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The death of GABAergic interneurons has long been hypothesized to contribute to acquired epilepsy. These experiments tested the hypothesis that focal interneuron lesions cause acute seizures [i.e., status epilepticus (SE)] and/or chronic epilepsy [i.e., persistent spontaneous recurrent seizures (SRSs)]. To selectively ablate interneurons, Gad2-ires-Cre mice were injected unilaterally in the CA1 area of the dorsal hippocampus with an adeno-associated virus containing the diphtheria toxin receptor (DTR). Simultaneously, an electrode, connected to a miniature telemetry device, was positioned at the injection site for chronic recordings of local field potentials (LFPs). Two weeks after virus transfection, intraperitoneal injection of DT consistently caused focal, specific, and extensive ablation of interneurons. Long-term, continuous monitoring revealed that all mice with DT-induced interneuron lesions had SRSs. Seizures lasted tens of seconds and interseizure intervals were several hours (or days); therefore, these interneuron lesions did not induce SE. The SRSs occurred 3-5 d after DT treatment, which is the estimated time required for DT-induced cell death; therefore, induction of SRSs occurred without the latent period typical of acquired epilepsy. In five of six DT-treated mice, SRSs stopped within days, suggesting that the DT-induced interneuron lesions did not usually cause epilepsy. In one mouse, however, SRSs occurred for ≥34 d after interneuron ablation, similar to epilepsy after experimental SE. Sham control mice had no detectable seizures, confirming that the SRSs were due to ablation of interneurons. These data show that selective interneuron ablation consistently caused SRSs but not SE; and, at least under the conditions used here, interneuron lesions rarely led to persistent SRSs (i.e., epilepsy).

Vascular dementia (VD) models were made first by repeating cerebral ischemia-reperfusion and followed by treating with estrogen. Learning-memory ability was measured by Morris water maze. Concentration of Ca 2+ in hippocampus was determined by Fura-2/AM fluorescence probe and the expression of Calbindin-D28K (CB) in hippocampal CA1 was tested by immunohistochemistry. Learning-memory ability was improved in E group rats; Concentration of Ca 2+ in hippocampus was decreased in E group rats. The expression of CB was less in E group rats. It implies that estrogen could improve learning-memory ability in VD rats, which may be associated with suppressing intracellular Ca 2+ overload and increasing the expression of CB in hippocampus.

Fasudil has been demonstrated to possess a protective effect in neural injury; however, its protective effect on convulsive brain injury remains to be assessed. The aim of the present study was to investigate the latent mechanism and effect of fasudil on cognitive function following status convulsion (SC) in rats. Initially, to determine the effects of SC, the expression levels of Ras homolog gene family, member A (RhoA)/Rho‑associated protein kinase (ROCK) signaling pathway‑associated proteins were measured by western blot analysis in 16 rats. To investigate the effects of fasudil on cognitive function in SC rats, a further 40 rats were assigned to four groups: Group I (healthy untreated rats), group II (healthy rats treated with fasudil), group III (SC rats) and group IV (SC rats treated with fasudil). An object‑in‑place memory task and the Morris Water Maze test were subsequently performed. Histopathological alterations in brain tissue and SC latency were additionally analyzed. Following SC, protein expression levels of myelin‑associated glycoprotein, myelin oligodendrocyte glycoprotein and leucine rich repeat and immunoglobulin‑like domain‑containing protein 1 were significantly increased (P<0.05) and levels of neurite outgrowth inhibitor protein A were significantly decreased (P<0.01). SC had no effect on RhoA level (P=0.921); however, it significantly increased the levels of phosphorylated RhoA (P<0.01). Cognitive function was significantly decreased following SC and significantly increased following fasudil intervention. Fasudil intervention improved CA1 structure, which was lost following SC. SC severely impaired cognitive function and affected the expression of neurite growth inhibitory factors. Fasudil treatment improved cognitive function and central nervous system (CNS) injury, and decreased SC susceptibility in rats. Fasudil and SC may regulate the CNS by affecting the expression of neurite growth inhibitory factors in the RhoA/ROCK signaling pathway.

Memory traces are reactivated selectively during sharp-wave ripples. The mechanisms of selective reactivation, and how degraded reactivation affects memory, are poorly understood. We evaluated hippocampal single-cell activity during physiological and pathological sharp-wave ripples using juxtacellular and intracellular recordings in normal and epileptic rats with different memory abilities. CA1 pyramidal cells participate selectively during physiological events but fired together during epileptic fast ripples. We found that firing selectivity was dominated by an event- and cell-specific synaptic drive, modulated in single cells by changes in the excitatory/inhibitory ratio measured intracellularly. This mechanism collapses during pathological fast ripples to exacerbate and randomize neuronal firing. Acute administration of a use- and cell-type-dependent sodium channel blocker reduced neuronal collapse and randomness and improved recall in epileptic rats. We propose that cell-specific synaptic inputs govern firing selectivity of CA1 pyramidal cells during sharp-wave ripples., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Accumulating evidence has suggested resveratrol as a promising drug candidate for the treatment of epilepsy. To validate this, we tested the protective effect of resveratrol on a kainic acid (KA)-induced epilepsy model in rats and investigated the underlying mechanism. We found that acute resveratrol application partially inhibited evoked epileptiform discharges in the hippocampal CA1 region. During acute, silent and chronic phases of epilepsy, the expression of hippocampal kainate glutamate receptor (GluK2) and the GABA A receptor alpha1 subunit (GABA A R-alpha1) was up-regulated and down-regulated, respectively. Resveratrol reversed these effects and induced an antiepileptic effect. Furthermore, in the chronic phase, resveratrol treatment inhibited the KA-induced increased glutamate/GABA ratio in the hippocampus. The antiepileptic effects of resveratrol may be partially attributed to the reduction of glutamate-induced excitotoxicity and the enhancement in GABAergic inhibition.

Although the key contributors of altering neurological function in hepatic encephalopathy are relatively well known, the electrophysiological mechanism of CA1 damage, a key vulnerable area during hyperammonemia, have not yet been defined. Therefore, here we focus on the electrophysiological mechanisms of cognitive impairments following bile duct ligation (BDL). We performed patch-clamp recordings from the CA1 pyramidal neurons in hippocampus of male Wistar rats, which underwent sham or BDL surgery. A striking electrophysiological change of hippocampal neurons in experimental model of BDL was observed in the present study. Spontaneous firing frequency and rate of action potential (AP) rebound was decreased and afterhyperpolarization amplitude (AHP) was increased significantly in hippocampal cells of BDL animals compared to sham group. Together, the results suggest that altered intrinsic properties of the hippocampal neurons may contribute to the cognitive abnormalities during hepatic encephalopathy (HE), highlighting the electrophysiological mechanisms for providing new treatments against HE.

Objective: To understand how monosynaptic inputs onto adult-born dentate granule cells (DGCs) are altered in experimental mesial temporal lobe epilepsy (mTLE) and whether their integration differs from early-born DGCs that are mature at the time of epileptogenesis., Methods: A dual-virus tracing strategy combining retroviral birthdating with rabies virus-mediated putative retrograde trans-synaptic tracing was used to identify and compare presynaptic inputs onto adult-born and early-born DGCs in the rat pilocarpine model of mTLE., Results: Our results demonstrate that hilar ectopic DGCs preferentially synapse onto adult-born DGCs after pilocarpine-induced status epilepticus (SE), whereas normotopic DGCs synapse onto both adult-born and early-born DGCs. We also find that parvalbumin - and somatostatin - interneuron inputs are greatly diminished onto early-born DGCs after SE. However, somatostatin - interneuron inputs onto adult-born DGCs are maintained, likely due to preferential sprouting. Intriguingly, CA3 pyramidal cell backprojections that specifically target adult-born DGCs arise in the epileptic brain, whereas axons of interneurons and pyramidal cells in CA1 appear to sprout across the hippocampal fissure to preferentially synapse onto early-born DGCs., Interpretation: These data support the presence of substantial hippocampal circuit remodeling after an epileptogenic insult that generates prominent excitatory monosynaptic inputs, both local recurrent and widespread feedback loops, onto DGCs. Both adult-born and early-born DGCs are targets of new inputs from other DGCs as well as from CA3 and CA1 pyramidal cells after pilocarpine treatment, changes that likely contribute to epileptogenesis in experimental mTLE. Ann Neurol 2017;81:790-803., (© 2017 American Neurological Association.)

