Modulation Of Neuronal Excitability Research Articles

New GABA-Targeting Therapies for the Treatment of Seizures and Epilepsy: II. Treatments in Clinical Development.

The inhibitory neurotransmitter γ-aminobutyric acid (GABA) plays an important role in the modulation of neuronal excitability, and a disruption of GABAergic transmission contributes to the pathogenesis of some seizure disorders. Although many currently available antiseizure medications do act at least in part by potentiating GABAergic transmission, there is an opportunity for further research aimed at developing more innovative GABA-targeting therapies. The present article summarises available evidence on a number of such treatments in clinical development. These can be broadly divided into three groups. The first group consists of positive allosteric modulators of GABAA receptors and includes Staccato® alprazolam (an already marketed benzodiazepine being repurposed in epilepsy as a potential rescue inhalation treatment for prolonged and repetitive seizures), the α2/3/5 subtype-selective agents darigabat and ENX-101, and the orally active neurosteroids ETX155 and LPCN 2101. A second group comprises two drugs already marketed for non-neurological indications, which could be repurposed as treatments for seizure disorders. These include bumetanide, a diuretic agent that has undergone clinical trials in phenobarbital-resistant neonatal seizures and for which the rationale for further development in this indication is under debate, and ivermectin, an antiparasitic drug currently investigated in a randomised double-blind trial in focal epilepsy. The last group comprises a series of highly innovative therapies, namely GABAergic interneurons (NRTX-001) delivered via stereotactic cerebral implantation as a treatment for mesial temporal lobe epilepsy, an antisense oligonucleotide (STK-001) aimed at upregulating NaV1.1 currents and restoring the function of GABAergic interneurons, currently tested in a trial in patients with Dravet syndrome, and an adenoviral vector-based gene therapy (ETX-101) scheduled for investigation in Dravet syndrome. Another agent, a subcutaneously administered neuroactive peptide (NRP2945) that reportedly upregulates the expression of GABAA receptor α and β subunits is being investigated, with Lennox-Gastaut syndrome and other epilepsies as proposed indications. The diversity of the current pipeline underscores a strong interest in the GABA system as a target for new treatment development in epilepsy. To date, limited clinical data are available for these investigational treatments and further studies are required to assess their potential value in addressing unmet needs in epilepsy management.

Repetitive Transcranial Magnetic Stimulation in Stroke: A Literature Review of the Current Role and Controversies of Neurorehabilitation Through Electromagnetic Pulses.

Repetitive transcranial magnetic stimulation (rTMS) is an effective method used for the treatment of various neurological diseases, including stroke, epilepsy, and movement disorders. The pathophysiological mechanism for the effect of TMS is not clear. In this literature review, we conducted a detailed search regarding the effect of rTMS on neurotransmission and neuronal plasticity through the modulation of neuronal excitability. Evidence suggests that intramolecular subatomic mechanisms, including genetic changes related to neuronal prevention and death, play an important role. We also discuss the use of rTMS in the rehabilitation of patients with stroke and its main complications, as well as alternative mechanisms related to recovery, emphasizing the findings of available evidence and touching on possible controversies and limitations of the method.

Decreased expression of synaptic genes in the vestibular ganglion of rodents following subchronic ototoxic stress.

