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Iyengar S.S.,The Nathan Kline Institute for Psychiatric Research | LaFrancois J.J.,The Nathan Kline Institute for Psychiatric Research | Friedman D.,New York University | Drew L.J.,University College London | And 9 more authors.
Experimental Neurology | Year: 2015

Adult neurogenesis, the generation of new neurons in the adult brain, occurs in the hippocampal dentate gyrus (DG) and the olfactory bulb (OB) of all mammals, but the functions of these new neurons are not entirely clear. Originally, adult-born neurons were considered to have excitatory effects on the DG network, but recent studies suggest a net inhibitory effect. Therefore, we hypothesized that selective removal of newborn neurons would lead to increased susceptibility to the effects of a convulsant. This hypothesis was tested by evaluating the response to the chemoconvulsant kainic acid (KA) in mice with reduced adult neurogenesis, produced either by focal X-irradiation of the DG, or by pharmacogenetic deletion of dividing radial glial precursors. In the first 4. hrs after KA administration, when mice have the most robust seizures, mice with reduced adult neurogenesis had more severe convulsive seizures, exhibited either as a decreased latency to the first convulsive seizure, greater number of convulsive seizures, or longer convulsive seizures. Nonconvulsive seizures did not appear to change or they decreased. Four-21. hrs after KA injection, mice with reduced adult neurogenesis showed more interictal spikes (IIS) and delayed seizures than controls. Effects were greater when the anticonvulsant ethosuximide was injected 30. min prior to KA administration; ethosuximide allows forebrain seizure activity to be more easily examined in mice by suppressing seizures dominated by the brainstem. These data support the hypothesis that reduction of adult-born neurons increases the susceptibility of the brain to effects of KA. © 2014 Elsevier Inc.


Harte-Hargrove L.C.,The Nathan Kline Institute for Psychiatric Research | Harte-Hargrove L.C.,New York University | Varga-Wesson A.,The Nathan Kline Institute for Psychiatric Research | Duffy A.M.,The Nathan Kline Institute for Psychiatric Research | And 5 more authors.
Journal of Neuroscience | Year: 2015

The mossy fiber (MF) pathway is critical to hippocampal function and influenced by gonadal hormones. Physiological data are limited, so we asked whether basal transmission and long-term potentiation (LTP) differed in slices of adult male and female rats. The results showed small sex differences in basal transmission but striking sex differences in opioid receptor sensitivity and LTP. When slices were made from females on proestrous morning, when serum levels of 17β-estradiol peak, the nonspecific opioid receptor antagonist naloxone (1µM) enhanced MF transmission but there was no effect in males, suggesting preferential opioid receptor-dependent inhibition in females when 17 β -estradiol levels are elevated. The µ-opioid receptor (MOR) antagonist Cys2,Tyr3,Orn5,Pen7-amide (CTOP; 300 nM) had a similar effect but the δ-opioid receptor (DOR) antagonist naltrindole (NTI; 1 µM) did not, implicating MORs in female MF transmission. The GABAB receptor antagonist saclofen (200µM) occluded effects of CTOP but the GABAA receptor antagonist bicuculline (10 µM) did not. For LTP, a low-frequency (LF) protocol was used because higher frequencies elicited hyperexcitability in females. Proestrous females exhibited LF-LTP but males did not, suggesting a lower threshold for synaptic plasticity when 17β-estradiol is elevated. NTI blocked LF-LTP in proestrous females, but CTOP did not. Electron microscopy revealed more DOR-labeled spines of pyramidal cells in proestrous females than males. Therefore, we suggest that increased postsynaptic DORs mediate LF-LTP in proestrous females. The results show strong MOR regulation of MF transmission only in females and identify a novel DOR-dependent form of MF LTP specific to proestrus. ©2015 the authors.


VonDran M.W.,New York Medical College | LaFrancois J.,The Nathan Kline Institute for Psychiatric Research | Padow V.A.,New York Medical College | Friedman W.J.,Rutgers University | And 3 more authors.
ASN neuro | Year: 2014