Mammalian target of rapamycin (mTOR) has an important role in various biological processes in cells. In the present study, we investigated temporal changes in mTOR and phosphorylated-mTOR (p-mTOR) expressions in the rat hippocampal CA1 region following chronic cerebral hypoperfusion (CCH) induced by permanent bilateral common carotid arteries occlusion (2VO). The mTOR immunoreactivity in the pyramidal neurons and mTOR protein level in the hippocampal CA1 region were markedly decreased at 21 and 28 days after 2VO surgery. However, p-mTOR protein expression was significantly increased at 7 days following CCH but then decreased with time. The results indicate that mTOR and p-mTOR expressions change in the hippocampal CA1 region after 2VO surgery and that reduced expressions of mTOR and p-mTOR may be closely related to the CCH-induced neuronal damage in the hippocampal CA1 region.

Seizures produce brain inflammation, which in turn enhances neuronal excitability. Therefore, anti-inflammation has become a therapeutic strategy for antiepileptic treatment. Cycloxygenase-2 (COX-2) plays a critical role in postseizure brain inflammation and neuronal hyperexcitability. Our previous studies have shown that both electrical stimulation (ES) at the ear and electro-acupuncture (EA) at the Zusanli and Shangjuxu acupoints (ST36-ST37) for 6 weeks can reduce mossy fiber sprouting, spike population, and high-frequency hippocampal oscillations in kainic acid (KA)-induced epileptic seizure rats. This study further investigated the effect of long-term ear ES and EA at ST36-ST37 on the inflammatory response in KA-induced epileptic seizure rats. Both the COX-2 levels in the hippocampus and the number of COX-2 immunoreactive cells in the hippocampal CA1 region were increased after KA-induced epileptic seizures, and these were reduced through the 6-week application of ear ES or EA at ST36-ST37. Thus, long-term ear ES or long-term EA at ST36-ST37 have an anti-inflammatory effect, suggesting that they are beneficial for the treatment of epileptic seizures.

In the present study, we investigated the effects of microinjection of vitamin B 12 into the hippocampus on the orofacial pain and memory impairments induced by scopolamine and orofacial pain. In ketamine-xylazine anesthetized rats, the right and left sides of the dorsal hippocampus (CA1) were implanted with two guide cannulas. Orofacial pain was induced by subcutaneous injection of formalin (1.5%, 50μl) into the right vibrissa pad, and the durations of face rubbing were recorded at 3-min blocks for 45min. Morris water maze (MWM) was used for evaluation of learning and memory. Finally, locomotor activity was assessed using an open-field test. Vitamin B 12 attenuated both phases of formalin-induced orofacial pain. Prior administration of naloxone and naloxonazine, but not naltrindole and nor-binaltorphimine, prevented this effect. Vitamin B 12 and physostigmine decreased latency time as well as traveled distance in Morris water maze. In addition, these chemicals improved scopolamine-induced memory impairment. The memory impairment induced by orofacial pain was improved by vitamin B 12 and physostigmine used alone. Naloxone prevented, whereas physostigmine enhanced the memory improving effect of vitamin B 12 in the pain-induced memory impairment. All the above-mentioned chemicals did not alter locomotor activity. The results of the present study showed that at the level of the dorsal hippocampus, vitamin B 12 modulated orofacial pain through a mu-opioid receptor mechanism. In addition, vitamin B 12 contributed to hippocampal cholinergic system in processing of memory. Moreover, cholinergic and opioid systems may be involved in improving effect of vitamin B 12 on pain-induced memory impairment., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Sensory mismatch between actual motion information and anticipated sensory patterns (internal model) is the etiology of motion sickness (MS). Some evidence supports that hippocampus might involve the neural storage of the "internal model". This study established an "internal model" acquisition-retention behavioral model using a repeated habituation rotation training protocol. We tried to identify the hippocampal subregion involved in "internal model" retention using chemical lesion methods. Hippocampal kinases (CaMK, CaMKIV, CREB and ERK1/2) phosphorylation in the target subregion was assayed and the effects of kinase inhibitors (KN93 or U0126) on "internal model" retention were investigated. The activities of potential kinases (CaMKII and CREB) were also examined in otoliths deficit het/het mice. In habituated rats, CA1 lesion reproduced MS-related behavioral responses on "internal model" retention day. Habituation training increased CaMKII and CREB activity but had no effect on CaMKIV and ERK1/2 activity in the CA1, while inhibition of CaMKII but not ERK1/2 impaired "internal model" retention. In het/het mice, CaMKII and CREB were not activated in the CA1 on the retention day. These results suggested that CaMKII/CREB pathway might potentially contribute to the storage of the "internal model" in the hippocampal CA1 after motion sickness induced by vestibular stimulation.

Moderate traumatic brain injury (TBI) in children often happen when there's a sudden blow to the frontal bone, end with long unconscious which can last for hours and progressive cognitive deficits. However, with regard to the influences of moderate TBI during children adulthood, injury-induced alterations of locomotive ability, long-term memory performance, and hippocampal electrophysiological firing changes have not yet been fully identified. In this study, lateral fluid percussion (LFP) method was used to fabricate moderate TBI in motor and somatosensory cortex of the 6-weeks-old mice. The motor function, learning and memory function, extracellular CA1 neural spikes were assessed during acute and subacute phase. Moreover, histopathology was performed on day post injury (DPI) 16 to evaluate the effect of TBI on tissue and cell morphological changes in cortical and hippocampal CA1 subregions. After moderate LFP injury, the 6-weeks-old mice showed severe motor deficits at the early stage in acute phase but gradually recovered later during adulthood. At the time points in acute and subacute phase after TBI, novel object recognition (NOR) ability and spatial memory functions were consistently impaired in TBI mice; hippocampal firing frequency and burst probability were hampered. Analysis of the altered burst firing shows a clear hippocampal theta rhythm drop. These electrophysiological impacts were associated with substantially lowered NOR preference as compared to the sham group during adulthood. These results suggest that moderate TBI introduced at motorsenory cortex in 6-weeks-old mice causes obvious motor and cognitive deficits during their adulthood. While the locomotive ability progressively recovers, the cognitive deficits persisted while the mice mature as adult mice. The cognitive deficits may be attributed to the general suppressing of whole neural network, which could be labeled by marked reduction of excitability in hippocampal CA1 subregion., Competing Interests: The authors have declared that no competing interests exist.