The vestibular ganglion contains primary sensory neurons that are postsynaptic to the transducing hair cells (HC) and project to the central nervous system. Understanding the response of these neurons to HC stress or loss is of great interest as their survival and functional competence will determine the functional outcome of any intervention aiming at repair or regeneration of the HCs. We have shown that subchronic exposure to the ototoxicant 3,3′-iminodipropionitrile (IDPN) in rats and mice causes a reversible detachment and synaptic uncoupling between the HCs and the ganglion neurons. Here, we used this paradigm to study the global changes in gene expression in vestibular ganglia using RNA-seq. Comparative gene ontology and pathway analyses of the data from both model species indicated a robust downregulation of terms related to synapses, including presynaptic and postsynaptic functions. Manual analyses of the most significantly downregulated transcripts identified genes with expressions related to neuronal activity, modulators of neuronal excitability, and transcription factors and receptors that promote neurite growth and differentiation. For choice selected genes, the mRNA expression results were replicated by qRT-PCR, validated spatially by RNA-scope, or were demonstrated to be associated with decreased expression of the corresponding protein. We conjectured that decreased synaptic input or trophic support on the ganglion neurons from the HC was triggering these expression changes. To support this hypothesis, we demonstrated decreased expression of BDNF mRNA in the vestibular epithelium after subchronic ototoxicity and also downregulated expression of similarly identified genes (e.g Etv5, Camk1g, Slc17a6, Nptx2, Spp1) after HC ablation with another ototoxic compound, allylnitrile. We conclude that vestibular ganglion neurons respond to decreased input from HCs by decreasing the strength of all their synaptic contacts, both as postsynaptic and presynaptic players.

Astrocytic TRPV4 Channels and Their Role in Brain Ischemia

Transient receptor potential cation channels subfamily V member 4 (TRPV4) are non-selective cation channels expressed in different cell types of the central nervous system. These channels can be activated by diverse physical and chemical stimuli, including heat and mechanical stress. In astrocytes, they are involved in the modulation of neuronal excitability, control of blood flow, and brain edema formation. All these processes are significantly impaired in cerebral ischemia due to insufficient blood supply to the tissue, resulting in energy depletion, ionic disbalance, and excitotoxicity. The polymodal cation channel TRPV4, which mediates Ca2+ influx into the cell because of activation by various stimuli, is one of the potential therapeutic targets in the treatment of cerebral ischemia. However, its expression and function vary significantly between brain cell types, and therefore, the effect of its modulation in healthy tissue and pathology needs to be carefully studied and evaluated. In this review, we provide a summary of available information on TRPV4 channels and their expression in healthy and injured neural cells, with a particular focus on their role in ischemic brain injury.

Modulation of neuronal excitability by binge alcohol drinking.

Drug use poses a serious threat to health systems throughout the world. The number of consumers rises every year being alcohol the drug of abuse most consumed causing 3 million deaths (5.3% of all deaths) worldwide and 132.6 million disability-adjusted life years. In this review, we present an up-to-date summary about what is known regarding the global impact of binge alcohol drinking on brains and how it affects the development of cognitive functions, as well as the various preclinical models used to probe its effects on the neurobiology of the brain. This will be followed by a detailed report on the state of our current knowledge of the molecular and cellular mechanisms underlying the effects of binge drinking on neuronal excitability and synaptic plasticity, with an emphasis on brain regions of the meso-cortico limbic neurocircuitry.

Mutations affecting electro-mechanical coupling in KCNQ channels alter kinetics and voltage dependence of activation.

The KCNQ voltage-gated potassium channel family serves multiple physiological functions, from regulating heartbeat (by KCNQ1) to controlling neuronal excitability (by KCNQ2-5). In KCNQ1 channels, two steps of voltage sensor activation lead to two functionally distinct open states, the intermediate-open (IO) and activated-open (AO), which define the gating, pharmacology, and physiology of KCNQ1. However, whether all KCNQ channels share the same mechanism is unclear. Here, we provide functional evidence that KCNQ2/3 only conducts at the AO state, but the electro-mechanical (E-M) coupling mechanism is conserved between KCNQ1 and KCNQ2/3. We demonstrate that this conserved E-M coupling can be compromised by select epilepsy-linked mutations in KCNQ2/3 and also can be effectively targeted by the antiepileptic prototype drug retigabine, suggesting E-M coupling as a therapeutic target for epilepsy treatment. Interestingly, KCNQ1 and KCNQ2/3 exhibit distinct kinetics and voltage dependence of activation for the AO state. While these differences may have important implications for the primary physiological roles of KCNQ2/3 (modulation of neuronal excitability) versus KCNQ1 (repolarization of cardiac action potential), it remains unclear where they originate from. Here, we find that analogous mutations in the distal S6 of KCNQ1 and KCNQ2 both affect the AO state E-M coupling and lead to delays in current activation kinetics and right shifts in voltage dependence of activation. KCNQ2 mutations near this location are also found to be associated with epileptic encephalopathy. These results further support a common regulatory mechanism for KCNQ currents via E-M coupling and indicate the physiological relevance of altering AO state activation properties in KCNQ channels.

