Search

Angelman syndrome (AS) is a neurodevelopmental disorder with unique behavioral phenotypes, seizures, and distinctive electroencephalographic (EEG) patterns. Recent studies identified motor, social communication, and learning and memory deficits in a CRISPR engineered rat model with a complete maternal deletion of theUbe3agene. It is unknown whether this model recapitulates other aspects of the clinical disorder. We report here the effect ofUbe3amaternal deletion in the rat on epileptiform activity, seizure threshold, and quantitative EEG. Using video-synchronized EEG (vEEG) monitoring, we assessed spectral power and epileptiform activity early postnatally through adulthood. While EEG power was similar to wild-type (WT) at 1.5 weeks postnatally, at all other ages analyzed, our findings were similar to the AS phenotype in mice and humans with significantly increased δ power. Analysis of epileptiform activity in juvenile and adult rats showed increased time spent in epileptiform activity in AS compared with WT rats. We evaluated seizure threshold using pentylenetetrazol (PTZ), audiogenic stimulus, and hyperthermia to provoke febrile seizures (FSs). Behavioral seizure scoring following PTZ induction revealed no difference in seizure threshold in AS rats, however behavioral recovery from the PTZ-induced seizure was longer in the adult group with significantly increased hippocampal epileptiform activity during this phase. When exposed to hyperthermia, AS rat pups showed a significantly lower temperature threshold to first seizure than WT. Our findings highlight an age-dependence for the EEG and epileptiform phenotypes in a preclinical model of AS, and support the use of quantitative EEG and increased δ power as a potential biomarker of AS.

Status epilepticus (SE) is a prevalent disorder associated with significant morbidity, including the development of epilepsy and mortality. Cardiac arrhythmias (i.e. inappropriate sinus tachycardia and bradycardia, asystole, and atrioventricular blocks) are observed in patients following SE. We characterized ictal (during a seizure) and interictal (between seizure) cardiac arrhythmogenesis following SE using continuous electrocardiography and video electroencephalography (vEEG) recordings throughout a 14-day monitoring period in an intrahippocampal chemoconvulsant mouse model that develops epilepsy. We quantified heart rhythm abnormalities and examined whether the frequency of cardiac events correlated with epileptiform activity, circadian (light/dark) cycle, the presence of seizures, and survival during this period of early epileptogenesis (the development of epilepsy) following SE. Shortly following SE, mice developed an increased interictal heart rate and heart rhythm abnormalities (i.e. sinus pause and sinus arrhythmias) when compared to control mice. Heart rhythm abnormalities were more frequent during the light cycle and were not correlated with increased epileptiform activity or seizure frequency. Finally, SE animals had early mortality, and a death event captured during vEEG recording demonstrated severe bradycardia prior to death. These cardiac changes occurred within 14 days after SE and may represent an early risk factor for sudden death following SE.

Summary Objective Sympathetic predominance and ventricular repolarization abnormalities represent epilepsy‐associated cardiac alterations and may underlie seizure‐induced ventricular arrhythmias. Myocardial ion channel and electrical remodeling have been described early in epilepsy development and may contribute to ventricular repolarization abnormalities and excitability. Using the pilocarpine‐induced acquired epilepsy model we sought to examine whether altered myocardial ion channel levels and electrophysiological changes also occur in animals with long‐standing epilepsy. Methods We examined myocardial adrenergic receptor and ion channel protein levels of epileptic and age‐matched sham rats (9–20 months old) using western blotting. Cardiac electrical properties were examined using optical mapping ex vivo and electrophysiology in vivo. We investigated the propensity for ventricular tachycardia (VT) and the effects of β‐adrenergic blockade on ventricular electrical properties and excitability in vivo. Results In animals with long‐standing epilepsy, we observed decreased myocardial voltage‐gated K+ channels Kv4.2 and Kv4.3, which are known to underlie early ventricular repolarization in rodents. Decreased β1 and increased α1A adrenergic receptor protein levels occurred in the myocardium of chronically epileptic animals consistent with elevated sympathetic tone. These animals exhibited many cardiac electrophysiological abnormalities, represented by longer QRS and corrected QT (QTc) intervals in vivo, slower conduction velocity ex vivo, and stimulation‐induced VT. Administration of a β‐adrenergic antagonist late in epilepsy was beneficial, as the therapy shortened the QTc interval and decreased stimulation‐induced VT. Significance Our findings demonstrate that myocardial ion channel remodeling and sympathetic predominance, risk factors for increased ventricular excitability and arrhythmias, persist in chronic epilepsy. The beneficial effects of β‐adrenergic antagonist treatment late in the course of epilepsy suggest that attenuating elevated sympathetic tone may represent a therapeutic target for ameliorating epilepsy‐associated cardiac morbidity.