ProNGF and p75(NTR) are upregulated and induce cell death following status epilepticus (SE) in rats. However, less is known about the proneurotrophin response to SE in mice, a more genetically tractable species where mechanisms can be more readily dissected. We evaluated the temporal- and cell-specific induction of the proneurotrophins and their receptors, including p75(NTR), sortilin, and sorCS2, following mild SE induced with kainic acid (KA) or severe SE induced by pilocarpine. We found that mature NGF, p75(NTR), and proBDNF were upregulated following SE, while proNGF was not altered, indicating potential mechanistic differences between rats and mice. ProBDNF was localized to mossy fibers and microglia following SE. p75(NTR) was transiently induced primarily in axons and axon terminals following SE, as well as in neuron and astrocyte cell bodies. ProBDNF and p75(NTR) increased independently of cell death and their localization was different depending on the severity of SE. We also examined the expression of proneurotrophin co-receptors, sortilin and sorCS2. Following severe SE, sorCS2, but not sortilin, was elevated in neurons and astrocytes. These data indicate that important differences exist between rat and mouse in the proneurotrophin response following SE. Moreover, the proBDNF and p75(NTR) increase after seizures in the absence of significant cell death suggests that proneurotrophin signaling may play other roles following SE. © The Author(s) 2014 Reprints and permissions: sagepub.co.uk/journalsPermissions.nav.


Chin J.,Thomas Jefferson University | Scharfman H.E.,New York University | Scharfman H.E.,The Nathan Kline Institute for Psychiatric Research
Epilepsy and Behavior | Year: 2013

Seizures in patients with Alzheimer's disease (AD) have been examined by many investigators over the last several decades, and there are diverse opinions about their potential relevance to AD pathophysiology. Some studies suggest that seizures appear to be a fairly uncommon co-morbidity, whereas other studies report a higher incidence of seizures in patients with AD. It was previously thought that seizures play a minor role in AD pathophysiology because of their low frequency, and also because they may only be noticed during late stages of AD, suggesting that seizures are likely to be a consequence of neurodegeneration rather than a contributing factor. However, clinical reports indicate that seizures can occur early in the emergence of AD symptoms, particularly in familial AD. In this case, seizures may be an integral part of the emerging pathophysiology. This view has been supported by evidence of recurrent spontaneous seizures in transgenic mouse models of AD in which familial AD is simulated. Additional data from transgenic animals suggest that there may be a much closer relationship between seizures and AD than previously considered. There is also evidence that seizures facilitate production of amyloid β (Aβ) and can cause impairments in cognition and behavior in both animals and humans. However, whether seizures play a role in the early stages of AD pathogenesis is still debated. Therefore, it is timely to review the similarities and differences between AD and epilepsy, as well as data suggesting that seizures may contribute to cognitive and behavioral dysfunction in AD. Here we focus on AD and temporal lobe epilepsy (TLE), a particular type of epilepsy that involves the temporal lobe, a region that influences behavior and is critical to memory. We also consider potential neurobiological mechanisms that support the view that the causes of seizures in TLE may be related to the causes of cognitive dysfunction in AD. We suggest that similar underlying mechanisms may exist for at least some of the aspects of AD that are also found in TLE.This article is part of a Special Issue entitled "The Future of Translational Epilepsy Research". © 2012 Elsevier Inc.


Myers C.E.,NeuroBehavioral Research Laboratory | Myers C.E.,Rutgers University | Bermudez-Hernandez K.,New York University | Bermudez-Hernandez K.,The Nathan Kline Institute for Psychiatric Research | And 2 more authors.
PLoS ONE | Year: 2013

Postnatal neurogenesis of granule cells (GCs) in the dentate gyrus (DG) produces GCs that normally migrate from the subgranular zone to the GC layer. However, GCs can mismigrate into the hilus, the opposite direction. Previous descriptions of these hilar ectopic GCs (hEGCs) suggest that they are rare unless there are severe seizures. However, it is not clear if severe seizures are required, and it also is unclear if severe seizures are responsible for the abnormalities of hEGCs, which include atypical dendrites and electrophysiological properties. Here we show that large numbers of hEGCs develop in a transgenic mouse without severe seizures. The mice have a deletion of BAX, which normally regulates apoptosis. Surprisingly, we show that hEGCs in the BAX-/- mouse have similar abnormalities as hEGCs that arise after severe seizures. We next asked if there are selective effects of hEGCs, i.e., whether a robust population of hEGCs would have any effect on the DG if they were induced without severe seizures. Indeed, this appears to be true, because it has been reported that BAX-/- mice have defects in a behavior that tests pattern separation, which depends on the DG. However, inferring functional effects of hEGCs is difficult in mice with a constitutive BAX deletion because there is decreased apoptosis in and outside the DG. Therefore, a computational model of the normal DG and hippocampal subfield CA3 was used. Adding a small population of hEGCs (5% of all GCs), with characteristics defined empirically, was sufficient to disrupt a simulation of pattern separation and completion. Modeling results also showed that effects of hEGCs were due primarily to "backprojections" of CA3 pyramidal cell axons to the hilus. The results suggest that hEGCs can develop for diverse reasons, do not depend on severe seizures, and a small population of hEGCs may impair DG-dependent function. © 2013 Myers et al.