Seizing Control of Neuronal Activity: Chemogenetic Applications in Epilepsy.

The fundamental commonality across pharmacotherapies for the epilepsies is the modulation of neuronal excitability. This poses a clear challenge—patterned neuronal excitation is essential to normal function, thus disrupting this activity leads to side effects. Moreover, the efficacy of current pharmacotherapy remains incomplete despite decades of drug development. Approaches that allow for the selective targeting of critical populations of cells and particular pathways in the brain have the potential to both avoid side effects and improve efficacy. Chemogenetic methods, which combine the selective expression of designer receptors with designer drugs, have rapidly grown in use in the neurosciences, including in epilepsy. This review will briefly highlight the history of chemogenetics, their applications to date in epilepsy, and the potential (and potential hurdles to overcome) for future translation.

Gangliosidome of a Human Hippocampus in Temporal Lobe Epilepsy Resolved by High-Resolution Tandem Mass Spectrometry.

In this study, we developed a high-resolution tandem mass spectrometry (HR MS) approach to assess presumed changes in gangliosidome of a human hippocampus affected by temporal lobe epilepsy (TLE) in comparison with a normal hippocampus. Gangliosides, membrane glycolipids, are particularly diverse and abundant in the human brain, and participate in ion transport and modulation of neuronal excitability. Changes in structural ganglioside pattern potentially linked to TLE molecular pathogenesis have not been explored in detail. Aiming to characterize TLE-specific gangliosidome, we analyzed the native gangliosides purified from a human hippocampal tissue sample affected by TLE and a control hippocampus using HR MS. Marked differences of ganglioside expression were shown in TLE vs. control, particularly with respect to the sialylation degree of components, discovered as a characteristic feature of TLE. Another major finding is the occurrence of tetrasialofucogangliosides in TLE and species modified by either O-acetylation or CH3COO−. Structural analysis by higher-energy collisional dissociation (HCD) MS/MS gave rise to fragmentation patterns implying that the GQ1b (d18:1/18:0) isomer is specifically associated with TLE. Further investigation in a larger sample is needed in order to confirm the discovery of ganglioside structures specifically expressed in human TLE and to provide information on the probable role of gangliosides in the molecular events underlying seizures.

Glucose increases the length and spacing of the lattice structure of the axon initial segment.

The axon initial segment (AIS) plays an important role in maintaining neuronal polarity and initiating action potentials (APs). The AIS adapts to its environment by changing its length and distance from the cell body, resulting in modulation of neuronal excitability, which is referred to as AIS plasticity. Previous studies found an ~200 nm single periodic distribution of the key AIS components ankyrinG (AnkG), Nav 1.2, and βIV-spectrin, while it remains unclear how the lattice structure is altered by AIS plasticity. In this study, we found that the length of the AIS significantly increased, resulting in increased neuronal excitability, with high-concentration glucose treatment. Structured illumination microscopy (SIM) images of the lattice structure showed a dual-spacing periodic distribution (~200 nm and ~260 nm) of AnkG, Nav 1.2, and βIV-spectrin. Moreover, 480-kDa AnkG was crucial for AIS plasticity and increased lattice structure spacing. The discovery of new regulators for modulating AIS plasticity will help us to understand and manipulate the structure and function of the AIS. Glucose triggers axon initial segment (AIS) plasticity of cultured neurons. AIS lattice structure under glucose treatment shows an increased spacing by structured illumination microscopy imaging. 480-kDa AnkG contributes to AIS plasticity.

