Cardiorespiratory dysfunction during or after seizures may contribute to sudden unexpected death in epilepsy. Disruption of lower brainstem cardiorespiratory systems by seizures is postulated to ...impair respiratory and cardiac function. Here, we explore the effects of brainstem seizures and stimulation on cardiorespiratory function using a rat model of intrahippocampal 4-aminopyridine (4-AP)-induced acute recurrent seizures. Cardiac and respiratory monitoring together with local field potential recordings from hippocampus, contralateral parietal cortex and caudal dorsomedial brainstem, were conducted in freely moving adult male Wistar rats. Seizures were induced by intrahippocampal injection of 4-AP. Increased respiratory rate but unchanged heart rate occurred during hippocampal and secondarily generalized cortical seizures. Status epilepticus without brainstem seizures increased respiratory and heart rates, whereas status epilepticus with intermittent brainstem seizures induced repeated episodes of cardiorespiratory depression leading to death. Respiratory arrest occurred prior to asystole which was the terminal event. Phenytoin (100 mg/kg, intraperitoneal injection), administered after 4-AP intrahippocampal injection, terminated brainstem seizures and the associated cardiorespiratory depression, preventing death in five of six rats. Focal electrical stimulation of the caudal dorsomedial brainstem also suppressed cardiorespiratory rates. We conclude that in our model, brainstem seizures were associated with respiratory depression followed by cardiac arrest, and then death. We hypothesize this model shares mechanisms in common with the classic sudden unexpected death in epilepsy (SUDEP) syndrome associated with spontaneous seizures.
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•EEG with objectively measured respiratory and cardiac function in freely behaving rats.•Hippocampal seizures spread to cortex and then to brainstem.•Brainstem seizures followed by apnea and then asystole (SUDEP model).•Focal 8 Hz brainstem stimulation also caused respiratory and cardiac suppression.•Phenytoin terminated brainstem seizures and prevented cardiorespiratory depression.
In the human neocortex coherent interlaminar theta oscillations are driven by deep cortical layers, suggesting neurons in these layers exhibit distinct electrophysiological properties. To ...characterize this potential distinctiveness, we use in vitro whole-cell recordings from cortical layers 2 and 3 (L2&3), layer 3c (L3c) and layer 5 (L5) of the human cortex. Across all layers we observe notable heterogeneity, indicating human cortical pyramidal neurons are an electrophysiologically diverse population. L5 pyramidal cells are the most excitable of these neurons and exhibit the most prominent sag current (abolished by blockade of the hyperpolarization activated cation current, I
). While subthreshold resonance is more common in L3c and L5, we rarely observe this resonance at frequencies greater than 2 Hz. However, the frequency dependent gain of L5 neurons reveals they are most adept at tracking both delta and theta frequency inputs, a unique feature that may indirectly be important for the generation of cortical theta oscillations.
Activation of γ-aminobutyric acid (GABAA) receptors have been associated with the onset of epileptiform events. To investigate if a causal relationship exists between GABAA receptor activation and ...ictal event onset, we activated inhibitory GABAergic networks in the superficial layer (2/3) of the somatosensory cortex during hyperexcitable conditions using optogenetic techniques in mice expressing channelrhodopsin-2 in all GABAergic interneurons. We found that a brief 30ms light pulse reliably triggered either an interictal-like event (IIE) or ictal-like (“ictal”) event in the in vitro cortical 4-Aminopyridine (4-AP) slice model. The link between light pulse and epileptiform event onset was lost following blockade of GABAA receptors with bicuculline methiodide. Additionally, recording the chronological sequence of events following a light pulse in a variety of configurations (whole-cell, gramicidin-perforated patch, and multi-electrode array) demonstrated an initial hyperpolarization followed by post-inhibitory rebound spiking and a subsequent slow depolarization at the transition to epileptiform activity. Furthermore, the light-triggered ictal events were independent of the duration or intensity of the initiating light pulse, suggesting an underlying regenerative mechanism. Moreover, we demonstrated that brief GABAA receptor activation can initiate ictal events in the in vivo 4-AP mouse model, in another common in vitro model of epileptiform activity, and in neocortical tissue resected from epilepsy patients. Our findings reveal that the synchronous activation of GABAergic interneurons is a robust trigger for ictal event onset in hyperexcitable cortical networks.
•Brief GABA-mediated inhibition initiates ictal events in cortical 4-AP models.•Post-inhibitory rebound excitation was observed at transition to ictal activity.•Ictal events were observed to be an all-or-none phenomenon.•Key findings were replicated in neocortical tissue resected from epilepsy patients.•Inhibitory interneurons can play a critical role in the transition to ictal events.
