Intense Neuronal Activity Research Articles

Action potential bursts enhance transmitter release at a giant central synapse

Patterns of action potentials (APs), often in the form of bursts, are critical for coding and processing information in the brain. However, how AP bursts modulate secretion at synapses remains elusive. Here, using the calyx of Held synapse as a model we compared synaptic release evoked by AP patterns with a different number of bursts while the total number of APs and frequency were fixed. The ratio of total release produced by multiple bursts to that by a single burst was defined as 'burst-effect'.We found that four bursts of 25 stimuli at 100 Hz increased the totalcharge of EPSCs to 1.47 ± 0.04 times that by a single burst of 100 stimuli at the same frequency.Blocking AMPA receptor desensitization and saturation did not alter the burst-effect, indicating that it was mainly determined by presynaptic mechanisms. Simultaneous dual recordings of presynaptic membrane capacitance (Cm) and EPSCs revealed a similar burst-effect, being 1.58±0.13by Cm and 1.49±0.05 by EPSCs. Reducing presynapticCa2+ influx by lowering extracellular Ca2+concentration or buffering residual intracellular Ca2+ with EGTA inhibited the burst-effect. We further developed a computational model largely recapitulating the burst-effect and demonstrated that this effect is highly sensitive to dynamic change in availability of the releasable pool of synaptic vesicles during various patterns of activities. Taken together, we conclude that AP bursts modulate synaptic output mainly through intricate interaction between depletion and replenishment of the large releasable pool. This burst-effect differs from the somatic burst-effect previously described from adrenal chromaffin cells, which substantially depends on activity-induced accumulation of Ca2+ to facilitate release of a limited number of vesicles in the releasable pool. Hence, AP bursts may play an important role in dynamically regulating synaptic strength and fidelity during intense neuronal activity at central synapses.

Predominant Enhancement of Glucose Uptake in Astrocytes versus Neurons during Activation of the Somatosensory Cortex

Glucose is the primary energetic substrate of the brain, and measurements of its metabolism are the basis of major functional cerebral imaging methods. Contrary to the general view that neurons are fueled solely by glucose in proportion to their energetic needs, recent in vitro and ex vivo analyses suggest that glucose preferentially feeds astrocytes. However, the cellular fate of glucose in the intact brain has not yet been directly observed. We have used a real-time method for measuring glucose uptake in astrocytes and neurons in vivo in male rats by imaging the trafficking of the nonmetabolizable glucose analog 6-deoxy-N-(7-nitrobenz-2-oxa-1,3-diazol-4-yl)-aminoglucose (6-NBDG) using two-photon microscopy. During resting conditions we found that astrocytes and neurons both take up 6-NBDG at the same rate in the barrel cortex of the rat. However, during intense neuronal activity triggered by whisker stimulation, astrocytes rapidly accelerated their uptake, whereas neuronal uptake remained almost unchanged. After the stimulation period, astrocytes returned to their preactivation rates of uptake paralleling the neuronal rate of uptake. These observations suggest that glucose is taken up primarily by astrocytes, supporting the view that functional imaging experiments based on glucose analogs extraction may predominantly reflect the metabolic activity of the astrocytic network.

Changes in Membrane Potential and the Intracellular Calcium Concentration During CSD and OGD in Layer V and Layer II/III Mouse Cortical Neurons