The Influence of AA29504 on GABAA Receptor Ligand Binding Properties and Its Implications on Subtype Selectivity

The unique pharmacological properties of δ-containing γ-aminobutyric acid type A receptors (δ-GABAARs) make them an attractive target for selective and persistent modulation of neuronal excitability. However, the availability of selective modulators targeting δ-GABAARs remains limited. AA29504 ([2-amino-4-(2,4,6-trimethylbenzylamino)-phenyl]-carbamic acid ethyl ester), an analog of K+ channel opener retigabine, acts as an agonist and a positive allosteric modulator (Ago-PAM) of δ-GABAARs. Based on electrophysiological studies using recombinant receptors, AA29504 was found to be a more potent and effective agonist in δ-GABAARs than in γ2-GABAARs. In comparison, AA29504 positively modulated the activity of recombinant δ-GABAARs more effectively than γ2-GABAARs, with no significant differences in potency. The impact of AA29504's efficacy- and potency-associated GABAAR subtype selectivity on radioligand binding properties remain unexplored. Using [3H]4'-ethynyl-4-n-propylbicycloorthobenzoate ([3H]EBOB) binding assay, we found no difference in the modulatory potency of AA29504 on GABA- and THIP (4,5,6,7-tetrahydroisoxazolo[5,4-c]pyridin-3-ol)-induced responses between native forebrain GABAARs of wild type and δ knock-out mice. In recombinant receptors expressed in HEK293 cells, AA29504 showed higher efficacy on δ- than γ2-GABAARs in the GABA-independent displacement of [3H]EBOB binding. Interestingly, AA29504 showed a concentration-dependent stimulation of [3H]muscimol binding to γ2-GABAARs, which was absent in δ-GABAARs. This was explained by AA29504 shifting the low-affinity γ2-GABAAR towards a higher affinity desensitized state, thereby rising new sites capable of binding GABAAR agonists with low nanomolar affinity. Hence, the potential of AA29504 to act as a desensitization-modifying allosteric modulator of γ2-GABAARs deserves further investigation for its promising influence on shaping efficacy, duration and plasticity of GABAAR synaptic responses.

Orai1 is a crucial downstream partner of group I metabotropic glutamate receptor signaling in dorsal horn neurons.

Group I metabotropic glutamate receptors (group I mGluRs) have been implicated in several central nervous system diseases including chronic pain. It is known that activation of group I mGluRs results in the production of inositol triphosphate (IP3) and diacylglycerol that leads to activation of extracellular signal-regulated kinases (ERKs) and an increase in neuronal excitability, but how group I mGluRs mediate this process remains unclear. We previously reported that Orai1 is responsible for store-operated calcium entry and plays a key role in central sensitization. However, how Orai1 is activated under physiological conditions is unknown. Here, we tested the hypothesis that group I mGluRs recruit Orai1 as part of its downstream signaling pathway in dorsal horn neurons. We demonstrate that neurotransmitter glutamate induces STIM1 puncta formation, which is not mediated by N-Methyl-D-aspartate (NMDA) or α-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors. Glutamate-induced Ca2+ entry in the presence of NMDA or AMPA receptor antagonists is eliminated in Orai1-deficient neurons. Dihydroxyphenylglycine (DHPG) (an agonist of group I mGluRs)-induced Ca2+ entry is abolished by Orai1 deficiency, but not affected by knocking down of transient receptor potential cation channel 1 (TRPC1) or TRPC3. Dihydroxyphenylglycine-induced activation of ERKs and modulation of neuronal excitability are abolished in cultured Orai1-deficient neurons. Moreover, DHPG-induced nociceptive behavior is markedly reduced in Orai1-deficient mice. Our findings reveal previously unknown functional coupling between Orai1 and group I mGluRs and shed light on the mechanism underlying group I mGluRs-mediated neuronal plasticity.

Progress on the application of positron emission tomography imaging of cannabinoid type 1 receptor in neuropsychiatric diseases.