Angelman syndrome (AS) is a genetic neurodevelopmental disorder, most commonly caused by deletion or mutation of the maternal allele of the UBE3A gene, with behavioral phenotypes and seizures as key features. Currently no treatment is available, and therapeutics are often ineffective in controlling AS-associated seizures. Previous publications using the Ube3a maternal deletion model have shown behavioral and seizure susceptibility phenotypes, however findings have been variable and merit characterization of electroencephalographic (EEG) activity. In this study, we extend previous studies comparing the effect of genetic background on the AS phenotype by investigating the behavioral profile, EEG activity, and seizure threshold. AS C57BL/6J mice displayed robust behavioral impairments, spontaneous EEG polyspikes, and increased cortical and hippocampal power primarily driven by delta and theta frequencies. AS 129 mice performed poorly on wire hang and contextual fear conditioning and exhibited a lower seizure threshold and altered spectral power. AS F1 hybrid mice (C57BL/6J × 129) showed milder behavioral impairments, infrequent EEG polyspikes, and fewer spectral power alterations. These findings indicate the effect of common genetic backgrounds on the Ube3a maternal deletion behavioral, EEG, and seizure threshold phenotypes. Our results will inform future studies on the optimal strain for evaluating therapeutics with different AS-like phenotypes.

Visual Abstract, Numerous studies have shown epilepsy-associated cognitive deficits, but less is known about the effects of one single generalized seizure. Recent studies demonstrate that a single, self-limited seizure can result in memory deficits and induces hyperactive phosphoinositide 3-kinase/Akt (protein kinase B)/mechanistic target of rapamycin (PI3K/Akt/mTOR) signaling. However, the effect of a single seizure on subcellular structures such as dendritic spines and the role of aberrant PI3K/Akt/mTOR signaling in these seizure-induced changes are unclear. Using the pentylenetetrazole (PTZ) model, we induced a single generalized seizure in rats and: (1) further characterized short- and long-term hippocampal and amygdala-dependent memory deficits, (2) evaluated whether there are changes in dendritic spines, and (3) determined whether inhibiting hyperactive PI3K/Akt/mTOR signaling rescued these alterations. Using the PI3K inhibitor wortmannin (Wort), we partially rescued short- and long-term memory deficits and altered spine morphology. These studies provide evidence that pathological PI3K/Akt/mTOR signaling plays a role in seizure-induced memory deficits as well as aberrant spine morphology.