ten Oever S.,Maastricht University | Schroeder C.E.,Columbia University | Schroeder C.E.,The Nathan Kline Institute for Psychiatric Research | Poeppel D.,New York University | And 5 more authors.
Neuropsychologia | Year: 2014

Temporal structure in the environment often has predictive value for anticipating the occurrence of forthcoming events. In this study we investigated the influence of two types of predictive temporal information on the perception of near-threshold auditory stimuli: 1) intrinsic temporal rhythmicity within an auditory stimulus stream and 2) temporally-predictive visual cues. We hypothesized that combining predictive temporal information within- and across-modality should decrease the threshold at which sounds are detected, beyond the advantage provided by each information source alone. Two experiments were conducted in which participants had to detect tones in noise. Tones were presented in either rhythmic or random sequences and were preceded by a temporally predictive visual signal in half of the trials. We show that detection intensities are lower for rhythmic (vs. random) and audiovisual (vs. auditory-only) presentation, independent from response bias, and that this effect is even greater for rhythmic audiovisual presentation. These results suggest that both types of temporal information are used to optimally process sounds that occur at expected points in time (resulting in enhanced detection), and that multiple temporal cues are combined to improve temporal estimates. Our findings underscore the flexibility and proactivity of the perceptual system which uses within- and across-modality temporal cues to anticipate upcoming events and process them optimally. © 2014 Elsevier Ltd.


Bath K.G.,Brown University | Scharfman H.E.,The Nathan Kline Institute for Psychiatric Research | Scharfman H.E.,New York University
Epilepsy and Behavior | Year: 2013

Epilepsy affects approximately 1% of children under the age of 15, making it a very common neurological disorder in the pediatric population (Russ et al., 2012 [1]). In addition, ~. 0.4-0.8% of all pregnant women have some form of epilepsy (Hauser et al., 1996a,b; Borthen et al., 2009; Krishnamurthy, 2012 [2-5]). Despite the potential deleterious effects of antiepileptic drugs (AEDs) on the developing brain, their use is still required for seizure control in pregnant women (Krishnamurthy, 2012 [5]), and they represent the standard approach for treating children with epilepsy (Chu-Shore and Thiele, 2010; Quach et al., 2010; Verrotti et al., 2011 [6-8]). Even when AEDs are effective, there are potential side effects, including cognitive and affective changes or altered sleep and appetite. The consequences of AED exposure in development have been studied extensively (Canger et al., 1999; Modi et al., 2011a,b; Oguni, 2011 [9-12]). Despite intensive study, there is still debate about the long-term consequences of early life AED exposure. Here, we consider the evidence to date that AED exposure, either prenatally or in early postnatal life, has significant adverse effects on the developing brain and incorporate studies of laboratory animals as well as those of patients. We also note the areas of research where greater clarity seems critical in order to make significant advances. A greater understanding of the impact of AEDs on somatic, cognitive and behavioral development has substantial value because it has the potential to inform clinical practice and guide studies aimed at understanding the genetic and molecular bases of comorbid pathologies associated with common treatment regimens. Understanding these effects has the potential to lead to AEDs with fewer side effects. Such advances would expand treatment options, diminish the risk associated with AED exposure in susceptible populations, and improve the quality of life and health outcomes of children with epilepsy and children born to women who took AEDs during pregnancy.This article is part of a Special Issue entitled "The Future of Translational Epilepsy Research". © 2012.


Pearce P.S.,The Nathan Kline Institute for Psychiatric Research | Pearce P.S.,New York University | Friedman D.,New York University | LaFrancois J.J.,The Nathan Kline Institute for Psychiatric Research | And 5 more authors.
Epilepsy and Behavior | Year: 2014