Enhanced gap junctional communication (GJC) between neurons is considered a major factor underlying the neuronal synchrony driving seizure activity. In addition, the hippocampal sharp wave ripple ...complexes, associated with learning and seizures, are diminished by GJC blocking agents. Although gap junctional blocking drugs inhibit experimental seizures, they all have other non-specific actions. Besides interneuronal GJC between dendrites, inter-axonal and inter-glial GJC is also considered important for seizure generation. Interestingly, in most studies of cerebral tissue from animal seizure models and from human patients with epilepsy, there is up-regulation of glial, but not neuronal gap junctional mRNA and protein. Significant changes in the expression and post-translational modification of the astrocytic connexin Cx43, and Panx1 were observed in an in vitro Co(++) seizure model, further supporting a role for glia in seizure-genesis, although the reasons for this remain unclear. Further suggesting an involvement of astrocytic GJC in epilepsy, is the fact that the expression of astrocytic Cx mRNAs (Cxs 30 and 43) is several fold higher than that of neuronal Cx mRNAs (Cxs 36 and 45), and the number of glial cells outnumber neuronal cells in mammalian hippocampal and cortical tissue. Pannexin expression is also increased in both animal and human epileptic tissues. Specific Cx43 mimetic peptides, Gap 27 and SLS, inhibit the docking of astrocytic connexin Cx43 proteins from forming intercellular gap junctions (GJs), diminishing spontaneous seizures. Besides GJs, Cx membrane hemichannels in glia and Panx membrane channels in neurons and glia are also inhibited by traditional gap junctional pharmacological blockers. Although there is no doubt that connexin-based GJs and hemichannels, and pannexin-based membrane channels are related to epilepsy, the specific details of how they are involved and how we can modulate their function for therapeutic purposes remain to be elucidated.
Alzheimer's disease (AD) is pathologically characterized by amyloid‐β peptide (Aβ) accumulation, neurofibrillary tangle formation, and neurodegeneration. Preclinical studies on neuronal impairments ...associated with progressive amyloidosis have demonstrated some Aβ‐dependent neuronal dysfunction including modulation of gamma‐aminobutyric acid‐ergic signaling. The present work focuses on the early stage of disease progression and uses TgF344‐AD rats that recapitulate a broad repertoire of AD‐like pathologies to investigate the neuronal network functioning using simultaneous intracranial recordings from the hippocampus (HPC) and the medial prefrontal cortex (mPFC), followed by pathological analyses of gamma‐aminobutyric acid (GABAA) receptor subunits α1, α5, and δ, and glutamic acid decarboxylases (GAD65 and GAD67). Concomitant to amyloid deposition and tau hyperphosphorylation, low‐gamma band power was strongly attenuated in the HPC and mPFC of TgF344‐AD rats in comparison to those in non‐transgenic littermates. In addition, the phase‐amplitude coupling of the neuronal networks in both areas was impaired, evidenced by decreased modulation of theta band phase on gamma band amplitude in TgF344‐AD animals. Finally, the gamma coherence between HPC and mPFC was attenuated as well. These results demonstrate significant neuronal network dysfunction at an early stage of AD‐like pathology. This network dysfunction precedes the onset of cognitive deficits and is likely driven by Aβ and tau pathologies.
This article is part of the Special Issue “Vascular Dementia”.
Preclinical studies on neuronal impairments associated with progressive amyloidosis have demonstrated some Aβ‐dependent neuronal dysfunction including modulation of GABAergic signaling. At 8 months of age, the TgF344‐AD rat models of Alzheimer's disease presents Aβ plaques and tau hyperphosphorylation but no cognitive impairments. These animals were found to exhibit decreased phase‐amplitude coupling between theta and high‐gamma bands in the hippocampus and in the medial prefrontal cortex, accompanied by a reduction in GAD67+ cells in CA1 and CA3 of the hippocampus.
This article is part of the Special Issue “Vascular Dementia”.
The human brain, largely accepted as the most complex biological system known, is still far from being understood in its parts or as a whole. More specifically, biological mechanisms of epileptic ...states and state transitions are not well understood. Here, we explore the concept of the epilepsy as a manifestation of a multistate network composed of coupled oscillatory units. We also propose that functional coupling between neuroglial elements is a dynamic process, characterized by temporal changes both at short and long time scales. We review various experimental and modelling data suggesting that epilepsy is a pathological manifestation of such a multistate network – both when viewed as a coupled oscillatory network, and as a system of multistate stable state attractors. Based on a coupled oscillators model, we propose a significant role for glial cells in modulating hyperexcitability of the neuroglial networks of the brain. Also, using these concepts, we explain a number of observable phenomena such as propagation patterns of bursts within a seizure in the isolated intact hippocampus in vitro, postictal generalized suppression in human encephalographic seizure data, and changes in seizure susceptibility in epileptic patients. Based on our conceptual model we propose potential clinical applications to estimate brain closeness to ictal transition by means of active perturbations and passive measures during on-going activity.