Purpose: Lamotrigine (LTG) is a broad-spectrum antiepileptic drug that is widely used in clinic. However, the effect of LTG on cognition and neurodegeneration during epilepsy treatment remains controversial. In this study, we compared the cognitive effects of LTG and sodium valproate in pentylenetetrazole (PTZ)-kindled animal model, and the dose dependency was tested for LTG., Methods: PTZ-kindled animals were divided into the following treatment groups: control group, treated with 3.5 mL/kg of 0.9% sodium chloride; low-dose LTG group, treated with 12.5 mg/kg of LTG; middle-dose LTG group, treated with 25 mg/kg of LTG; high-dose LTG group, treated with 50 mg/kg of LTG; VPA group, treated with 300 mg/kg of VPA. The Morris Water Maze (MWM) test commenced from the 10th day of treatment. Hippocampal cell apoptosis was determined by TUNEL staining after two weeks of treatment., Results: Compared to the vehicle-treated control group, escape latency was significantly reduced in the middle- and high-dose LTG- and VPA-treated groups on the 3rd and 4th day of the MWM test (p < .05), and spatial probe frequency was significantly improved in the middle- and high-dose LTG- and VPA-treated groups (p < .05). Furthermore, the immunohistochemical score of TUNEL positive cells significantly decreased in the hippocampal CA1 region in the middle- and high-dose LTG- and VPA-treated groups (p < .05)., Conclusion: Our data suggests that LTG may ameliorate epilepsy-induced cognitive impairment and neuronal cell apoptosis during epilepsy treatment. LTG may ameliorate cognitive impairment and neuronal cell apoptosis during epilepsy treatment., (© 2016 The Authors Synapse Published by Wiley Periodicals, Inc.)

Clinical investigations have highlighted a biological link between reduced brain glucose metabolism and Alzheimer's disease (AD). Previous studies showed that glucose deprivation may influence amyloid beta formation in vivo but no data are available on the effect that this condition might have on tau protein metabolism. In the current paper, we investigated the effect of glucose deficit on tau phosphorylation, memory and learning, and synaptic function in a transgenic mouse model of tauopathy, the h-tau mice. Compared with controls, h-tau mice with brain glucose deficit showed significant memory impairments, reduction of synaptic long-term potentiation, increased tau phosphorylation, which was mediated by the activation of P38 MAPK Kinase pathway. We believe our studies demonstrate for the first time that reduced glucose availability in the central nervous system directly triggers behavioral deficits by promoting the development of tau neuropathology and synaptic dysfunction. Since restoring brain glucose levels and metabolism could afford the opportunity to positively influence the entire AD phenotype, this approach should be considered as a novel and viable therapy for preventing and/or halting the disease progression.

Neuropeptide Y (NPY) has robust anxiolytic properties and is reduced in patients with anxiety disorders. However, the mechanisms by which NPY modulates circuit function to reduce anxiety behavior are not known. Anxiolytic effects of NPY are mediated in the CA1 region of hippocampus, and NPY injection into hippocampus alleviates anxiety symptoms in the predator scent stress model of stress-induced anxiety. The mechanisms that regulate NPY release, and its effects on CA1 synaptic function, are not fully understood. Here we show in acute hippocampal slices from mice that endogenous NPY, released in response to optogenetic stimulation or synaptically evoked spiking of NPY+ cells, suppresses both of the feedforward pathways to CA1. Stimulation of temporoammonic synapses with a physiologically derived spike train causes NPY release that reduces short-term facilitation, whereas the release of NPY that modulates Schaffer collateral synapses requires integration of both the Schaffer collateral and temporoammonic pathways. Pathway specificity of NPY release is conferred by three functionally distinct NPY+ cell types, with differences in intrinsic excitability and short-term plasticity of their inputs. Predator scent stress abolishes the release of endogenous NPY onto temporoammonic synapses, a stress-sensitive pathway, thereby causing enhanced short-term facilitation. Our results demonstrate how stress alters CA1 circuit function through the impairment of endogenous NPY release, potentially contributing to heightened anxiety., Significance Statement: Neuropeptide Y (NPY) has robust anxiolytic properties, and its levels are reduced in patients with post-traumatic stress disorder. The effects of endogenously released NPY during physiologically relevant stimulation, and the impact of stress-induced reductions in NPY on circuit function, are unknown. By demonstrating that NPY release modulates hippocampal synaptic plasticity and is impaired by predator scent stress, our results provide a novel mechanism by which stress-induced anxiety alters circuit function. These studies fill an important gap in knowledge between the molecular and behavioral effects of NPY. This article also advances the understanding of NPY+ cells and the factors that regulate their spiking, which could pave the way for new therapeutic targets to increase endogenous NPY release in patients in a spatially and temporally appropriate manner., (Copyright © 2017 the authors 0270-6474/17/370023-15$15.00/0.)

A primary pathogeny of epilepsy is excessive activation of α-amino-3-hydroxy-5-methyl-4-isoxazole propionate receptors (AMPARs). To find potential molecules to inhibit AMPARs, high-throughput screening was performed in a library of tetrapeptides in silico. Computational results suggest that some tetrapeptides bind stably to the AMPAR. We aligned these sequences of tetrapeptide candidates with those from in vitro digestion of the trout skin protein. Among salmon-derived products, Glu-Gly-Ala-Arg (EGAR) showed a high biological affinity toward AMPAR when tested in silico. Accordingly, natural EGAR was hypothesized to have anticonvulsant activity, and in vitro experiments showed that EGAR selectively inhibited AMPAR-mediated synaptic transmission without affecting the electrophysiological properties of hippocampal pyramidal neurons. In addition, EGAR reduced neuronal spiking in an in vitro seizure model. Moreover, the ability of EGAR to reduce seizures was evaluated in a rodent epilepsy model. Briefer and less severe seizures versus controls were shown after mice were treated with EGAR. In conclusion, the promising experimental results suggest that EGAR inhibitor against AMPARs may be a target for antiepilepsy pharmaceuticals. Epilepsy is a common brain disorder characterized by the occurrence of recurring, unprovoked seizures. Twenty to 30 % of persons with epilepsy do not achieve adequate seizure control with any drug. Here we provide a possibility in which a natural and edible tetrapeptide, EGAR, can act as an antiepileptic agent. We have combined computation with in vitro experiments to show how EGAR modulates epilepsy. We also used an animal model of epilepsy to prove that EGAR can inhibit seizures in vivo. This study suggests EGAR as a potential pharmaceutical for the treatment of epilepsy., Competing Interests: Compliance with Ethical Standards Funding and disclosure This work was supported by Science and Technology Planning Project of Guangdong Province (2013B010404011). The authors declare no conflict of interest.

Sympathetic nervous system activity is increased after cardiopulmonary arrest, resulting in vasoconstrictor release from the perivascular sympathetic nerves of cerebral arteries. However, the pathophysiological function of the perivascular sympathetic nerves in the ischemic brain remains unclear. A rat model of global cerebral ischemia (asphyxial cardiac arrest, ACA) was used to investigate perivascular sympathetic nerves of cerebral arteries via bilateral decentralization (preganglionic lesion) of the superior cervical ganglion (SCG). Decentralization of the SCG 5 days before ACA alleviated hypoperfusion and afforded hippocampal neuroprotection and improved functional outcomes. These studies can provide further insights into the functional mechanism(s) of the sympathetic nervous system during ischemia., New & Noteworthy: Interruption of the perivascular sympathetic nerves can alleviate CA-induced hypoperfusion and neuronal cell death in the CA1 region of the hippocampus to enhance functional learning and memory., (Copyright © 2017 the American Physiological Society.)

