Mechanisms of epileptogenesis: a convergence on neural circuit dysfunction
TL;DR: It is suggested that insights into the mechanisms of epileptogenesis converge at the level of cortical circuit dysfunction, with the hope of preventing epilepsy before seizures emerge.
Abstract: Epilepsy is a prevalent neurological disorder associated with significant morbidity and mortality, but the only available drug therapies target its symptoms rather than the underlying cause The process that links brain injury or other predisposing factors to the subsequent emergence of epilepsy is termed epileptogenesis Substantial research has focused on elucidating the mechanisms of epileptogenesis so as to identify more specific targets for intervention, with the hope of preventing epilepsy before seizures emerge Recent work has yielded important conceptual advances in this field We suggest that such insights into the mechanisms of epileptogenesis converge at the level of cortical circuit dysfunction
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TL;DR: Current understanding of neocortical interneuron diversity and the properties that distinguish cell types are reviewed and it is illustrated how recent advances in the field have shed light onto the mechanisms by which GABAergic inhibition contributes to network operations.
1,358 citations
Cites background from "Mechanisms of epileptogenesis: a co..."
...Although impairment of PV and Sst INs has been implicated in the generation of hypersynchronous activity and epilepsy (Goldberg and Coulter, 2013; Hunt et al., 2013; Ito-Ishida et al., 2015; Paz and Huguenard, 2015), there are differences in the recruitment and functional impact of these circuits that reflect the specialized properties of these two types of INs....
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...Although impairment of PV and Sst INs has been implicated in the generation of hypersynchronous activity and epilepsy (Goldberg and Coulter, 2013; Hunt et al., 2013; Ito-Ishida et al., 2015; Paz and Huguenard, 2015), there are differences in the recruitment and functional impact of these circuits…...
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TL;DR: This work has shown that one family of ion transporters, cation-chloride cotransporters (CCCs), and in particular K+–Cl− cOTransporter 2 (KCC2), have seminal roles in shaping GABAergic signalling and neuronal connectivity.
Abstract: Electrical activity in neurons requires a seamless functional coupling between plasmalemmal ion channels and ion transporters. Although ion channels have been studied intensively for several decades, research on ion transporters is in its infancy. In recent years, it has become evident that one family of ion transporters, cation-chloride cotransporters (CCCs), and in particular K(+)-Cl(-) cotransporter 2 (KCC2), have seminal roles in shaping GABAergic signalling and neuronal connectivity. Studying the functions of these transporters may lead to major paradigm shifts in our understanding of the mechanisms underlying brain development and plasticity in health and disease.
577 citations
TL;DR: The mechanisms by which glia, particularly astrocytes and microglia, may contribute to epilepsy and consequently could be harnessed therapeutically are discussed in this Review.
Abstract: Epilepsy is a neurological disorder afflicting ~65 million people worldwide. It is caused by aberrant synchronized firing of populations of neurons primarily due to imbalance between excitatory and inhibitory neurotransmission. Hence, the historical focus of epilepsy research has been neurocentric. However, the past two decades have enjoyed an explosion of research into the role of glia in supporting and modulating neuronal activity, providing compelling evidence of glial involvement in the pathophysiology of epilepsy. The mechanisms by which glia, particularly astrocytes and microglia, may contribute to epilepsy and consequently could be harnessed therapeutically are discussed in this Review.
225 citations
TL;DR: Data suggest that a shift in the relative expression of neuronal NKCC1 and KCC2, similar to that observed in immature neurons during development, may contribute to astrogliosis-associated seizures.
Abstract: Epilepsy is one of the most common chronic neurologic diseases, yet approximately one-third of affected patients do not respond to anticonvulsive drugs that target neurons or neuronal circuits. Reactive astrocytes are commonly found in putative epileptic foci and have been hypothesized to be disease contributors because they lose essential homeostatic capabilities. However, since brain pathology induces astrocytes to become reactive, it is difficult to distinguish whether astrogliosis is a cause or a consequence of epileptogenesis. We now present a mouse model of genetically induced, widespread chronic astrogliosis after conditional deletion of β1-integrin (Itgβ1). In these mice, astrogliosis occurs in the absence of other pathologies and without BBB breach or significant inflammation. Electroencephalography with simultaneous video recording revealed that these mice develop spontaneous seizures during the first six postnatal weeks of life and brain slices show neuronal hyperexcitability. This was not observed in mice with neuronal-targeted β1-integrin deletion, supporting the hypothesis that astrogliosis is sufficient to induce epileptic seizures. Whole-cell patch-clamp recordings from astrocytes further suggest that the heightened excitability was associated with impaired astrocytic glutamate uptake. Moreover, the relative expression of the cation-chloride cotransporters (CCC) NKCC1 (Slc12a2) and KCC2 (Slc12a5), which are responsible for establishing the neuronal Cl− gradient that governs GABAergic inhibition were altered and the NKCC1 inhibitor bumetanide eliminated seizures in a subgroup of mice. These data suggest that a shift in the relative expression of neuronal NKCC1 and KCC2, similar to that observed in immature neurons during development, may contribute to astrogliosis-associated seizures.
219 citations
Cites background from "Mechanisms of epileptogenesis: a co..."
...Neuronal hyperexcitability characterizes 1 / mice Epileptic seizures result from abnormal changes in neuronal excitability (Goldberg and Coulter, 2013)....
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TL;DR: It is shown that two major types of inhibitory neurons are impaired in generation of electrical signals by a DS mutation, whereas excitatory neurons are unaffected, and two major subtypes of interneurons in layer V of the neocortex, parvalbumin-expressing and somatostatin- expressing, both have impaired excitability, resulting in disinhibition of the cortical network.