Cortical spreading depression (CSD) is an episode of electrical silence following intense neuronal activity that propagates across the cortex at ∼3-6 mm/min and is associated with transient neuronal depolarization. CSD is benign in normally perfused brain tissue, but there is evidence suggesting that repetitive CSD contributes to infarct growth following focal ischemia. Studies to date have assumed that the cellular responses to CSD are uniform across neuronal types because there are no data to the contrary. In this study, we investigated the effect of CSD on membrane potential and the intracellular calcium concentration ([Ca(2+)](i)) of mouse layer V and layer II/III pyramidal neurons in brain slices. To place the data in context, we made similar measurements during anoxic depolarization induced by oxygen and glucose deprivation (OGD). The [Ca(2+)](i) was quantified using the low-affinity ratiometric indicator Fura-4F. During both CSD- and OGD-induced depolarization, the membrane potential approached 0 mV in all neurons. In layer V pyramids OGD resulted in an increase in [Ca(2+)](i) to a maximum of 3.69 ± 0.73 (SD) μM (n = 12), significantly greater than the increase to 1.81 ± 0.70 μM in CSD (n = 34; P < 0.0001). Membrane potential and [Ca(2+)](i) returned to nearly basal levels following CSD but not OGD. Layer II/III neurons responded to CSD with a greater peak increase in [Ca(2+)](i) than layer V neurons (2.88 ± 0.6 μM; n = 9; P < 0.01). We conclude there is a laminar difference in the response of pyramidal neurons to CSD; possible explanations are discussed.

Activity-Dependent Bulk Endocytosis and Clathrin-Dependent Endocytosis Replenish Specific Synaptic Vesicle Pools in Central Nerve Terminals

Multiple synaptic vesicle (SV) retrieval modes exist in central nerve terminals to maintain a continual supply of SVs for neurotransmission. Two such modes are clathrin-mediated endocytosis (CME), which is dominant during mild neuronal activity, and activity-dependent bulk endocytosis (ADBE), which is dominant during intense neuronal activity. However, little is known about how activation of these SV retrieval modes impact the replenishment of the total SV recycling pool and the pools that reside within it, the readily releasable pool (RRP) and reserve pool. To address this question, we examined the replenishment of all three SV pools by triggering these SV retrieval modes during both high- and low-intensity stimulation of primary rat neuronal cultures. SVs generated by CME and ADBE were differentially labeled using the dyes FM1-43 and FM2-10, and their replenishment of specific SV pools was quantified using stimulation protocols that selectively depleted each pool. Our studies indicate that while the RRP was replenished by CME-generated SVs, ADBE provided additional SVs to increase the capacity of the reserve pool. Morphological analysis of the uptake of the fluid phase marker horseradish peroxidase corroborated these findings. The differential replenishment of specific SV pools by independent SV retrieval modes illustrates how previously experienced neuronal activity impacts the capability of central nerve terminals to respond to future stimuli.

Central Sensitization and CaVα2δ Ligands in Chronic Pain Syndromes: Pathologic Processes and Pharmacologic Effect

Central sensitization is one form of long-term plasticity in the central nervous system. Sustained activation of primary sensory fibers supplying dorsal horn can induce long-lasting increases in the discharge amplitude of primary afferent synapses. This is similar to the long-term potentiation that occurs in many other CNS regions. Drugs that limit the short-duration wind-up component of central sensitization include sodium channel blockers, NMDA antagonists, fast-acting opioids and the calcium-channel ligands gabapentin and pregabalin (S-3-(aminomethyl)-5-methylhexanoic acid). Pregabalin, like gabapentin, binds selectively to the Ca(V)α₂δ auxiliary subunit of presynaptic voltage-gated calcium channels. The conformational changes induced by this binding inhibit abnormally intense neuronal activity by reducing the synaptic release of glutamate and other neurotransmitters. Recent identification in animal models of increased Ca(V)α₂δ protein expression in chronic pain, allodynia, and hyperalgesia have drawn additional interest to drugs that bind the Ca(V)α₂δ site. Experimental studies with animal models and healthy human volunteers have shown that pregabalin reduces nociceptive responses, particularly in conditions involving central sensitization. Since these actions occur with relatively modest effects on physiological and cognitive functions, pregabalin may be an important consideration in the pharmacotherapy of otherwise difficult-to-treat pain syndromes. This focus article discusses how the central nervous system plasticity phenomenon, central sensitization, is established in the induction and maintenance of chronic pain, allodynia, and hyperalgesia. In addition, it explores the neurophysiologic actions of the calcium-channel ligands gabapentin and pregabalin in limiting pathological manifestations of central sensitization.