Spatial learning and associating spatial information with individual experience are crucial for rodents and higher mammals. Hence, studying the cellular and molecular cascades involved in the key mechanism of information storage in the brain, synaptic plasticity, has led to enormous knowledge in this field. A major open question applies to the interdependence between synaptic plasticity and its behavioral correlates. In this context, it has become clear that behavioral aspects may impact subsequent synaptic plasticity, a phenomenon termed behavioral metaplasticity. Here, we trained control and pilocarpine-treated chronically epileptic rats of two different age groups (adolescent and adult) in a spatial memory task and subsequently tested long-term potentiation (LTP) in vitro at Schaffer collateral-CA1 synapses. As expected, memory acquisition in the behavioral task was significantly impaired both in pilocarpine-treated animals and in adult controls. Accordingly, these groups, without being tested in the behavioral training task, showed reduced CA1-LTP levels compared to untrained young controls. Spatial memory training significantly reduced subsequent CA1-LTP in vitro in the adolescent control group yet enhanced CA1-LTP in the adult pilocarpine-treated group. Such training in the adolescent pilocarpine-treated and adult control groups resulted in intermediate changes. Our study demonstrates age-dependent functional metaplasticity following a spatial memory training task and its reversal under pathological conditions.

Aim: To study an effect of corticosterone (100 nM) on spontaneous inhibitory postsynaptic currents (sIPSC) in pyramidal neurons of CA1 area and a role of inhibitory CB1-expressing synapses in the development of corticosterone-induced effects., Material and Methods: The experiments were performed on acute slices of the rat ventral hippocampus using whole-cell configuration of the patch-clamp technique., Results and Conclusion: The addition of corticosterone resulted in a small, but significant, increase in the frequency of sIPSCs during the first 10 minutes and then this parameter returned to the basal level. Corticosterone treatment resulted in a considerable decrease in the sIPSC amplitude 40 minutes after the beginning of treatment. The activation of CB1 receptors weakly affected sIPSC characteristics, however, the addition of corticosterone did not induce the rapid elevation in the sIPSC frequency, which occurred on the 10th minute in the control, as well as a decrease in the sIPSC amplitude, which was observed in the control on the 40th min after the beginning of corticosterone treatment. The data obtained suggest that both rapid and slow effects of corticosterone are associated with the activity of CB1-expressing inhibitory synapses of the hippocampus.

Manganese (Mn) is an essential element but neurotoxic at higher exposure levels. The effects of Mn overexposure (MnOE) on hippocampal and striatal-dependent learning and memory in rats were tested in combination with iron deficiency (FeD) and developmental stress that often co-occur with MnOE. Moderate FeD affects up to 15% of U.S. children and developmental stress is common in lower socio-economic areas where MnOE occurs. Pregnant Sprague-Dawley rats and their litters were housed in cages with or without (barren cage (BAR)) standard bedding from embryonic day (E)7 to postnatal day (P)28. Dams were fed a 90% FeD or iron sufficient (FeS) diet from E15-P28. Within each litter, separate offspring were treated with 100mg/kg Mn (MnOE) or vehicle (VEH) by gavage on alternate days from P4-28. Offspring were tested as adults in the Morris and Cincinnati water mazes. FeD and developmental stress interactively impaired spatial learning in the Morris water maze. Developmental stress and MnOE impaired learning and memory in both mazes. MnOE resulted in reduced CA1 hippocampal long-term potentiation (LTP) and increased levels of α-synuclein. Preweaning MnOE resulted in cognitive deficits on multiple domains of learning and memory accompanied by impaired LTP and α-synuclein changes, effects worsened by developmental stress., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Introduction: Chronic stress induces dendritic atrophy and decreases spine density in excitatory hippocampal neurons, although there is also ample evidence indicating that the GABAergic system is altered in the hippocampus after this aversive experience. Chronic stress causes dendritic remodeling both in excitatory neurons and interneurons in the medial prefrontal cortex and the amygdala., Methods: In order to know whether it also has an impact on the structure and neurotransmission of hippocampal interneurons, we have analyzed the dendritic arborization, spine density, and the expression of markers of inhibitory synapses and plasticity in the hippocampus of mice submitted to 21 days of mild restrain stress. The analyses were performed in GIN mice, a strain that displays EGFP-labeled interneurons., Results: We observed a significant decrease in the dendritic arborization of interneurons in the CA1 region, which did not occur in those in CA3. We found neither changes in dendritic spine density in these regions nor alterations in the number of EGFP-positive interneurons. Nevertheless, the expression of glutamic acid decarboxylase 67 was reduced in different layers of CA1 and CA3 regions of the hippocampus. No significant changes were found in the expression of the polysialylated form of the neural cell adhesion molecule (PSA-NCAM) or synaptophysin., Conclusions: Chronic stress reduces the interneuronal dendritic arborization in CA1 region of the hippocampus but not in CA3.

Mild cognitive impairment (MCI) is considered as an intermediate zone between normal aging and dementia. The most prominent feature of MCI is an isolated mild decline in memory, whereas other cognitive functions remain intact. The symptoms of vascular cognitive impairment (VCI) range from MCI to dementia, and an animal model of VCI has been established in a gerbil by transient bilateral common carotid artery occlusion (BCCAO). In the current study, we set out to investigate whether electroacupuncture (EA) could improve memory in gerbils with BCCAO-induced MCI. Animals were randomly divided into two groups: sham-operated group (n = 17) and a model group that was subdivided into BCCAO, n = 17, and EA-treated BCCAO, n = 28. Gerbils were treated with EA at KI3 or GV20 four times every other day using a set of electrical stimulus pulses (1 mA, 2 Hz) that were applied for 20 min. For investigation of cognitive function, we performed a Y-maze test and Western blotting to identify the expression of neuroinflammatory proteins. EA treatment at KI3 ("Taegye" acupoint) improved cognitive function and reduced the expression of neuroinflammatory proteins including ionized calcium-binding adaptor molecule 1, toll-like receptor 4, tumor necrosis factor alpha, and phospho-extracellular signal-regulated kinase in the hippocampus of gerbils that had undergone BCCAO. Furthermore, using micro-positron emission tomography/computed tomography, we demonstrated that EA treatment increased glucose metabolism in the hippocampus of these animals. The present study highlights the neuroprotective effect of EA treatment against BCCAO-induced memory dysfunction, neuroinflammation, and glucose metabolism. Our findings suggest that EA, which has previously been used in complementary and alternative medicine, might also be considered as a therapy that can improve memory and reduce neuroinflammation associated with dementia.

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 Aβ 1-42 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.

Memory deficits are characteristic of HIV-associated neurocognitive disorders (HAND) and co-occur with hippocampal pathology. The HIV-1 transactivator of transcription (Tat), a regulatory protein, plays a significant role in these events, but the cellular mechanisms involved are poorly understood. Within the hippocampus, diverse populations of interneurons form complex networks; even subtle disruptions can drastically alter synaptic output, resulting in behavioral dysfunction. We hypothesized that HIV-1 Tat would impair cognitive behavior and injure specific hippocampal interneuron subtypes. Male transgenic mice that inducibly expressed HIV-1 Tat (or non-expressing controls) were assessed for cognitive behavior or had hippocampal CA1 subregions evaluated via interneuron subpopulation markers. Tat exposure decreased spatial memory in a Barnes maze and mnemonic performance in a novel object recognition test. Tat reduced the percentage of neurons expressing neuronal nitric oxide synthase (nNOS) without neuropeptide Y immunoreactivity in the stratum pyramidale and the stratum radiatum, parvalbumin in the stratum pyramidale, and somatostatin in the stratum oriens, which are consistent with reductions in interneuron-specific interneuron type 3 (IS3), bistratified, and oriens-lacunosum-moleculare interneurons, respectively. The findings reveal that an interconnected ensemble of CA1 nNOS-expressing interneurons, the IS3 cells, as well as subpopulations of parvalbumin- and somatostatin-expressing interneurons are preferentially vulnerable to HIV-1 Tat. Importantly, the susceptible interneurons form a microcircuit thought to be involved in feedback inhibition of CA1 pyramidal cells and gating of CA1 pyramidal cell inputs. The identification of vulnerable CA1 hippocampal interneurons may provide novel insight into the basic mechanisms underlying key functional and neurobehavioral deficits associated with HAND., Competing Interests: The authors declare that they have no conflicts of interest.