Abstract: Haploinsufficiency of the voltage-gated sodium channel NaV1.1 causes Dravet syndrome, an intractable developmental epilepsy syndrome with seizure onset in the first year of life. Specific heterozygous deletion of NaV1.1 in forebrain GABAergic-inhibitory neurons is sufficient to cause all the manifestations of Dravet syndrome in mice, but the physiological roles of specific subtypes of GABAergic interneurons in the cerebral cortex in this disease are unknown. Voltage-clamp studies of dissociated interneurons from cerebral cortex did not detect a significant effect of the Dravet syndrome mutation on sodium currents in cell bodies. However, current-clamp recordings of intact interneurons in layer V of neocortical slices from mice with haploinsufficiency in the gene encoding the NaV1.1 sodium channel, Scn1a, revealed substantial reduction of excitability in fast-spiking, parvalbumin-expressing interneurons and somatostatin-expressing interneurons. The threshold and rheobase for action potential generation were increased, the frequency of action potentials within trains was decreased, and action-potential firing within trains failed more frequently. Furthermore, the deficit in excitability of somatostatin-expressing interneurons caused significant reduction in frequency-dependent disynaptic inhibition between neighboring layer V pyramidal neurons mediated by somatostatin-expressing Martinotti cells, which would lead to substantial disinhibition of the output of cortical circuits. In contrast to these deficits in interneurons, pyramidal cells showed no differences in excitability. These results reveal that the two major subtypes of interneurons in layer V of the neocortex, parvalbumin-expressing and somatostatin-expressing, both have impaired excitability, resulting in disinhibition of the cortical network. These major functional deficits are likely to contribute synergistically to the pathophysiology of Dravet syndrome.
199 citations
Cites methods from "Mechanisms of epileptogenesis: a co..."
...In current-clamp recordings, WT Martinotti cells displayed a low discharge rate and typical AP frequency accommodation in response to incremental steps of current injection (1 s), as previously reported (27, 28, 32, 33) (Fig....
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References
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01 Apr 2012
TL;DR: The mechanistic target of rapamycin (mTOR) signaling pathway senses and integrates a variety of environmental cues to regulate organismal growth and homeostasis as mentioned in this paper, and is implicated in an increasing number of pathological conditions, including cancer, obesity, type 2 diabetes, and neurodegeneration.
Abstract: The mechanistic target of rapamycin (mTOR) signaling pathway senses and integrates a variety of environmental cues to regulate organismal growth and homeostasis. The pathway regulates many major cellular processes and is implicated in an increasing number of pathological conditions, including cancer, obesity, type 2 diabetes, and neurodegeneration. Here, we review recent advances in our understanding of the mTOR pathway and its role in health, disease, and aging. We further discuss pharmacological approaches to treat human pathologies linked to mTOR deregulation.
6,268 citations
TL;DR: Recent advances in understanding of the mTOR pathway are reviewed and pharmacological approaches to treat human pathologies linked to mTOR deregulation are discussed.
5,792 citations
3,359 citations
TL;DR: A large-scale chromatin immunoprecipitation assay based on direct ultrahigh-throughput DNA sequencing was developed, which was then used to map in vivo binding of the neuron-restrictive silencer factor (NRSF; also known as REST) to 1946 locations in the human genome.
Abstract: In vivo protein-DNA interactions connect each transcription factor with its direct targets to form a gene network scaffold. To map these protein-DNA interactions comprehensively across entire mammalian genomes, we developed a large-scale chromatin immunoprecipitation assay (ChIPSeq) based on direct ultrahigh-throughput DNA sequencing. This sequence census method was then used to map in vivo binding of the neuron-restrictive silencer factor (NRSF; also known as REST, for repressor element–1 silencing transcription factor) to 1946 locations in the human genome. The data display sharp resolution of binding position [±50 base pairs (bp)], which facilitated our finding motifs and allowed us to identify noncanonical NRSF-binding motifs. These ChIPSeq data also have high sensitivity and specificity [ROC (receiver operator characteristic) area ≥ 0.96] and statistical confidence (P <10^(–4)), properties that were important for inferring new candidate interactions. These include key transcription factors in the gene network that regulates pancreatic islet cell development.
2,789 citations
TL;DR: The timing of a sensory input relative to a gamma cycle determined the amplitude and precision of evoked responses and provided the first causal evidence that distinct network activity states can be induced in vivo by cell-type-specific activation.
Abstract: Corticalgammaoscillations(20280Hz)predictincreasesinfocusedattention,andfailureingammaregulationisahallmark of neurological and psychiatric disease. Current theory predicts that gamma oscillations are generated by synchronous activity of fast-spiking inhibitory interneurons, with the resulting rhythmic inhibition producing neural ensemble synchrony by generating a narrow window for effective excitation. We causally tested these hypotheses in barrel cortex in vivo by targeting optogenetic manipulation selectively to fast-spiking interneurons. Here we show that light-driven activation of fast-spiking interneurons atvariedfrequencies (82200Hz) selectivelyamplifies gamma oscillations. Incontrast, pyramidal neuron activation amplifies only lower frequency oscillations, a cell-type-specific double dissociation. We found that the timing of a sensory input relative to a gamma cycle determined the amplitude and precision of evoked responses. Our data directly support the fast-spiking-gamma hypothesis and provide the first causal evidence that distinct network activity states can be induced in vivo by cell-type-specific activation.
2,453 citations