Cannabinoid type 1 receptor (CB1R), as the major member of the endocannabinoid system, is among the most abundant receptors expressed in the central nervous system. CB1R is mainly located on the axon terminals of presynaptic neurons and participate in the modulation of neuronal excitability and synaptic plasticity, playing an important role in the pathogenesis of various neuropsychiatric diseases. In recent years, the consistent development of CB1R radioligands and the maturity of molecular imaging techniques, particularly positron emission tomography (PET) may help to visualize the expression and distribution of CB1R in central nervous system . At present, CB1R PET imaging can effectively evaluate the changes of CB1R levels in neuropsychiatric diseases such as Huntington's disease and schizophrenia, and its correlation with the disease severity, therefore providing new insights for the diagnosis and treatment of neuropsychiatric diseases. This article reviews the application of CB1R PET imaging in Alzheimer's disease, Parkinson's disease, Huntington's disease, schizophrenia, post-traumatic stress disorder, cannabis use disorder and depression.

Anoctamin 2-chloride channels reduce simple spike activity and mediate inhibition at elevated calcium concentration in cerebellar Purkinje cells.

Modulation of neuronal excitability is a prominent way of shaping the activity of neuronal networks. Recent studies highlight the role of calcium-activated chloride currents in this context, as they can both increase or decrease excitability. The calcium-activated chloride channel Anoctamin 2 (ANO2 alias TMEM16B) has been described in several regions of the mouse brain, including the olivo-cerebellar system. In inferior olivary neurons, ANO2 was proposed to increase excitability by facilitating the generation of high-threshold calcium spikes. An expression of ANO2 in cerebellar Purkinje cells was suggested, but its role in these neurons remains unclear. In the present study, we confirmed the expression of Ano2 mRNA in Purkinje cells and performed electrophysiological recordings to examine the influence of ANO2-chloride channels on the excitability of Purkinje cells by comparing wildtype mice to mice lacking ANO2. Recordings were performed in acute cerebellar slices of adult mice, which provided the possibility to study the role of ANO2 within the cerebellar cortex. Purkinje cells were uncoupled from climbing fiber input to assess specifically the effect of ANO2 channels on Purkinje cell activity. We identified an attenuating effect of ANO2-mediated chloride currents on the instantaneous simple spike activity both during strong current injections and during current injections close to the simple spike threshold. Moreover, we report a reduction of inhibitory currents from GABAergic interneurons upon depolarization, lasting for several seconds. Together with the role of ANO2-chloride channels in inferior olivary neurons, our data extend the evidence for a role of chloride-dependent modulation in the olivo-cerebellar system that might be important for proper cerebellum-dependent motor coordination and learning.

Modulation of Neuronal Excitability by Low- Intensity Ultrasound in Two Principal Neurons of Rat Anteroventral Cochlear Nucleus.

Ultrasonic neuromodulation has proved to be a promising new approach for direct neuromodulation or potential noninvasive deep brain stimulation technology for treating various neurological disorders. Previous studies have demonstrated that ultrasonic waves can noninvasively diffuse through the intact skull and thus precisely target specific brain regions with high spatial resolution. However, its neuromodulatory effects over different cell types of target nuclei have not been fully elucidated. In the present study, we investigated the neuronal excitability resulted from ultrasound stimulation on the two major neurons of anteroventral cochlear nucleus (AVCN) in vitro. Our results demonstrated that bushy cells (BCs) were well maintaining one action potential (AP) in response to the pairing of a sequence of depolarizing current pulses and 60-s continuous low-intensity ultrasound (LIUS), and meanwhile, stellate cells (SCs) significantly increased the firing rate. The ultrasonic waves with an acoustic pressure of 0.13 MPa were elicited by an on-chip ultrasonic stimulation system compatible with patch-clamp recording. Furthermore, LIUS significantly improved the neuronal excitability in both BCs and SCs based on their intrinsic excitability. Modulation of membrane properties among cell types was due to the LIUS-induced increase in the total inward sodium currents ( INa ) and outward potassium currents ( IKv ). LIUS significantly, at a similar rate, increased the amplitude of total inward sodium currents in both cell types. Meanwhile, LIUS induces a higher rate of the outward potassium currents in the BCs compared with SCs. Therefore, this study could provide new evidence for safe use of ultrasonic neuromodulation and its potential therapy for many auditory diseases, such as the central auditory processing disorder.