Recent reports in human demonstrate a role of theta-gamma coupling in memory for spatial episodes and a lack of coupling in people experiencing temporal lobe epilepsy, but the mechanisms are unknown. Using multisite silicon probe recordings of epileptic rats engaged in episodic-like object recognition tasks, we sought to evaluate the role of theta-gamma coupling in the absence of epileptiform activities. Our data reveal a specific association between theta-gamma (30-60 Hz) coupling at the proximal stratum radiatum of CA1 and spatial memory deficits. We targeted the microcircuit mechanisms with a novel approach to identify putative interneuronal types in tetrode recordings (parvalbumin basket cells in particular) and validated classification criteria in the epileptic context with neurochemical identification of intracellularly recorded cells. In epileptic rats, putative parvalbumin basket cells fired poorly modulated at the falling theta phase, consistent with weaker inputs from Schaffer collaterals and attenuated gamma oscillations, as evaluated by theta-phase decomposition of current-source density signals. We propose that theta-gamma interneuronal rhythmopathies of the temporal lobe are intimately related to episodic memory dysfunction in this condition.

A lack of nitric oxide (NO) may be a possible factor in the pathogenesis of an acute decrease of cerebral blood flow (CBF) after subarachnoid hemorrhage (SAH). This study was conducted to investigate whether early therapy with an NO-donor can improve CBF and offer neuroprotection after experimental SAH in rats. Male Sprague-Dawley rats were subjected to SAH by the endovascular filament model and treated with 1.5μg/kg/min of intravenous sodium nitroprusside (SNP) or vehicle (n=10) starting 15min after induction of SAH until 180min thereafter. SNP caused a moderate decrease of arterial blood pressure and cerebral perfusion pressure. Conversely, CBF measured by laser-Doppler flowmetry increased significantly in SNP-treated animals. The rate of injured neurons in the hippocampal CA1-field was significantly reduced in SNP-treated animals (10.5±5%) compared to controls (14.2±7%), as well as the number of Caspase-3 positive neurons. Low-dose treatment with SNP can attenuate an early perfusion deficit after SAH and reduce neuronal damage in spite of a hypotensive side effect. This may reflect the reversal of an early NO-deficit. In the clinical setting, the moderate hypotensive effect may be welcome since SAH-patients frequently present with elevated blood pressure., (Copyright © 2016. Published by Elsevier B.V.)

Ethnopharmacological Relevance: In-vitro cultured calculus bovis (ICCB) is a quality substitute for natural bezoar which is used for the therapeutic purpose of treating encephalopathy. ICCB has been authorized to use on clinic. The aim of the study is to evaluate the effects and the potential mechanisms of in-vitro cultured calculus bovis (ICCB) on learning and memory impairments of hyperlipemia vascular dementia (HVD) rats., Materials and Methods: The HVD model was established by permanent occlusion of bilateral common carotid arteries based on hyperlipemia rats. Learning and memory abilities were evaluated by morris water maze test and shuttle box test. Ultraviolet-visible spectrophotometry (UV-vis) was employed to determine the SOD, MDA and NO in cerebral tissue, as well as the TG in serum. HE staining and toluidine blue staining were employed to evaluate cone cells damage in hippocampus CA1. An immunohistochemistry was used to measure the Bax and Bcl-2 expressions in cerebral tissue., Results: Compared with control group, the abilities of spatial learning and memory and conditional memory were decreased significantly in HVD group (P<0.01, P<0.05). MDA content in cerebral tissue was remarkably increased while the SOD activity and NO content were both decreased (P<0.01). TG content in serum was increased remarkably (P<0.01). And the cone cells in hippocampus CA1 were damaged obviously. Compared with HVD group, ICCB treatment improved the abilities of learning and memory, elevated the SOD activity (P<0.01, P<0.05), reduced the MDA content (P<0.01) as well as the TG content in serum (P<0.01), increased the NO content (P<0.01), improved the damaged cone cells in hippocampus CA1, increased the number of cones cells (P<0.01), decreased the Bax expression, and increased the Bcl-2 expression (P<0.01)., Conclusion: ICCB could improve the abilities of learning and memory in HVD rats. It might be related to anti-oxidative, regulation of Bax and Bcl-2 expressions, and the alleviation of cone cells damage., (Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.)

Objective: To observe the influence of scalp-acupuncture on the expression of acid-sensing ion channels (ASICs) 1 a and 2 b of hippocampal CA 1 region in cerebral ischemia (CI) rats, so as to investigate its mechanism underlying improvement of ischemic stroke., Methods: Thirty-two male SD rats were randomly allocated to normal control, model, scalp-acupuncture and Amiloride group ( n =8 in each group). The model of focal CI was established by middle cerebral artery occlusion (MCAO). Scalp acupuncture stimulation was applied to bilateral Dingnieqianxiexian (MS 6) and Dingniehouxiexian (MS 7), once daily for 7 days. Rats of the Amiloride group were fed with Amiloride solution, twice a day for 7 days, and those of the normal control and model groups were grabbled and fixed in the same way with the acupuncture and Amiloride groups. The neurological deficit score was given according to Longa's method. The expression of hippocampal ASIC 1 a and ASIC 2 b was detected by immunohistochemistry, and the Ca 2+ concentration in the hippocampal tissue assayed using flowing cytometry., Results: After the intervention, the neurological deficit score of both the scalp-acupuncture and Amiloride groups were significantly decreased in comparison with pre-treatment ( P <0.01), and the effect of scalp-acupuncture was markedly superior to that of Amiloride in reducing neurological deficit score ( P <0.05). The expression of ASIC 1 a and ASIC 2 b in the hippocampal CA 1 region and hip-pocampal Ca 2+ concentration were significantly up-regulated in the model group compared with the normal control group ( P <0.01), and obviously down-regulated in both scalp-acupuncture and Amiloride groups ( P <0.01, P <0.05),without significant differences between the two treatment groups in the ASIC 1 a and ASIC 2 b expression and Ca 2+ concentration ( P >0.05)., Conclusions: Scalp-acupuncture stimulation can improve neurological function in CI rats, which may be related to its effects in suppressing the increased expression of hippocampal ASIC 1 a and ASIC 2 b proteins and in reducing calcium overload in hip-pocampal neurocytes.

Excitatory pyramidal neurons in the entorhinal cortical layer II region (ECII PN ) form functional excitatory synapses with CA1 parvalbumin inhibitory neurons (CA1 PV ) and undergo selective degeneration in the early stages of Alzheimer's disease (AD). Here, we show that death-associated protein kinase 1 (DAPK1) is selectively activated in ECII PN of AD mice. Inhibition of DAPK1 by deleting a catalytic domain or a death domain of DAPK1 rescues the ECII PN -CA1 PV synaptic loss and improves spatial learning and memory in AD mice. This study demonstrates that activation of DAPK1 in ECII PN contributes to a memory loss in AD and hence warrants a promising target for the treatment of AD., Significance Statement: Our recent study reported that excitatory pyramidal neurons in the entorhinal cortical layer II region (ECII PN ) target to CA1 parvalbumin-type inhibitory neurons (CA1 PV ) at a direct pathway and are one of the most vulnerable brain cells that are selectively degenerated in the early stage of Alzheimer's disease (AD). Our present study shows that death-associated protein kinase 1 (DAPK1) is selectively activated in ECII PN of AD mice. Inhibition of DAPK1 by deleting a catalytic domain or a death domain of DAPK1 rescues the ECII PN -CA1 PV synaptic loss and improves spatial learning and memory in the early stage of AD. These data not only demonstrate a crucial molecular event for synaptic degeneration but also provide a therapeutic target for the treatment of AD., (Copyright © 2016 Shu et al.)

