Age-related impact of phenobarbital in suppressing prenatal alcohol exposure-related seizures in developing rats.

Prenatal alcohol exposure (PAE) during pregnancy can increase the prevalence of N-methyl-D-aspartate (NMDA)-induced generalized tonic-clonic seizures (GTCSs) in developing rats. However, it is unclear whether phenobarbital (PB) can suppress these PAE-related seizures. To explore this knowledge gap, we investigated the effects of acute PB treatment on NMDA-induced seizures in postpartum rats, prenatally exposed to alcohol on gestational day 18 (GD18), at two developmental stages: day 7 (P7), the equivalent of pre-term neonates, and day 15 (P15), the equivalent of full-term neonates.

Inhibition of TRPC3 channels suppresses seizure susceptibility in the genetically-epilepsy prone rats.

Transient receptor potential canonical 3 (TRPC3) channels are important in regulating Ca homeostasis and have been implicated in the pathophysiology of chemically induced seizures. Inherited seizure susceptibility in genetically epilepsy-prone rats (GEPR-3s) has been linked to increased voltage-gated Ca channel currents in the inferior colliculus neurons, which can affect intraneuronal Ca homeostasis. However, whether TRPC3 channels also contribute to inherited seizure susceptibility in GEPR-3s is unclear.

Inhibition of the Sodium-Calcium Exchanger Reverse Mode Activity Reduces Alcohol Consumption in Rats.

Excessive and uncontrolled consumption of alcohol can cause alcohol use disorder (AUD), but its pharmacological mechanisms are not fully understood. Inhibiting the reverse mode activity of the sodium-calcium exchanger (NCX) can reduce the risk of alcohol withdrawal seizures, suggesting that NCX could play a role in controlling alcohol consumption. Here, we investigated how two potent inhibitors of NCX reverse mode activity, SN-6 (NCX1) and KB-R7943 (NCX3), affect voluntary alcohol consumption in adult male and female rats using the intermittent alcohol access two-bottle choice paradigm.

Influence of Inherited Seizure Susceptibility on Intermittent Voluntary Alcohol Consumption and Alcohol Withdrawal Seizures in Genetically Epilepsy-Prone Rats (GEPR-3s).

Background: The link between epilepsy and alcohol consumption is complex, with conflicting reports. To enhance our understanding of this link, we conducted a study to determine how inherited seizure susceptibility affects voluntary alcohol consumption and influences alcohol withdrawal seizures in male and female genetically epilepsy-prone rats (GEPR-3s) compared to Sprague Dawley (SD) rats.

Methods: In the first experiment, animals were given access to two bottles simultaneously, one containing water and the other 7.

Seizure-suppressor genes: can they help spearhead the discovery of novel therapeutic targets for epilepsy?

Introduction: Epilepsies are disorders of neuronal excitability characterized by spontaneously recurrent focal and generalized seizures, some of which result from genetic mutations. Despite the availability of antiseizure medications, pharmaco-resistant epilepsy is seen in about 23% of epileptic patients worldwide. Therefore, there is an urgent need to develop novel therapeutic strategies for epilepsies.

Pathogenesis and Targeted Therapy of Epilepsy.

The Special Issue (BSI) of "Pathogenesis and Targeted Therapy of Epilepsy" seeks papers providing new insights into the roles of voltage-gated and ligand-gated ion channels and their related signaling in the pathogenesis and pathophysiology of acquired epilepsy and inherited epilepsy [...

Targeted Inhibition of Upregulated Sodium-Calcium Exchanger in Rat Inferior Colliculus Suppresses Alcohol Withdrawal Seizures.

The inferior colliculus (IC) is critical in initiating acoustically evoked alcohol withdrawal-induced seizures (AWSs). Recently, we reported that systemic inhibition of Ca entry via the reverse mode activity of the Na/Ca exchanger (NCX) suppressed AWSs, suggesting remodeling of NCX expression and function, at least in the IC, the site of AWS initiation. Here, we probe putative changes in protein expression in the IC of NCX isoforms, including NCX type 1 (NCX1), 2 (NCX2), and 3 (NCX3).

Activation of Calcium-Activated Chloride Channels Suppresses Inherited Seizure Susceptibility in Genetically Epilepsy-Prone Rats.

Inherited seizure susceptibility in genetically epilepsy-prone rats (GEPR-3s) is associated with increased voltage-gated calcium channel currents suggesting a massive calcium influx resulting in increased levels of intraneuronal calcium. Cytosolic calcium, in turn, activates many processes, including chloride channels, to restore normal membrane excitability and limit repetitive firing of the neurons. Here we used EACT and T16Ainh-A01, potent activator and inhibitor of calcium-activated channels transmembrane protein 16A (TMEM16A), respectively, to probe the role of these channels in the pathophysiology of acoustically evoked seizures in the GEPR-3s.