Endogenous purinergic signaling is required for osmotic volume regulation of retinal glial cells

Intense neuronal activity in the sensory retina is associated with a volume increase of neuronal cells (Uckermann et al., J. Neurosci. 2004, 24:10149) and a decrease in the osmolarity of the extracellular space fluid (Dmitriev et al., Vis. Neurosci. 1999, 16:1157). Here, we show the existence of an endogenous purinergic mechanism that prevents hypoosmotic swelling of retinal glial (Müller) cells in mice. In contrast to the cells from wild-type mice, hypoosmotic stress induced rapid swelling of glial cell somata in retinal slices from mice deficient in P2Y(1), adenosine A(1) receptors, or ecto-5'-nucleotidase (CD73). Consistently, glial cell bodies in retinal slices from wild-type mice displayed osmotic swelling when P2Y(1) or A(1) receptors, or CD73, were pharmacologically blocked. Exogenous ATP, UTP, and UDP inhibited glial swelling in retinal slices, while the swelling of isolated glial cells was prevented by ATP but not by UTP or UDP, suggesting that uracil nucleotides indirectly regulate the glial cell volume via activation of neuronal P2Y(4/6) and neuron-to-glia signaling. It is suggested that autocrine/paracrine activation of purinergic receptors and enzymes is crucially involved in the regulation of the glial cell volume.

Synaptic mitochondria in synaptic transmission and organization of vesicle pools in health and disease

Cell types rich in mitochondria, including neurons, display a high energy demand and a need for calcium buffering. The importance of mitochondria for proper neuronal function is stressed by the occurrence of neurological defects in patients suffering from a great variety of diseases caused by mutations in mitochondrial genes. Genetic and pharmacological evidence also reveal a role of these organelles in various aspects of neuronal physiology and in the pathogenesis of neurodegenerative disorders. Yet the mechanisms by which mitochondria can affect neurotransmission largely remain to be elucidated. In this review we focus on experimental data that suggest a critical function of synaptic mitochondria in the function and organization of synaptic vesicle pools, and in neurotransmitter release during intense neuronal activity. We discuss how calcium handling, ATP production and other mitochondrial mechanisms may influence synaptic vesicle pool organization and synaptic function. Given the link between synaptic mitochondrial function and neuronal communication, efforts toward better understanding mitochondrial biology may lead to novel therapeutic approaches of neurological disorders including Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis and psychiatric disorders that are at least in part caused by mitochondrial deficits.

Elevated activity of the crayfish stretch receptor neuron increases resistance of surrounding glial cells to apoptosis induced by photodynamic treatment

Neuroglial interaction is very important for functioning and survival of nerve and glial cells. In the present work, we studied the influence of the intense neuronal activity on survival of the isolated crayfish stretch receptor neuron and surrounding glial cells subjected to photodynamic treatment, which induces intense oxidative stress. In the experimental group, neurons were stimulated by multiple extensions of the receptor muscle for 1 h so that the firing rate did not fall below 10–15 Hz, whereas in the control group, the receptor muscles were relaxed and neurons were silent. After stimulation, the preparations were photosensitized with alumophthalocyanine Photosens and irradiated by 670 nm laser diode. The isolated stretch receptors were stained with propidium iodide and Hoechst 33342, which reveal the nuclei of the necrotic and the apoptotic cells, respectively. The level of apoptosis of photosensitized glial cells was significantly lower in the experimental group compared to the resting control. Necrosis of neurons and glial cells was not significantly influenced. Therefore, elevated neuronal activity increased the resistance of the surrounding glial cells to photoinduced apoptosis. This could be attributed to the depletion of the energetic resources, which are transferred from glia into the neuron to support its firing, or to the neurotrophic neuron-to-glia signaling.