We present a fully differential 128-channel integrated neural interface. It consists of an array of 8 X 16 low-power low-noise signal-recording and generation circuits for electrical neural activity ...monitoring and stimulation, respectively. The recording channel has two stages of signal amplification and conditioning with and a fully differential 8-b column-parallel successive approximation (SAR) analog-to-digital converter (ADC). The total measured power consumption of each recording channel, including the SAR ADC, is 15.5 ¿W. The measured input-referred noise is 6.08 ¿ Vrms over a 5-kHz bandwidth, resulting in a noise efficiency factor of 5.6. The stimulation channel performs monophasic or biphasic voltage-mode stimulation, with a maximum stimulation current of 5 mA and a quiescent power dissipation of 51.5 ¿W. The design is implemented in 0.35-¿m complementary metal-oxide semiconductor technology with the channel pitch of 200 ¿m for a total die size of 3.4 mm × 2.5 mm and a total power consumption of 9.33 mW. The neural interface was validated in in vitro recording of a low-Mg 2+ /high-K + epileptic seizure model in an intact hippocampus of a mouse.
Epilepsy afflicts up to 1.6% of the population and the mechanisms underlying the appearance of seizures are still not understood. In past years, many efforts have been spent trying to understand the ...mechanisms underlying the excessive and synchronous firing of neurons. Traditionally, attention was pointed towards synaptic (dys)function and extracellular ionic species (dys)regulation. Recently, novel clinical and preclinical studies explored the role of brain metabolism (i.e., glucose utilization) of seizures pathophysiology revealing (in most cases) reduced metabolism in the inter-ictal period and increased metabolism in the seconds preceding and during the appearance of seizures. In the present review, we summarize the clinical and preclinical observations showing metabolic dysregulation during epileptogenesis, seizure initiation, and termination, and in the inter-ictal period. Recent preclinical studies have shown that 2-Deoxyglucose (2-DG, a glycolysis blocker) is a novel therapeutic approach to reduce seizures. Furthermore, we present initial evidence for the effectiveness of 2-DG in arresting 4-Aminopyridine induced neocortical seizures in vivo in the mouse.
Raised extracellular potassium ion (K+) concentration is associated with several disorders including migraine, stroke, neurotrauma and epilepsy. K+ spatial buffering is a well-known mechanism for ...extracellular K+ regulation/distribution. Astrocytic gap junction-mediated buffering is a controversial candidate for K+ spatial buffering. To further investigate the existence of a K+ spatial buffering and to assess the involvement of astrocytic gap junctional coupling in K+ redistribution, we hypothesized that neocortical K+ and concomitant spreading depolarization (SD)-like responses are controlled by powerful local K+ buffering mechanisms and that K+ buffering/redistribution occurs partially through gap junctional coupling. Herein, we show, in vivo, that a threshold amount of focally applied KCl is required to trigger local and/or distal K+ responses, accompanied by a SD-like response. This observation indicates the presence of powerful local K+ buffering which mediates a rapid return of extracellular K+ to the baseline. Application of gap junctional blockers, carbenoxolone and Gap27, partially modulated the amplitude and shape of the K+ response and noticeably decreased the velocity of the spreading K+ and SD-like responses. Opening of gap junctions by trimethylamine, slightly decreased the amplitude of the K+ response and markedly increased the velocity of redistribution of K+ and SD-like events. We conclude that spreading K+ responses reflect powerful local K+ buffering mechanisms which are partially modulated by gap junctional communication. Gap junctional coupling mainly affected the velocity of the K+ and SD-like responses.
•K+o and local field potentials are measured in 2 nearby locations in vivo.•Focal increases in K+o are very tightly regulated, preventing local spread.•To overcome local buffering, a threshold amount of K+ needs to be applied.•Astrocytic gap junctional coupling partially modulates K+o redistribution.•This coupling affects velocity much more than amplitude of responses.
Loss of function mutations of the WW domain-containing oxidoreductase (WWOX) gene are associated with severe and fatal drug-resistant pediatric epileptic encephalopathy. Epileptic seizures are ...typically characterized by neuronal hyperexcitability; however, the specific contribution of WWOX to that hyperexcitability has yet to be investigated. Using a mouse model of neuronal Wwox-deletion that exhibit spontaneous seizures, in vitro whole-cell and field potential electrophysiological characterization identified spontaneous bursting activity in the neocortex, a marker of the underlying network hyperexcitability. Spectral analysis of the neocortical bursting events highlighted increased phase-amplitude coupling, and a propagation from layer II/III to layer V. These bursts were NMDAR and gap junction dependent. In layer II/III pyramidal neurons, Wwox knockout mice demonstrated elevated amplitude of excitatory post-synaptic currents, whereas the frequency and amplitude of inhibitory post-synaptic currents were reduced, as compared to heterozygote and wild-type littermate controls. Furthermore, these neurons were depolarized and demonstrated increased action potential frequency, sag current, and post-inhibitory rebound. These findings suggest WWOX plays an essential role in balancing neocortical excitability and provide insight towards developing therapeutics for those suffering from WWOX disorders.
•Neuronal wwox knockout (s-KO) causes neocortical bursting activity, in vitro.•Bursts are NMDAR and gap-junction dependent, propagating L2/3 to L5.•Loss of spontaneous inhibition to s-KO superficial neocortical pyramidal neurons.•Wwox s-KO superficial neocortical pyramidal neurons are hyperexcitable.
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