Absence epilepsy in male and female WAG/Rij rats: A longitudinal EEG analysis of seizure expression.

The WAG/Rij strain of rats is commonly used as a preclinical model of genetic absence epilepsy. While widely utilized, the developmental trajectory of absence seizure expression has been only partially described. Moreover, sex differences in this strain have been under-explored.

Inhibition of the Sodium Calcium Exchanger Suppresses Alcohol Withdrawal-Induced Seizure Susceptibility.

Calcium influx plays important roles in the pathophysiology of seizures, including acoustically evoked alcohol withdrawal-induced seizures (AWSs). One Ca influx route of interest is the Na/Ca exchanger (NCX) that, when operating in its reverse mode (NCX) activity, can facilitate Ca entry into neurons, possibly increasing neuronal excitability that leads to enhanced seizure susceptibility. Here, we probed the involvement of NCX activity on AWS susceptibility by quantifying the effects of SN-6 and KB-R7943, potent blockers of isoform type 1 (NCX1) and 3 (NCX3), respectively.

Divergent Effects of Systemic and Intracollicular CB Receptor Activation Against Forebrain and Hindbrain-Evoked Seizures in Rats.

Cannabinoid (CB) receptor agonists are of growing interest as targets for anti-seizure therapies. Here we examined the effect of systemic administration of the CB receptor agonist WIN 55,212-2 (WIN) against audiogenic seizures (AGSs) in the Genetically Epilepsy Prone Rat (GEPR)-3 strain, and against seizures evoked focally from the (AT). We compared these results to the effect of focal administration of the CB1/2 receptor agonist CP 55940 into the deep layers of the superior colliculus (DLSC), a brain site expressing CB1 receptors.

Prenatal alcohol exposure in the second trimester-equivalent increases the seizure susceptibility in developing rats.

We have previously reported that prenatal alcohol exposure (PAE) in the 2nd trimester-equivalent of gestation is associated with increased N-methyl-d-aspartate (NMDA)-induced generalized tonic-clonic seizures (GTCSs) prevalence in postpartum developing rats. Whether the 1st trimester-equivalent of gestation is also a vulnerable period for developing GTCSs following PAE is unknown. Here, we investigated the effects of a single episode of PAE at embryonic day 8 (E8, in the 1st trimester-equivalent) or E18 (in the 2nd trimester-equivalent) on NMDA-induced seizures in developing rats at postnatal day 7 (P7, the equivalent of preterm newborns) and P15 (the equivalent of term infants).

Descending projections from the differentially control seizures.

Three decades of studies have shown that inhibition of the (SNpr) attenuates seizures, yet the circuits mediating this effect remain obscure. SNpr projects to the deep and intermediate layers of the superior colliculus (DLSC) and the pedunculopontine nucleus (PPN), but the contributions of these projections are unknown. To address this gap, we optogenetically silenced cell bodies within SNpr, nigrotectal terminals within DLSC, and nigrotegmental terminals within PPN.

Activation of small conductance calcium-activated potassium channels suppresses seizure susceptibility in the genetically epilepsy-prone rats.

Small conductance calcium-activated potassium (SK) channels dampen neuronal excitability by contributing to slow afterhyperpolarization (AHP) that follows a series of action potentials, and therefore may represent an intrinsic inhibitory mechanism to prevent seizures. We have previously reported that susceptibility to acoustically evoked seizures was associated with downregulation of SK1 and SK3 subtypes of SK channels in the inferior colliculus of the moderated seizure severity strain of the genetically epilepsy-prone rats (GEPR-3s). Here, we evaluated the effects of 1-ethyl-2-benzimidazolinone (1-EBIO), a potent activator of SK channels, on acoustically evoked seizures in both male and female adult GEPR-3s at various time points post-treatment.

Genetically Epilepsy-Prone Rats Display Anxiety-Like Behaviors and Neuropsychiatric Comorbidities of Epilepsy.

Epilepsy is associated with a variety of neuropsychiatric comorbidities, including both anxiety and depression. Despite high occurrences of depression and anxiety seen in human epilepsy populations, little is known about the etiology of these comorbidities. Experimental models of epilepsy provide a platform to disentangle the contribution of acute seizures, genetic predisposition, and underlying circuit pathologies to anxious and depressive phenotypes.

Voltage-Sensitive Calcium Channels in the Brain: Relevance to Alcohol Intoxication and Withdrawal.