The molecular physiology of activity‐dependent bulk endocytosis of synaptic vesicles

Central nerve terminals release neurotransmitter in response to a wide variety of stimuli. Because maintenance of neurotransmitter release is dependent on the continual supply of synaptic vesicles (SVs), nerve terminals possess an array of endocytosis modes to retrieve and recycle SV membrane and proteins. During mild stimulation conditions, single SV retrieval modes such as clathrin-mediated endocytosis predominate. However, during increased neuronal activity, additional SV retrieval capacity is required, which is provided by activity-dependent bulk endocytosis (ADBE). ADBE is the dominant SV retrieval mechanism during elevated neuronal activity. It is a high capacity SV retrieval mode that is immediately triggered during such stimulation conditions. This review will summarize the current knowledge regarding the molecular mechanism of ADBE, including molecules required for its triggering and subsequent steps, including SV budding from bulk endosomes. The molecular relationship between ADBE and the SV reserve pool will also be discussed. It is becoming clear that an understanding of the molecular physiology of ADBE will be of critical importance in attempts to modulate both normal and abnormal synaptic function during intense neuronal activity.

Quantitative monitoring of activity-dependent bulk endocytosis of synaptic vesicle membrane by fluorescent dextran imaging

Activity-dependent bulk endocytosis (ADBE) is the dominant synaptic vesicle (SV) retrieval mode in central nerve terminals during periods of intense neuronal activity. Despite this fact there are very few real time assays that report the activity of this critical SV retrieval mode. In this paper we report a simple and quantitative assay of ADBE using uptake of large flourescent dextrans as fluid phase markers. We show that almost all dextran uptake occurs in nerve terminals, using co-localisation with the fluorescent probe FM1-43. We also demonstrate that accumulated dextran cannot be unloaded by neuronal stimulation, indicating its specific loading into bulk endosomes and not SVs. Quantification of dextran uptake was achieved by using thresholding analysis to count the number of loaded nerve terminals, since monitoring the average fluorescence intensity of these nerve terminals did not accurately report the extent of ADBE. Using this analysis we showed that dextran uptake occurs very soon after stimulation and that it does not persist when stimulation terminates. Thus we have devised a simple and quantitative method to monitor ADBE in living neurones, which will be ideal for real time screening of small molecule inhibitors of this key SV retrieval mode.

EEG spectral changes underlying BOLD responses contralateral to spikes in patients with focal epilepsy

Simultaneous electroencephalogram and functional magnetic resonance imaging (EEG-fMRI) in patients with focal epilepsy and unilateral spikes often shows positive blood oxygenation level-dependent (BOLD) responses (activations), not only ipsilateral but also contralateral to the spikes. We aimed to investigate whether minimal EEG changes could underlie these contralateral BOLD responses by using EEG spectral analysis. We studied 19 patients with focal epilepsy and unilateral spikes. According to the pattern of BOLD activation, patients were divided into Group 1 (ipsi- and contralateral to the spikes) or Group 2 (only ipsilateral). EEG from outside the scanner was used to mark spikes similar to those recorded in the scanner. Epochs of 640 ms before and after the peak of the spikes were chosen as baseline and spike epochs. Spectral analysis was performed in referential montage (FCz reference), and differences between baselines and spikes were analyzed by paired t-test. Significant EEG changes in electrodes contralateral to the spikes were seen in 9 of 10 patients in Group 1 and in only 2 of 10 patients in Group 2 (one patient had two types of spikes that were analyzed separately). Spectral changes were seen in delta and/or theta bands in all patients except one (in Group 1) who had changes in all bands. Significant contralateral EEG changes occurred in 90% of contralateral BOLD activations and in only 20% of patients without contralateral BOLD responses. The reason why these changes predominate in lower frequencies rather than in higher frequencies is unclear. These spectral changes in areas corresponding to contralateral activations might reflect poorly synchronized but possibly intense neuronal activity.