The Kappa Opioid Receptor System in Temporal Lobe Epilepsy.

Temporal lobe epilepsy is considered to be one of the most common and severe forms of focal epilepsies. Patients frequently develop cognitive deficits and emotional blunting along progression of the disease. The high incidence of refractoriness to antiepileptic drugs and a frequent lack of admissibility to surgery pose an unmet medical challenge. In the urgent quest for novel treatment strategies, neuropeptides and their receptors are interesting candidates. However, their therapeutic potential has not yet been fully exploited. This chapter focuses on the functional role of the dynorphins (Dyns) and the kappa opioid receptor (KOR) system in temporal lobe epilepsy and the hippocampus.Genetic polymorphisms in the prepro-dynorphin (pDyn) gene causing lower levels of Dyns in humans and pDyn gene knockout in mice increase the risk to develop epilepsy. This suggests a role of Dyns and KOR as modulators of neuronal excitability. Indeed, KOR agonists induce inhibition of presynaptic neurotransmitter release, as well as postsynaptic hyperpolarization in glutamatergic neurons, both producing anticonvulsant effects.The development of new approaches to modulate the complex KOR signalling cascade (e.g. biased agonism and gene therapy) opens up new exciting therapeutic opportunities with regard to seizure control and epilepsy. Potential adverse side effects of KOR agonists may be minimized through functional selectivity or locally restricted treatment. Preclinical data suggest a high potential of such approaches to control seizures.

Expression Pattern of ALOXE3 in Mouse Brain Suggests Its Relationship with Seizure Susceptibility.

Arachidonic acid (AA), a polyunsaturated fatty acid, is involved in the modulation of neuronal excitability in the brain. Arachidonate lipoxygenase 3 (ALOXE3), a critical enzyme in the AA metabolic pathway, catalyzes the derivate of AA into hepoxilins. However, the expression pattern of ALOXE3 and its role in the brain has not been described until now. Here we showed that the levels of Aloxe3 mRNA and protein kept increasing since birth and reached the highest level at postnatal day 30 in the mouse hippocampus and temporal cortex. Histomorphological analyses indicated that ALOXE3 was enriched in adult hippocampus, somatosensory cortex and striatum. The distribution was restricted to the neurites of function-specific subregions, such as mossy fibre connecting hilus and CA3 neurons, termini of Schaffer collateral projections, and the layers III and IV of somatosensory cortex. The spatiotemporal expression pattern of ALOXE3 suggests its potential role in the modulation of neural excitability and seizure susceptibility. In fact, decreased expression of ALOXE3 and elevated concentration of AA in the hippocampus was found after status epilepticus (SE) induced by pilocarpine. Local overexpression of ALOXE3 via adeno-associated virus gene transfer restored the elevated AA level induced by SE, alleviated seizure severities by increasing the latencies to myclonic switch, clonic convulsions and tonic hindlimb extensions, and decreased the mortality rate in the pilocarpine-induced SE model. These results suggest that the expression of ALOXE3 is a crucial regulator of AA metabolism in brain, and potentially acts as a regulator of neural excitability, thereby controlling brain development and seizure susceptibility.

The proposed mechanisms of action of CBD in epilepsy.

Highly purified cannabidiol (CBD) (approved as Epidiolex® in the United States and as EPIDYOLEX from the EU agency) has demonstrated efficacy with an acceptable safety profile in patients with Lennox-Gastaut or Dravet syndrome in four randomized controlled trials. While the mechanism of action of CBD underlying the reduction of seizures in humans is unknown, CBD possesses affinity for multiple targets, across a range of target classes, resulting in functional modulation of neuronal excitability, relevant to the pathophysiology of many disease types, including epilepsy. Here we present the pharmacological data supporting the role of three such targets, namely Transient receptor potential vanilloid-1 (TRPV1), the orphan G protein-coupled receptor-55 (GPR55) and the equilibrative nucleoside transporter 1 (ENT-1).

Roles of Glutamate Receptors in Parkinson's Disease.