Introduction: Early life stress (ELS) increases the risk for developing psychopathology in adulthood. When these effects occur is largely unknown. We here studied at which time during development ELS affects hippocampal synaptic plasticity, from early life to adulthood, in a rodent ELS model. Moreover, we investigated whether the sensitivity of synaptic plasticity to the stress-hormone corticosterone is altered by exposure to ELS., Materials & Methods: Male and female Wistar rats were exposed to maternal deprivation (MD) for 24h on postnatal day (P)3 or left undisturbed with their mother (control). On P8-9, 22-24 and P85-95, plasma corticosterone (CORT) levels, body weight, and thymus and adrenal weights were determined to validate the neuroendocrine effects of MD. Field potentials in the CA1 hippocampus were recorded in vitro before and after high frequency stimulation. Brain slices were incubated for 20 min with 100nM CORT or vehicle 1-4h prior to high frequency stimulation, to mimic high-stress conditions in vitro., Results & Discussion: Body weight was decreased by MD only at P4 (p = 0.02). There were minimal effects on P8-9, 22-24 or 85-95 thymus and adrenal weight and basal CORT levels. Glutamate transmission underwent strong developmental changes: half-maximal signal size strongly increased (p<0.0001) while the required half-maximal stimulation intensity concomitantly decreased with age (p = 0.04). Synaptic plasticity developed from long-term depression at P8-9 to increasing levels of long-term potentiation at later ages (p = 0.0001). MD caused a significant increase in long-term potentiation of P22-24 males (p = 0.03) and P85-95 females (p = 0.04). Bayesian modeling strongly supported the age-dependent development, with some evidence for accelerated maturation after MD in males (Bayes factor 1.23). CORT suppressed LTP in adult males; synaptic plasticity at other ages and in females remained unaffected. Thus, MD affects the development of synaptic plasticity in the CA1 hippocampus in a sex-dependent manner, with some support for the notion that maturation is accelerated in MD males., Competing Interests: The authors have declared that no competing interests exist.

Purpose: Genetic absence epilepsy rats from Strasbourg (GAERS), a well-validated genetic rat model for typical absence epilepsy, are known to manifest a resistance to secondary generalization of abnormal focal electrical activity evoked by kindling. The mechanism of this resistance is still unclear. In order to understand the possible mechanism of kindling resistance, we investigated for the first time, the differences of short-term synaptic plasticity by using a paired-pulse paradigm as an indicator of GABAergic activity in CA1 region of hippocampus in GAERS and non-epileptic Wistar rats in-vivo., Methods: Rats were subjected to kindling process, basolateral amygdala was stimulated twice a day, with a supra-threshold current, until they displayed limbic or convulsive seizures. One hour after the last kindling stimulation, evoked field potentials from CA1 pyramidal layer of hippocampus were recorded in-vivo under urethane anesthesia., Results: In response to supra-threshold kindling stimulations GAERS showed a significantly delayed kindling progression and displayed a significant increase in hippocampal excitability at early stages of kindling that is the critical for the development of convulsive seizures. In control rats that were not received kindling stimulation, paired-pulse depression (PPD) was significantly pronounced in GAERS with respect to the Wistar group. During the kindling course, PPD was gradually reduced in the Wistar rats as kindling progression was advanced. However in GAERS, PPD ratios were not significantly changed at early stages of kindling. When GAERS reached convulsive stage, their PPD ratios became similar to that of Wistar rats., Discussion: The increased inhibition in paired-pulse responses at early stages of kindling in GAERS suggests the role of augmented GABAergic activity as one of the underlying mechanisms of kindling resistance observed in genetic rat models of absence epilepsy., (Copyright © 2016. Published by Elsevier B.V.)

Zinc, an essential micronutrient and biochemical element of the human body, plays structural, catalytic, and regulatory roles in numerous physiological functions. In the current study, the effects of a pretraining oral administration of zinc chloride (10, 25, and 50 mg/kg) for 14 consecutive days and post-training bilateral intra-hippocampal infusion of 1400W as a selective inducible nitric oxide synthase (iNOS) inhibitor (10, 50, and 100 μM/side), alone and in combination, on the spatial memory retention in Morris water maze (MWM) were investigated. Animals were trained for 4 days and tested 48 h after completion of training. Also, the molecular effects of these compounds on the expression of choline acetyltransferase (ChAT), as a cholinergic marker in the CA1 region of the hippocampus and medial septal area (MSA), were evaluated. Behavioral and molecular findings of this study showed that a 2-week oral administration of zinc chloride (50 mg/kg) impaired spatial memory retention in MWM and decreased ChAT expression. Immunohistochemical analysis of post-training bilateral intra-hippocampal infusion of 1400W revealed a significant increase in ChAT immunoreactivity. Furthermore, post-training bilateral intra-hippocampal infusion of 1400W into the CA1 region of the hippocampus reversed zinc chloride-induced spatial memory impairment in MWM and significantly increased ChAT expression in comparison with zinc chloride-treated animals. Taken together, these results emphasize the role of selective iNOS inhibitors in reversing zinc chloride-induced spatial memory deficits via modulation of cholinergic marker expression.

Hypoxic circumstances result in functional and structural impairments of the brain. Oxygen-glucose deprivation (OGD) on hippocampal slices is a technique widely used to investigate the consequences of ischemic stroke and the potential neuroprotective effects of different drugs. Acetyl-l-carnitine (ALC) is a naturally occurring substance in the body, and it can therefore be administered safely even in relatively high doses. In previous experiments, ALC pretreatment proved to be effective against global hypoperfusion. In the present study, we investigated whether ALC can be protective in an OGD model. We are not aware of any earlier study in which the long-term potentiation (LTP) function on hippocampal slices was measured after OGD. Therefore, we set out to determine whether an effective ALC concentration has an effect on synaptic plasticity after OGD in the hippocampal CA1 subfield of rats. A further aim was to investigate the mechanism underlying the protective effect of this compound. The experiments revealed that ALC is neuroprotective against OGD in a dose-dependent manner, which is manifested not only in the regeneration of the impaired synaptic transmission after the OGD, but also in the inducibility and stability of the LTP. In the case of the most effective concentration of ALC (500μM), use of a phosphoinositide 3-kinase (PI3K) inhibitor (LY294002) revealed that the PI3K/Akt signaling pathway has a key role in the restoration of the synaptic transmission and plasticity reached by ALC treatment., (Copyright © 2016 IBRO. Published by Elsevier Ltd. All rights reserved.)

Nedd4-2 (NEDD4L in humans) is a ubiquitin protein ligase best known for its role in regulating ion channel internalization and turnover. Nedd4-2 deletion in mice causes perinatal lethality associated with increased epithelial sodium channel (ENaC) expression in lung and kidney. Abundant data suggest that Nedd4-2 plays a role in neuronal functions and may be linked to epilepsy and dyslexia in humans. We used a mouse model of Nedd4-2 haploinsufficiency to investigate whether an alteration in Nedd4-2 levels of expression affects general nervous system functions. We found that Nedd4-2 heterozygous mice are hyperactive, have increased basal synaptic transmission and have enhanced sensitivity to inflammatory pain. Thus, Nedd4-2 heterozygous mice provide a new genetic model to study inflammatory pain. These data also suggest that in human, SNPs affecting NEDD4L levels may be involved in the development of neuropsychological deficits and peripheral neuropathies and may help unveil the genetic basis of comorbidities.