Calcium responses mediated by type 2 IP3-receptors are required for osmotic volume regulation of retinal glial cells in mice

Prevention of osmotic swelling of retinal glial (Müller) cells is required to avoid detrimental decreases in the extracellular space volume during intense neuronal activity. Here, we show that glial cells in slices of the wildtype mouse retina maintain the volume of their somata constant up to ∼4min of perfusion with a hypoosmolar solution. However, calcium chelation with BAPTA/AM induced a rapid swelling of glial cell bodies. In glial cells of retinas from inositol-1,4,5-trisphosphate-receptor type 2-deficient (IP3R2−/−) mice, hypotonic conditions caused swelling of the cell bodies without delay. Exogenous ATP (acting at P2Y1 receptors) prevented the swelling of glial cells in retinal slices from wildtype but not from IP3R2−/− mice. Müller cells from IP3R2−/− mice displayed a strongly reduced amplitude of the ATP-evoked calcium responses as compared to cells from wildtype mice. It is concluded that endogenous calcium signaling mediated by IP3R2 is required for the osmotic volume regulation of retinal glial cells.

Glial cell‐derived glutamate mediates autocrine cell volume regulation in the retina: activation by VEGF

Astroglial cells are a source for gliotransmitters such as glutamate and ATP. We demonstrate here that gliotransmitters have autocrine functions in the regulation of cellular volume. Hypoosmotic stress in the presence of inflammatory mediators or oxidative stress, and during blockade or down-regulation of potassium channels, induces swelling of retinal glial cells. Vascular endothelial growth factor inhibits the osmotic swelling of glial cells in retinal slices or isolated cells. This effect was mediated by a kinase domain region/flk-1 receptor-evoked calcium dependent release of glutamate from glial cells, and subsequent stimulation of glial group I/II metabotropic glutamate receptors. Activation of kinase domain region/flk-1 or glutamate receptors evoked an autocrine swelling-inhibitory purinergic signaling cascade that was calcium-independent. This cascade involved the release of ATP and adenosine, and the activation of purinergic P2Y(1) and adenosine A1 receptors, resulting in the opening of potassium and chloride channels and inhibition of cellular swelling. The glutamatergic-purinergic regulation of the glial cell volume may be functionally important in the homeostasis of the extracellular space volume during intense neuronal activation which is associated with a swelling of neuronal cell structures in the retina. However, glial cell-derived glutamate may also contribute to the swelling of activated neurons since metabolic poisoning of glial cells by iodoacetate inhibits the neuronal cell swelling mediated by activation of ionotropic glutamate receptors.

Plasticity in Sublesionally Located Neurons Following Spinal Cord Injury

Neuronal plasticity has been traditionally associated with learning and memory processes in the hippocampal regions of the brain. It is now generally accepted that plasticity phenomena are also associated with other kinds of cellular changes and modifications occurring in all areas of the CNS after injury or intense neuronal activity. For instance, spinal cord injuries have been associated with a series of cellular modifications and adaptations taking place distally in sublesional areas. Some of these modifications include changes in the expression of immediate early genes (e.g., c-fos and nor-1), TNF-alpha, preprodynorphin, neurotrophic factors (e.g., BDNF and NT-3), and several subtypes of transmembranal receptors (e.g., 5-HT(1A) and 5-HT(2A)). This review constitutes an update of the current knowledge regarding this broadly defined plasticity phenomenon that occurs spontaneously or can be modulated by training in sublesional segments of the spinal cord. Spinal cord plasticity is an increasingly popular field of research, believed by many as being a complex phenomenon that may contribute to the development of innovative therapeutics and rehabilitative approaches for spinal cord injured patients.