Physiological and behavioral evidence supports that dopamine (DA) receptor signaling influences hippocampal function. While several recent studies examined how DA influences CA1 plasticity and learning, there are fewer studies investigating the influence of DA signaling to the dentate gyrus. The dentate gyrus receives convergent cortical input through the perforant path fiber tracts and has been conceptualized to detect novelty in spatial memory tasks. To test whether DA-receptor activity influences novelty-detection, we used a novel object recognition (NOR) task where mice remember previously presented objects as an indication of learning. Although DA innervation arises from other sources and the main DA signaling may be from those sources, our molecular approaches verified that midbrain dopaminergic fibers also sparsely innervate the dentate gyrus. During the NOR task, wild-type mice spent significantly more time investigating novel objects rather than previously observed objects. Dentate granule cells in slices cut from those mice showed an increased AMPA/NMDA-receptor current ratio indicative of potentiated synaptic transmission. Post-training injection of a D1-like receptor antagonist not only effectively blocked the preference for the novel objects, but also prevented the increased AMPA/NMDA ratio. Consistent with that finding, neither NOR learning nor the increase in the AMPA/NMDA ratio were observed in DA-receptor KO mice under the same experimental conditions. The results indicate that DA-receptor signaling contributes to the successful completion of the NOR task and to the associated synaptic plasticity of the dentate gyrus that likely contributes to the learning.

Inadequate sleep is prevalent in modern societies and is known to profoundly impair cognitive function. We examined the impact of 4 weeks of regular treadmill exercise on sleep deprivation induced spatial learning and memory, synaptic plasticity and related signaling molecules in area CA1 of the rat hippocampus. Rats were exercised on a treadmill and subsequently sleep-deprived for 24 h using the modified multiple platform technique. Testing of learning and short-term memory performance in the radial arm water maze showed that although sedentary sleep deprived rats were severely impaired, exercised sleep deprived rats' performance was normal. Extracellular recording from area CA1 of anesthetized rats revealed that early phase LTP (E-LTP) was markedly impaired in the sedentary sleep deprived animals, but was normal in the exercised sleep deprived group. Additionally, immunoblot analysis of CA1 area before (basal) and after expression of E-LTP indicated that the significant down-regulation of the brain derived neurotrophic factor (BDNF) and phosphorylated calcium–calmodulin dependent protein kinase II (P-CaMKII) levels in sleep deprived animals was prevented by the regular exercise regimen. The results suggest that the regular exercise protocol prevents the sleep deprivation induced impairments in short-term memory and E-LTP by preventing deleterious changes in the basal and post-stimulation levels of P-CaMKII and BDNF associated with sleep deprivation.

Our previous work suggests that pharmacological induction of oxidative stress causes anxiety-like behavior in rats. Interestingly, sleep deprivation is reported to cause oxidative damage in the brain and is also reported to be anxiogenic. Minimal mechanistic insights are available. In this study, using a behavioral and biochemical approach, we investigated involvement of oxidative stress mechanisms in sleep deprivation-induced anxiety-like behavior of rats and the protective role of treadmill exercise in this process. We report that acute sleep deprivation (SD) increases oxidative stress in the cortex, hippocampus and amygdala while prior treadmill exercise prevents this increase. Serum corticosterones also increase with SD but its levels are normalized in exercised sleep-deprived rats. Also, anxiety-like behavior of rats significantly increases with SD while prior treadmill exercise prevents this increase. Protein expression of two enzymes involved in antioxidant defense, glyoxalase (GLO)-1 and glutathione reductase (GSR)-1 increased after 24h SD in the hippocampus, cortex and amygdala while their levels were normalized in exercised sleep-deprived rats. It is plausible that oxidative stress via regulation of GLO1 and GSR1 is involved in sleep deprivation-induced anxiety-like behavior of rats.