The major objective of this study was to investigate the probable effects of genistein (one of the most important soy phytoestrogens-SPEs) on seizure-induced cognitive dysfunction, hippocampal early long-term potentiation (E-LTP) impairment and morphological damage to CA1 neurons in ovariectomized (OVX) rats. Three weeks after ovariectomy, cannulae were implanted over the left lateral ventricle. After a 7-day recovery period, animals were injected by genistein (0.5 or 5mg/kg) or vehicle during four consecutive days, each 24h. One h after the last treatment, kainic acid (KA) or vehicle was perfused into the left lateral ventricle to induce generalized tonic-clonic seizures. Finally, 7 days later, spatial learning and memory of animals were examined using the Morris water maze (MWM) task, hippocampal E-LTP was assessed using in-vivo field potential recordings and the morphology of hippocampal CA1 area was examined using Fluoro-Jade C staining. KA-induced generalized seizures resulted in spatial learning and memory impairment, E-LTP deficit and CA1 cell injury. Seizure-induced abnormalities improved partially only by the lower dose of genistein (0.5mg/kg). However, genistein at the higher dose (5mg/kg) did not have any beneficial effects. Also, genistein did not affect seizure activity. It is concluded that genistein may have partially preventive effects against seizure-induced cognitive impairment in OVX rats. Also, it seems that such effects of genistein are correlated with its beneficial effects on hippocampal synaptic plasticity and morphology., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Post-traumatic stress disorder (PTSD) occurs after exposure to traumatic situations and it is characterized by cognitive deficits that include impaired explicit memory. The neurobiological bases of such PTSD-associated memory alterations are yet to be elucidated and no satisfactory treatment for them exists. To address this issue, we first studied whether a single exposure of young adult rats (60 days) to immobilization on boards (IMO), a putative model of PTSD, produces long-term behavioral effects (2-8 days) similar to those found in PTSD patients. Subsequently, we investigated whether the administration of the TrkB agonist 7,8-dihydroxyflavone (DHF) 8 h after stress (therapeutic window) ameliorated the PTSD-like effect of IMO and the associated changes in synaptic plasticity. A single IMO exposure induced a spatial memory impairment similar to that found in other animal models of PTSD or in PTSD patients. IMO also increased spine density and long-term potentiation (LTP) in the CA3-CA1 pathway. Significantly, DHF reverted both spatial memory impairment and the increase in LTP, while it produced no effect in the controls. These data provide novel insights into the possible neurobiological substrate for explicit memory impairment in PTSD patients, supporting the idea that the activation of the BDNF/TrkB pathway fulfils a protective role after severe stress. Administration of DHF in the aftermath of a traumatic experience might be relevant to prevent its long-term consequences. © 2016 Wiley Periodicals, Inc., (© 2016 Wiley Periodicals, Inc.)

The proximal and distal segments of CA1 are thought to perform distinct computations. Neurons in proximal CA1 are reciprocally connected with the medial entorhinal cortex (MEC) and exhibit precise spatial firing. In contrast, cells in distal CA1 communicate with the lateral entorhinal cortex (LEC), exhibit more diffuse spatial firing and are affected by the presence of objects in the environment. To determine if these segments make unique contributions to memory retrieval, we examined cellular activity along the proximodistal axis of CA1 using transgenic reporter mice. Neurons tagged during context learning in proximal CA1 were more likely to be reactivated during testing than those in distal CA1. This was true following context fear conditioning and after exposure to a novel environment. Reactivation was also higher in brain regions connected to proximal CA1 (MEC, distal CA3) than those connected to the distal segment (LEC, proximal CA3). To examine contributions to memory retrieval, we performed neurotoxic lesions of proximal or distal CA1 after training. Lesions of the proximal segment significantly impaired memory retrieval while damage to distal CA1 had no effect. These data suggest that context memories are retrieved by a hippocampal microcircuit that involves the proximal but not distal segment of CA1. © 2016 Wiley Periodicals, Inc., (© 2016 Wiley Periodicals, Inc.)

Cognitive impairment caused by traumatic brain injury (TBI) can lead to devastating consequences for both patients and their families. The underlying neurological basis for TBI-induced cognitive dysfunction remains unknown. However, many lines of research have implicated the hippocampus in the pathophysiology of TBI. In particular, past research has found that theta oscillations, long thought to be the electrophysiological basis of learning and memory, are decreased in the hippocampus post-TBI. Here, we recorded in vivo electrophysiological activity in the hippocampi of 16 mice, 8 of which had previously undergone a TBI. Consistent with previous data, we found that theta power in the hippocampus was decreased in TBI animals compared to sham controls; however, this effect was driven by changes in broadband power and not theta oscillations. This result suggests that broadband fluctuations in the hippocampal local field potential can be used as an electrophysiological surrogate of abnormal neurological activity post-TBI.

More than half of children with epilepsy outgrow their seizures, yet the underlying mechanism is unknown. GABAergic inhibition increases at puberty in female mice due to expression of extrasynaptic α4βδ GABAA receptors (GABARs). Therefore, we tested the role of these receptors in regulating seizure-like discharges in CA1 hippocampus using a high K(+) (8.5 mM) seizure model. Spontaneous field potentials were recorded from hippocampus of pre-pubertal (~28-32 PND) and pubertal (~35-44 PND) female wild-type or α4-/- mice. The coastline length, a measure of burst intensity, was assessed. 8.5 mM K(+) induced seizure-like discharges in over 60% of pre-pubertal slices, but only in 7% of pubertal slices, where the coastline length was reduced by 70% (P = 0.04). However, the pubertal decrease in seizure-like discharges was not seen in the α4-/-, implicating α4βδ GABARs as the cause of the decreased seizure-like activity during puberty. Administration of THIP or DS2, to selectively increase α4βδ current, reduced activity in 8.5 mM K(+) at puberty, while blockade of α5-GABARs had no effect. GABAergic current was depolarizing but inhibitory in 8.5 mM K(+), suggesting a mechanism for the effects of α4βδ and α5-GABARs, which exhibit different polarity-dependent desensitization. These data suggest that α4βδ GABARs are anti-convulsant during adolescence.

Low frequency stimulation (LFS) has been proposed as a new approach in the treatment of epilepsy. The anticonvulsant mechanism of LFS may be through its effect on GABAA receptors, which are the main target of phenobarbital anticonvulsant action. We supposed that co-application of LFS and phenobarbital may increase the efficacy of phenobarbital. Therefore, the interaction of LFS and phenobarbital on GABAergic inhibitory post-synaptic currents (IPSCs) in kindled and control rats was investigated. Animals were kindled by electrical stimulation of basolateral amygdala in a semi rapid manner (12 stimulations/day). The effect of phenobarbital, LFS and phenobarbital+LFS was investigated on GABAA-mediated evoked and miniature IPSCs in the hippocampal brain slices in control and fully kindled animals. Phenobarbital and LFS had positive interaction on GABAergic currents. In vitro co-application of an ineffective pattern of LFS (100 pulses at afterdischarge threshold intensity) and a sub-threshold dose of phenobarbital (100μM) which had no significant effect on GABAergic currents alone, increased the amplitude and area under curve of GABAergic currents in CA1 pyramidal neurons of hippocampal slices significantly. Interestingly, the sub-threshold dose of phenobarbital potentiated the GABAergic currents when applied on the hippocampal slices of kindled animals which received LFS in vivo. Post-synaptic mechanisms may be involved in observed interactions. Obtained results implied a positive interaction between LFS and phenobarbital through GABAA currents. It may be suggested that a combined therapy of phenobarbital and LFS may be a useful manner for reinforcing the anticonvulsant action of phenobarbital., (Copyright © 2016 IBRO. Published by Elsevier Ltd. All rights reserved.)