ATP release and hydrolysis contribute to rat pial arteriolar dilatation elicited by neuronal activation

Owing to their intimate anatomical relationship with cerebral arterioles, astrocytes have been postulated as signal transducers, transferring information from activated neurones to the cerebral microcirculation. These forwarded signals may involve the release of vasoactive factors from the end-feet of astrocytes. This mechanism is termed 'neurovascular coupling' and its anatomical components (i.e. neurone, astrocyte and vascular cells) are termed the 'neurovascular unit'. The process of neurovascular coupling often involves upstream dilatation. This is necessary during periods of increased metabolic demand, in order to permit more blood to reach dilated downstream vessels, thereby improving nutrient supply to the activated neurones. Without it, that downstream dilatation might be ineffective, placing neurones at risk, especially during episodes of intense neuronal activity, such as seizure. In the brain, pial arterioles represent important 'upstream' vascular segments. The pial arterioles overlie a thick layer of astrocytic processes, termed the glia limitans. This essentially isolates pial arterioles, anatomically, from the neurones below. Vasodilating signals that originate in the neurones therefore reach the pial arterioles via indirect pathways, primarily involving astrocytes and the glia limitans. Here we discuss a process whereby purinergic mechanisms play a key and neuronal activity-dependent role in astrocyte to astrocyte communication, as well as in glia limitans to pial arteriolar signals leading to vasodilatation.

Mitochondria at the Synapse

Synapses are packed with mitochondria, complex organelles with roles in energy metabolism, cell signaling, and calcium homeostasis. However, the precise mechanisms by which mitochondria influence neurotrans mission remain undefined. In this review, the authors discuss pharmacological and genetic analyses of synaptic mitochondrial function, focusing on their role in Ca2+ buffering and ATP production. Additionally, they will summarize recent data that implicate synaptic mitochondria in the regulation of neurotransmitter release during intense neuronal activity and link these findings to the pathogenesis of neurodegenerative diseases that feature disrupted synaptic mitochondria, including amyotrophic lateral sclerosis and hereditary spastic paraplegia.

A prominent role for amygdaloid complexes in the Variability in Heart Rate (VHR) during Rapid Eye Movement (REM) sleep relative to wakefulness

Rapid eye movement sleep (REMS) is associated with intense neuronal activity, rapid eye movements, muscular atonia and dreaming. Another important feature in REMS is the instability in autonomic, especially in cardiovascular regulation. The neural mechanisms underpinning the variability in heart rate (VHR) during REMS are not known in detail, especially in humans. During wakefulness, the right insula has frequently been reported as involved in cardiovascular regulation but this might not be the case during REMS. We aimed at characterizing the neural correlates of VHR during REMS as compared to wakefulness and to slow wave sleep (SWS), the other main component of human sleep, in normal young adults, based on the statistical analysis of a set of H 2 15O positron emission tomography (PET) sleep data acquired during SWS, REMS and wakefulness. The results showed that VHR correlated more tightly during REMS than during wakefulness with the rCBF in the right amygdaloid complex. Moreover, we assessed whether functional relationships between amygdala and any brain area changed depending the state of vigilance. Only the activity within in the insula was found to covary with the amygdala, significantly more tightly during wakefulness than during REMS in relation to the VHR. The functional connectivity between the amygdala and the insular cortex, two brain areas involved in cardiovascular regulation, differs significantly in REMS as compared to wakefulness. This suggests a functional reorganization of central cardiovascular regulation during REMS.

Evidence that GAD65 mediates increased GABA synthesis during intense neuronal activity in vivo