Voltage-sensitive Ca (Ca) channels are the primary route of depolarization-induced Ca entry in neurons and other excitable cells, leading to an increase in intracellular Ca concentration ([Ca]). The resulting increase in [Ca] activates a wide range of Ca-dependent processes in neurons, including neurotransmitter release, gene transcription, activation of Ca-dependent enzymes, and activation of certain K channels and chloride channels. In addition to their key roles under physiological conditions, Ca channels are also an important target of alcohol, and alcohol-induced changes in Ca signaling can disturb neuronal homeostasis, Ca-mediated gene transcription, and the function of neuronal circuits, leading to various neurological and/or neuropsychiatric symptoms and disorders, including alcohol withdrawal induced-seizures and alcoholism.

Alcohol withdrawal upregulates mRNA encoding for Ca2.1-α1 subunit in the rat inferior colliculus.

We previously reported increased current density through P-type voltage-gated Ca channels in inferior colliculus (IC) neurons during alcohol withdrawal. However, the molecular correlate of this increased P-type channel current is currently unknown. Here, we probe changes in mRNA and protein expression of the pore-forming Ca2.

Divergent brain changes in two audiogenic rat strains: A voxel-based morphometry and diffusion tensor imaging comparison of the genetically epilepsy prone rat (GEPR-3) and the Wistar Audiogenic Rat (WAR).

Acoustically evoked seizures (e.g., audiogenic seizures or AGS) are common in models of inherited epilepsy and occur in a variety of species including rat, mouse, and hamster.

Inhibition of transient potential receptor vanilloid type 1 suppresses seizure susceptibility in the genetically epilepsy-prone rat.

Aims: Intracellular calcium plays an important role in neuronal hyperexcitability that leads to seizures. One calcium influx route of interest is the transient receptor potential vanilloid type 1 (TRPV1) channel. Here, we evaluated the effects of capsazepine (CPZ), a potent blocker of TRPV1 channels on acoustically evoked seizures (audiogenic seizures, AGS) in the genetically epilepsy-prone rat (GEPR-3), a model of inherited epilepsy.

Prenatal alcohol exposure enhances the susceptibility to NMDA-induced generalized tonic-clonic seizures in developing rats.

Aims: Prenatal alcohol exposure (PAE) is associated with a higher likelihood of developing generalized tonic-clonic seizures (GTCS) in infants and children. However, experimental studies of PAE-related seizures have yielded conflicting results. Here, we investigated the effect of acute PAE on N-methyl-D-aspartate (NMDA)-induced seizures in developing rats.

Alcohol Withdrawal Increases Protein Kinase A Activity in the Rat Inferior Colliculus.

Background: Cyclic AMP-dependent protein kinase A (PKA) signaling is a key target for the action of alcohol and may therefore play a role in the pathophysiology of alcohol withdrawal seizures (AWSs). Here, we investigated the role of PKA activity with respect to increased seizure susceptibility in rats that were subjected to alcohol withdrawal.

Methods: Adult male Sprague Dawley rats received 3 daily doses of ethanol (EtOH) (or vehicle) for 4 consecutive days.

Increased DNA double-strand break was associated with downregulation of repair and upregulation of apoptotic factors in rat hippocampus after alcohol exposure.

Binge drinking is known to cause damage in critical areas of the brain, including the hippocampus, which is important for relational memory and is reported to be sensitive to alcohol toxicity. However, the roles of DNA double-strand break (DSB) and its repair pathways, homologous recombination (HR), and non-homologous end joining (NHEJ) in alcohol-induced hippocampal injury remain to be elucidated. The purpose of this first study was to assess alcohol-induced DNA DSB and the mechanism by which alcohol affects DSB repair pathways in rat hippocampus.

Optogenetic activation of superior colliculus neurons suppresses seizures originating in diverse brain networks.

Because sites of seizure origin may be unknown or multifocal, identifying targets from which activation can suppress seizures originating in diverse networks is essential. We evaluated the ability of optogenetic activation of the deep/intermediate layers of the superior colliculus (DLSC) to fill this role. Optogenetic activation of DLSC suppressed behavioral and electrographic seizures in the pentylenetetrazole (forebrain+brainstem seizures) and Area Tempestas (forebrain/complex partial seizures) models; this effect was specific to activation of DLSC, and not neighboring structures.

Altered voltage-gated calcium channels in rat inferior colliculus neurons contribute to alcohol withdrawal seizures.

We have previously reported that enhanced susceptibility to alcohol withdrawal seizures (AWS) parallels the enhancement of the current density of high-threshold voltage-gated Ca(2+) (CaV) channels in rat inferior colliculus (IC) neurons. However, whether this increased current density is a cause or consequence of AWS is unclear. Here, I report changes in the current density of CaV channels in IC neurons during the course of alcohol withdrawal and the potential anticonvulsant effect of intra-IC infusions of L- and P-type CaV channel antagonists.