefts. By setting excitatory synaptic strength, connexin 30 plays an important role in long-term synaptic plasticity and in hippocampus-based contextual memory. Taken together, these results establish connexin 30 as a critical regulator of synaptic strength by controlling the synaptic location of astroglial processes.

Ampakine CX546 bolsters energetic response of astrocytes: a novel target for cognitive-enhancing drugs acting as alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor modulators.

Glutamate was previously shown to enhance aerobic glycolysis i.e. increase glucose utilization and lactate production with no change in oxygen levels, in mouse cortical astrocytes by a mechanism involving glutamate uptake. It is reported here that a similar response is produced in both hippocampal and cerebellar astrocytes. Application of the cognitive-enhancing drug CX546 promoted further enhancement of glucose utilization by astrocytes from each brain area following glutamate exposure. alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors represent the purported molecular target of cognitive-enhancing drugs such as CX546, and the presence of AMPA receptor subunits GluR1-4 was evidenced in astrocytes from all three regions by immunocytochemistry. AMPA itself did not stimulate aerobic glycolysis, but in the presence of CX546, a strong enhancement of glucose utilization and lactate production was obtained in cortical, hippocampal and cerebellar astrocytes. The effect of CX546 was concentration-dependent, with an EC(50) of 93.2 microm in cortical astrocytes. AMPA-induced glucose utilization in the presence of CX546 was prevented by the AMPA receptor antagonist 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX) and the negative modulator GYKI 52466. In addition, the metabolic effect of CX546 in the presence of AMPA was mimicked by the AMPA receptor modulator cyclothiazide. Our data suggest that astrocyte energetics represents a novel target for cognitive-enhancing drugs acting as AMPA receptor modulators.

How local excitation-inhibition ratio impacts the whole brain dynamics.

The spontaneous activity of the brain shows different features at different scales. On one hand, neuroimaging studies show that long-range correlations are highly structured in spatiotemporal patterns, known as resting-state networks, on the other hand, neurophysiological reports show that short-range correlations between neighboring neurons are low, despite a large amount of shared presynaptic inputs. Different dynamical mechanisms of local decorrelation have been proposed, among which is feedback inhibition. Here, we investigated the effect of locally regulating the feedback inhibition on the global dynamics of a large-scale brain model, in which the long-range connections are given by diffusion imaging data of human subjects. We used simulations and analytical methods to show that locally constraining the feedback inhibition to compensate for the excess of long-range excitatory connectivity, to preserve the asynchronous state, crucially changes the characteristics of the emergent resting and evoked activity. First, it significantly improves the model's prediction of the empirical human functional connectivity. Second, relaxing this constraint leads to an unrealistic network evoked activity, with systematic coactivation of cortical areas which are components of the default-mode network, whereas regulation of feedback inhibition prevents this. Finally, information theoretic analysis shows that regulation of the local feedback inhibition increases both the entropy and the Fisher information of the network evoked responses. Hence, it enhances the information capacity and the discrimination accuracy of the global network. In conclusion, the local excitation-inhibition ratio impacts the structure of the spontaneous activity and the information transmission at the large-scale brain level.

Phasic, nonsynaptic GABA-A receptor-mediated inhibition entrains thalamocortical oscillations.

GABA-A receptors (GABA-ARs) are typically expressed at synaptic or nonsynaptic sites mediating phasic and tonic inhibition, respectively. These two forms of inhibition conjointly control various network oscillations. To disentangle their roles in thalamocortical rhythms, we focally deleted synaptic, γ2 subunit-containing GABA-ARs in the thalamus using viral intervention in mice. After successful removal of γ2 subunit clusters, spontaneous and evoked GABAergic synaptic currents disappeared in thalamocortical cells when the presynaptic, reticular thalamic (nRT) neurons fired in tonic mode. However, when nRT cells fired in burst mode, slow phasic GABA-AR-mediated events persisted, indicating a dynamic, burst-specific recruitment of nonsynaptic GABA-ARs. In vivo, removal of synaptic GABA-ARs reduced the firing of individual thalamocortical cells but did not abolish slow oscillations or sleep spindles. We conclude that nonsynaptic GABA-ARs are recruited in a phasic manner specifically during burst firing of nRT cells and provide sufficient GABA-AR activation to control major thalamocortical oscillations.

Quantitative electroencephalography reveals different physiological profiles between benign and remitting-relapsing multiple sclerosis patients

BACKGROUND A possible method of finding physiological markers of multiple sclerosis (MS) is the application of EEG quantification (QEEG) of brain activity when the subject is stressed by the demands of a cognitive task. In particular, modulations of the spectral content that take place in the EEG of patients with multiple sclerosis remitting-relapsing (RRMS) and benign multiple sclerosis (BMS) during a visuo-spatial task need to be observed. METHODS The sample consisted of 19 patients with RRMS, 10 with BMS, and 21 control subjects. All patients were free of medication and had not relapsed within the last month. The power spectral density (PSD) of different EEG bands was calculated by Fast-Fourier-Transformation (FFT), those analysed being delta, theta, alpha, beta and gamma. Z-transformation was performed to observe individual profiles in each experimental group for spectral modulations. Lastly, correlation analyses was performed between QEEG values and other variables from participants in the study (age, EDSS, years of evolution and cognitive performance). RESULTS Nearly half (42%) the RRMS patients showed a statistically significant increase of two or more standard deviations (SD) compared to the control mean value for the beta-2 and gamma bands (F = 2.074, p = 0.004). These alterations were localized to the anterior regions of the right hemisphere, and bilaterally to the posterior areas of the scalp. None of the BMS patients or control subjects had values outside the range of +/- 2 SD. There were no significant correlations between these values and the other variables analysed (age, EDSS, years of evolution or behavioural performance). CONCLUSION During the attentional processing, changes in the high EEG spectrum (beta-2 and gamma) in MS patients exhibit physiological alterations that are not normally detected by spontaneous EEG analysis. The different spectral pattern between pathological and controls groups could represent specific changes for the RRMS patients, indicative of compensatory mechanisms or cortical excitatory states representative of some phases during the RRMS course that are not present in the BMS group.