We investigated the neuroprotective effect of regular treadmill exercise training on long-term memory and its correlate: the late-phase long-term potentiation (L-LTP) and plasticity- and memory-related signaling molecules in the DG and CA1 areas of a rat model of Alzheimer's disease (AD) (i.c.v. infusion of Aβ1-42 peptides, 2 weeks, 250 pmol/day). Testing in the radial arm water maze revealed severe impairment of spatial long-term memory in Aβ-infused sedentary rats but not in exercised Aβ-infused rats. The L-LTP, measured as changes in the field (f)EPSP and in the amplitude of population spike (pspike), was induced by multiple high-frequency stimulation in the CA1 and DG areas of anesthetized rats. The L-LTP of fEPSP in both areas was severely impaired in the sedentary Aβ rats but not in exercised Aβ rats. However, L-LTP of the pspike was severely suppressed in the CA1 area but not in the DG of sedentary Aβ rats. Immunoblot analysis revealed no increase in the levels of phosphorylated (p)-CREB, CaMKIV, and brain-derived neurotrophic factor (BDNF) in both CA1 and DG areas of sedentary Aβ rats during L-LTP, whereas the levels of these molecules were robustly increased in exercised Aβ rats. Impairment of synaptic function may be due to deleterious changes in the molecular signaling cascades that mediate synaptic structural and functional changes. The protective effect of regular exercise can be a promising therapeutic measure for countering or delaying the AD-like pathology.

The original version of this article unfortunately does not include the second affiliating institution of Dr. Munder A. Zagaar. "Department of Pharmacy Pracce and Clinical Health Sciences, Texas Southern University, Houston, TX 77004" should have been included on the paper.

Study objectives The present study aimed to investigate the effects of treadmill exercise on sleep deprivation (S-D)-induced impairment of hippocampal dependent long-term memory, late phase long-term potentiation (L-LTP) and its signaling cascade in the cornu ammonis 1 (CA1) area. Experimental design Animals were conditioned to run on treadmills for 4 weeks then deprived of sleep for 24 h using the columns-in-water method. We tested the effect of exercise and/or S-D on behavioral performance using a post-learning paradigm in the radial arm water maze (RAWM) and in vivo extracellular recording in the CA1 area. The levels of L-LTP-related molecules in the CA1 area were then assessed both before and after L-LTP induction. Measurements and results After 24 h of S-D, spatial long-term memory impairment in the RAWM and L-LTP suppression was prevented by 4 weeks of regular exercise. Regular exercise also restored the S-D-associated decreases in the basal levels of key signaling molecules such as: calcium/calmodulin kinase IV (CaMKIV), mitogen-activated protein kinase (MAPK/ERK), phosphorylated cAMP response element-binding protein (P-CREB) and brain derived neurotrophic factor (BDNF), in the CA1 area. After L-LTP induction, regular exercise also prevented the S-D-induced down regulation of BDNF and P-CREB protein levels. Conclusions The results suggest that our exercise protocol may prevent 24-h S-D-induced impairments in long-term memory and LTP by preventing deleterious changes in the basal and post-stimulation levels of P-CREB and BDNF associated with S-D.

Attention-deficit hyperactive disorder (ADHD) is the most commonly studied and diagnosed psychiatric disorder in children. Methylphenidate (MPH, e.g., Ritalin) has been used to treat ADHD for over 50 years. It is the most commonly prescribed treatment for ADHD, and in the past decade it was the drug most commonly prescribed to teenagers. In addition, MPH has become one of the most widely abused drugs on college campuses. In this study, we examined the effects of MPH on hippocampal synaptic plasticity, which serves as a measurable quantification of memory mechanisms. Field potentials were recorded with permanently implanted electrodes in freely-moving mice to quantify MPH modulation of perforant path synaptic transmission onto granule cells of the dentate gyrus. Our hypothesis was that MPH affects hippocampal synaptic plasticity underlying learning because MPH boosts catecholamine signaling by blocking the dopamine and norepinephrine transporters (DAT and NET respectively). In vitro hippocampal slice experiments indicated MPH enhances perforant path plasticity, and this MPH enhancement arose from action via D1-type dopamine receptors and β-type adrenergic receptors. Similarly, MPH boosted in vivo initiation of long-term potentiation (LTP). While there was an effect via both dopamine and adrenergic receptors in vivo, LTP induction was more dependent on the MPH-induced action via D1-type dopamine receptors. Under biologically reasonable experimental conditions, MPH enhances hippocampal synaptic plasticity via catecholamine receptors.