Spike-wave discharges (SWDs) are thalamocortical oscillations that are often considered to be the EEG correlate of absence seizures. Genetic absence epilepsy rats of Strasbourg (GAERS) and Wistar Albino Glaxo rats from Rijswijk (WAG/Rij) exhibit SWDs and are considered to be genetic animal models of absence epilepsy. However, it has been reported that other rat strains have SWDs, suggesting that SWDs may vary in their prevalence, but all rats have a predisposition for them. This is important because many of these rat strains are used to study temporal lobe epilepsy (TLE), where it is assumed that there is no seizure-like activity in controls. In the course of other studies using the Sprague-Dawley rat, a common rat strain for animal models of TLE, we found that approximately 19% of 2- to 3-month-old naive female Sprague-Dawley rats exhibited SWDs spontaneously during periods of behavioral arrest, which continued for months. Males exhibited SWDs only after 3. months of age, consistent with previous reports (Buzsáki et al., 1990). Housing in atypical lighting during early life appeared to facilitate the incidence of SWDs.Spike-wave discharges were often accompanied by behaviors similar to stage 1-2 limbic seizures. Therefore, additional analyses were made to address the similarity. We observed that the frequency of SWDs was similar to that of hippocampal theta rhythm during exploration for a given animal, typically 7-8. Hz. Therefore, activity in the frequency of theta rhythm that occurs during frozen behavior may not reflect seizures necessarily. Hippocampal recordings exhibited high frequency oscillations (>. 250. Hz) during SWDs, suggesting that neuronal activity in the hippocampus occurs during SWDs, i.e., it is not a passive structure. The data also suggest that high frequency oscillations, if rhythmic, may reflect SWDs. We also confirmed that SWDs were present in a common animal model of TLE, the pilocarpine model, using female Sprague-Dawley rats. Therefore, damage and associated changes to thalamic, hippocampal, and cortical neurons do not prevent SWDs, at least in this animal model. The results suggest that it is possible that SWDs occur in rodent models of TLE and that investigators mistakenly assume that they are stage 1-2 limbic seizures. We discuss the implications of the results and ways to avoid the potential problems associated with SWDs in animal models of TLE. © 2014 Elsevier Inc.


Duffy T.M.,The Nathan Kline Institute for Psychiatric Research | Duffy T.M.,New York University | Morales-Corraliza J.,The Nathan Kline Institute for Psychiatric Research | Morales-Corraliza J.,New York University | And 8 more authors.
Neurobiology of Aging | Year: 2015

The entorhinal cortex (EC) is one of the first brain areas to display neuropathology in Alzheimer's disease. A mouse model which simulates amyloid-β (Aβ) neuropathology, the Tg2576 mouse, was used to address these early changes. Here, we show EC abnormalities occur in 2- to 4-month-old Tg2576 mice, an age before Aβ deposition and where previous studies suggest that there are few behavioral impairments. First we show, using a sandwich enzyme-linked immunosorbent assay, that soluble human Aβ40 and Aβ42 are detectable in the EC of 2-month-old Tg2576 mice before Aβ deposition. We then demonstrate that 2- to 4-month-old Tg2576 mice are impaired at object placement, an EC-dependent cognitive task. Next, we show that defects in neuronal nuclear antigen expression and myelin uptake occur in the superficial layers of the EC in 2- to 4-month-old Tg2576 mice. In slices from Tg2576 mice that contained the EC, there were repetitive field potentials evoked by a single stimulus to the underlying white matter, and a greater response to reduced extracellular magnesium ([Mg2+]o), suggesting increased excitability. However, deep layer neurons in Tg2576 mice had longer latencies to antidromic activation than wild type mice. The results show changes in the EC at early ages and suggest that altered excitability occurs before extensive plaque pathology. © 2015 Elsevier Inc.


Scharfman H.E.,The Nathan Kline Institute for Psychiatric Research | Scharfman H.E.,New York University
Epilepsy Currents | Year: 2012

There is a substantial body of evidence that spontaneous recurrent seizures occur in a subset of patients with Alzheimer disease (AD), especially the familial forms that have an early onset. In transgenic mice that simulate these genetic forms of AD, seizures or reduced seizure threshold have also been reported. Mechanisms underlying the seizures or reduced seizure threshold in these mice are not yet clear and are likely to be complex, because the synthesis of amyloid β (Aβ) involves many peptides and proteases that influence excitability. Based on transgenic mouse models of AD where Aβ and its precursor are elevated, it has been suggested thatseizures are caused by the downregulation of the Nav1.1 sodium channel in a subset of GABAergic interneurons, leading to a reduction in GABAergic inhibition. Anothermechanism of hyperexcitability appears to involve tau, because deletion of tau reduces seizures in some of the same transgenic mouse models of AD. Therefore, altered excitability may be as much a characteristic of AD as plaques and tangles-especially for the familial forms of AD. © American Epilepsy Society.

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