In this study we tested the hypothesis that the 65-kDa isoform of glutamate decarboxylase (GAD(65)) mediates activity-dependent GABA synthesis as invoked by seizures in anesthetized rats. GABA synthesis was measured following acute GABA-transaminase inhibition by gabaculine using spatially localized (1)H NMR spectroscopy before and after bicuculline-induced seizures. Experiments were conducted with animals pre-treated with vigabatrin 24 h earlier in order to reduce GAD(67) protein and also with non-treated controls. GAD isoform content was quantified by immunoblotting. GABA was higher in vigabatrin-treated rats compared to non-treated controls. In vigabatrin-treated animals, GABA synthesis was 28% lower compared to controls [p < 0.05; vigabatrin-treated, 0.043 +/- 0.011 micromol/(g min); non-treated, 0.060 +/- 0.014 micromol/(g min)] and GAD(67) was 60% lower. No difference between groups was observed for GAD(65). Seizures increased GABA synthesis in both control [174%; control, 0.060 +/- 0.014 micromol/(g min) vs. seizures, 0.105 +/- 0.043 micromol/(g min)] and vigabatrin-treated rats [214%; control, 0.043 +/- 0.011 micromol/(g min); seizures, 0.092 +/- 0.018 micromol/(g min)]. GAD(67) could account for at least half of basal GABA synthesis but only 20% of the two-fold increase observed in vigabatrin-treated rats during seizures. The seizure-induced activation of GAD(65) in control cortex occurs concomitantly with a 2.3-fold increase in inorganic phosphate, known to be a potent activator of apoGAD(65)in vitro. Our results are consistent with a major role for GAD(65) in activity-dependent GABA synthesis.

Grey matter heterotopia: what EEG-fMRI can tell us about epileptogenicity of neuronal migration disorders

Grey matter heterotopia are commonly associated with refractory epilepsy. Depth electrodes recordings have shown that epileptiform activity can be generated within these lesions, and also at a distance in the neocortex. Heterotopia seem to be part of a more complex circuitry involving also the surrounding and distant cerebral cortex. Blood oxygenation level-dependent (BOLD) changes to interictal spikes using continuous EEG and functional MRI (EEG-fMRI) can help to understand non-invasively the mechanisms of epileptogenicity in these patients. We studied 14 patients with epilepsy and heterotopia using simultaneous recording of EEG-fMRI. EEG was continuously acquired from inside the scanner during 2 h sessions. Epileptic spikes were visually identified in the filtered EEG and each type of spike determined one EEG-fMRI study. We looked at positive (activation) and negative (deactivation) changes in the BOLD signal. Eleven patients had nodular heterotopia and three band heterotopia. Four patients had more than one type of spikes, with a total of 26 EEG-fMRI studies. We excluded three with less than three spikes, and therefore a total of 23 studies (12 with nodular and 11 with band heterotopia) were analysed. Nodular heterotopia: Activation was present in nine studies, with involvement of the heterotopia or surrounding cortex in six, three of which had concomitant distant activation. Deactivation was also observed in nine studies, with involvement of the heterotopia and surrounding cortex in four, three of which had concomitant distant deactivation. Band heterotopia: Activation was present in all 11 studies, and always involved the heterotopia and surrounding cortex, 9 of which had concomitant distant activation. Deactivation was also observed in all 11 studies, with involvement of both the heterotopia and surrounding cortex, in addition to distant deactivation in 5 studies. EEG-fMRI studies reveal, non-invasively, metabolic responses in the heterotopia despite the fact that spikes are generated in the neocortex. The responses, activation or deactivation, had different correlation with the lesion and surrounding or distant cortex, activation reflecting intense neuronal activity, or excitation, and deactivation a possible distant (extra-lesional) inhibition. EEG-fMRI may become a useful tool to understand the epileptogenicity of such malformations.

Activation of the Trk Signaling Pathway by Extracellular Zinc: ROLE OF METALLOPROTEINASES

In certain brain regions, extracellular zinc concentrations can rise precipitously as intense neuronal activity releases large amounts of zinc from the nerve terminals. Although zinc release has been suggested to play a pathological role, its precise physiological effect is poorly understood. Here, we report that exposure to micromolar quantities of zinc for only a few minutes robustly and specifically activated tropomyosin-related kinase (Trk) receptors, most likely TrkB, in cultured cortical neurons. We further found that Trk activation by zinc is extracellularly mediated by activation of metalloproteinases, which release pro-BDNF from cells and convert pro-BDNF to mature BDNF. These results suggest that activity-dependent release of extracellular zinc leads to metalloproteinase activation, which plays a critically important role in Trk receptor activation at zinc-containing synapses.