Parkinson’s disease is a progressive neurodegenerative disorder resulting from the degeneration of pigmented dopaminergic neurons in the substantia nigra pars compacta. It induces a series of functional modifications in the circuitry of the basal ganglia nuclei and leads to severe motor disturbances. The amino acid glutamate, as an excitatory neurotransmitter, plays a key role in the disruption of normal basal ganglia function regulated through the interaction with its receptor proteins. It has been proven that glutamate receptors participate in the modulation of neuronal excitability, transmitter release, and long-term synaptic plasticity, in addition to being related to the altered neurotransmission in Parkinson’s disease. Therefore, they are considered new targets for improving the therapeutic strategies used to treat Parkinson’s disease. In this review, we discuss the biological characteristics of these receptors and demonstrate the receptor-mediated neuroprotection in Parkinson’s disease. Pharmacological manipulation of these receptors during anti-Parkinsonian processes in both experimental studies and clinical trials are also summarized.

The Role of Free Oxygen Radicals in Lasting Hyperexcitability of Rat Subicular Neurons After Exposure to General Anesthesia During Brain Development.

A large number of preclinical studies have established that general anesthetics (GAs) may cause neurodevelopmental toxicity in rodents and nonhuman primates, which is followed by long-term cognitive deficits. The subiculum, the main output structure of hippocampal formation, is one of the brain regions most sensitive to exposure to GAs at the peak of synaptogenesis (i.e., postnatal day (PND) 7). We have previously shown that subicular neurons exposed to GAs produce excessive amounts of reactive oxygen species (ROS), such as hydrogen peroxide (H2O2), which is a known modulator of neuronal excitability. To further explore the association between GA-mediated increase in ROS levels and long-term functional changes within subicular neurons, we sought to investigate the effects of ROS on excitability of these neurons using patch-clamp electrophysiology in acute rat brain slices. We hypothesized that both acute application of H2O2 and an early exposure (at PND 7) to GA consisting of midazolam (9mg/kg), 70% nitrous oxide, and 0.75% isoflurane can affect excitability of subicular neurons and that superoxide dismutase and catalase mimetic, EUK-134, may reverse GA-mediated hyperexcitability in the subiculum. Our results using whole-cell recordings demonstrate that acute application of H2O2 has bidirectional effects on neuronal excitability: lower concentrations (0.001%, 0.3mM) cause an excitatory effect, whereas higher concentrations (0.01%, 3mM) inhibited neuronal firing. Furthermore, 0.3mM H2O2 increased the average action potential frequency of subicular neurons by almost twofold, as assessed using cell-attach configuration. Finally, we found that preemptive in vivo administration of EUK-134 reduced GA-induced long-lasting hyperexcitability of subicular neurons ex vivo when studied in neonatal and juvenile rats. This finding suggests that the increase in ROS after GA exposure may play an important role in regulating neuronal excitability, thus making it an attractive therapeutic target for GA-induced neurotoxicity in neonates.

Increased CSF tau is associated with a higher risk of seizures in patients with Alzheimer's disease

IntroductionNeurofibrillary tangles and tau protein, the neuropathological hallmarks of Alzheimer's disease (AD), have been identified in patients with epilepsy. Tau protein was also associated with the modulation of neuronal excitability in animal models of AD. Materials and methodsWe evaluated in 292 patients with AD the association between the risk of seizure development and AD cerebrospinal fluid (CSF) biomarkers, demographic characteristics, baseline Mini-Mental State Examination (MMSE) score, comorbidities, and apolipoprotein E status. ResultsThe development of seizures was associated with younger age at dementia's onset, lower baseline MMSE, and higher CSF total tau protein levels, but only MMSE (hazard ratio [HR] = 0.935; 95% confidence interval [CI] = [0.903, 0.968]; p < 0.001) and CSF tau (HR = 1.001; 95%CI = [1.001, 1.002]; p = 0.001) were independent predictors on multivariate analysis. DiscussionWhile CSF tau and lower baseline MMSE association with seizure development could in part be explained by a greater degree of cortical damage, the role of tau in the modulation of neuronal excitability may also play a role and should be further investigated.