Loss- and gain-of-function mutations in methyl-CpG-binding protein 2 (MECP2) underlie two distinct neurological syndromes with strikingly similar features, but the synaptic and circuit-level changes mediating these shared features are undefined. Here we report three novel signs of neural circuit dysfunction in three mouse models of MECP2 disorders (constitutive Mecp2 null, mosaic Mecp2(+/-), and MECP2 duplication): abnormally elevated synchrony in the firing activity of hippocampal CA1 pyramidal neurons, an impaired homeostatic response to perturbations of excitatory-inhibitory balance, and decreased excitatory synaptic response in inhibitory neurons. Conditional mutagenesis studies revealed that MeCP2 dysfunction in excitatory neurons mediated elevated synchrony at baseline, while MeCP2 dysfunction in inhibitory neurons increased susceptibility to hypersynchronization in response to perturbations. Chronic forniceal deep brain stimulation (DBS), recently shown to rescue hippocampus-dependent learning and memory in Mecp2(+/-) (Rett) mice, also rescued all three features of hippocampal circuit dysfunction in these mice., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Deep brain stimulation (DBS) shows promises in the treatment of refractory epilepsy. Due to the complex causes of epilepsy, the mechanisms of DBS are still unclear. Depolarization block caused by the persistent excitation of neurons may be one of the possible mechanisms. To test the hypothesis, 4-aminopyridine (4-AP) was injected in rat hippocampal CA1 region in-vivo to induce epileptiform activity. Sinusoidal stimulation trains were applied to the afferent pathway (Schaffer collaterals) of CA1 region to suppress the epileptiform spikes. Results show that 2-min long trains of sinusoidal stimulation (50 Hz) decreased the firing rate of population spikes (PS) and decreased the PS amplitudes significantly. In addition, small positive sharp waves replaced PS activity during the periods of stimulation. A lower frequency sinusoidal stimulation (10 Hz) failed to decrease the firing rate of PS, but decreased the PS amplitudes significantly. These results suggest that stimulation trains of sinusoidal waves could suppress epileptiform spikes. Presumably, the stimulation with a high enough frequency might excite the downstream neurons persistently and elevate the membrane potentials continuously, thereby cause depolarization blocks in the neurons. The findings of the study provide insights in revealing the mechanisms of DBS, and have important implications to the clinical treatment of epilepsy.

Alzheimer's disease (AD) is a progressive neurodegenerative disease, and effective therapeutic drugs in the clinic are still lacking. Ideally, AD progression could be stopped at an early stage, such as at the mild cognitive impairment (MCI) stage. MCI refers to the clinical condition between normal aging and dementia. Patients with MCI experience memory loss but do not meet the criteria for the diagnosis of clinically probable AD. However, few MCI animal models have been established. Here, we used in vivo long-term potentiation (LTP) recording and the Morris water maze (MWM) to evaluate the effects of intracerebroventricular injection of streptozotocin (ICV-STZ) in mice. We found a relationship between cognitive behavior and LTP in vivo and determined the appropriate doses of STZ for a putative MCI animal model. Animals that received≥150μg of STZ exhibited cognitive impairment in the MWM test, and few changes in behavior tests were observed in animals receiving less than 150μg of STZ. In vivo LTP recordings revealed that the induction of LTP decreased significantly in STZ-treated animals, even at the lowest dose (25μg/mouse), in a dose-dependent manner. Pathology analysis revealed STZ-induced neuron loss in a dose-dependent manner, both in the cortex and in the hippocampus, as evidenced by a significantly decreased neuronal number in the cohort treated with 75μg of STZ/mouse. Our study indicated that a low dose (25μg/mouse) of STZ impaired neural plasticity; at a higher dose of 75μg/mouse STZ, further LTP deficits were noted along with induced neuronal loss in both the cortex and the hippocampus, which could be considered a possible MCI or pre-MCI animal model; and finally, at 150μg/mouse STZ, dementia was induced, feasibly indicating a state of AD.

Kainic acid (KA) is a glutamate agonist widely used in studies of neurodegeneration due to its ability to induce excitotoxic damage in the rodent brain. Previously, we reported that pre-treatment with prolactin (PRL) prevents the neuron loss induced by KA administration in CA1, CA3 and CA4 of the hippocampus of the female rat. Here, we investigated if PRL has a neuroprotective effect in the dorsal hippocampus when it is administered after KA. For this, 100ng of KA or 0.9% saline was administered intracerebroventricularly (ICV) to ovariectomized female rats. One hour later, they received subcutaneous PRL (103μg/day for 7days) or saline through an osmotic minipump. Also, to determine the hippocampal neurogenesis rate, the rats were administered bromodeoxyuridine along with the PRL treatment. Immunostaining for NeuN revealed that neuronal loss is lower in the CA1 of PRL-treated rats compared with the untreated group, but PRL did not confer any protection in the CA3 and CA4 subfields. Furthermore, PRL prevented the KA-induced cognitive deficit measured as a better performance in the novel object recognition test. The PRL treatment did not modify the neurogenesis rate. These data indicate that post-treatment with PRL confers differential neuroprotection against KA-induced neuronal loss in hippocampal subfield CA1, which correlates with a more mild cognitive deficit compared with the untreated control group., (Copyright © 2016 IBRO. Published by Elsevier Ltd. All rights reserved.)

To determine whether post-traumatic seizure severity would be affected by the interval between seizures and head injury, we measured seizures after various times with or without fluid percussion brain injury (2atm fluid percussion injury; FPI). To determine efficacy of anti-seizure medication, we also determined if levetiracetam (LEV) would alter the relationship between injury and subsequent seizures. Early post-traumatic seizures were induced by Kainic acid (KA) at one week after 2atm fluid percussion injury (FPI) in one group (FPI-ES). Seizures were induced at two weeks after FPI by KA in another group (FPI-LS). In addition, one group had induced seizures by KA without FPI, (sham-ES). Finally one group of animals received the antiepileptic agent (levetiracetam) infusion for one week after FPI and then had seizures induced by KA (FPI-LEV-ES). We measured seizure onset time, ictal duration and severity of seizures using a modified Racine's scale. Histopathological changes in the hippocampus CA1 region were also analyzed. Severity of seizures were increased in the FPI-ES group compared with sham-ES animals. Severity was also enhanced in early post-injury seizures induced by KA (FPI-ES vs. FPI-LS); this exacerbation of seizure severity could be ameliorated by levetiracetam infusion (FPI-ES vs. FPI-LEV-ES). Neuronal degeneration in CA1 was more severe in the FPI-ES group and this degeneration was also diminished by LEV. We conclude that early post injury seizures exacerbate susceptibility and severity of post traumatic seizures and increase neuronal degeneration in the CA1 layer of hippocampus. These changes are partially reversed by LEV infusion after FPI., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Objective: A considerable number of studies have demonstrated that nicotine, a α7-nicotinic acetylcholine receptor (α7-nAChR) agonist, can dampen immune response through the cholinergic anti-inflammatory pathway. Evidence suggests that inflammation plays a critical role in eclampsia, which contributes to maternal and fetal morbidity and mortality. In the present study, possible anti-inflammation and neuro-protective effects of nicotine via α7-nAChRs have been investigated after inducing eclampsia-like seizures in rats., Methods: Rat eclampsia-like models were established by administering lipopolysaccharide (LPS) plus pentylenetetrazol (PTZ) in pregnant rats. Rats were given nicotine from gestation day (GD) 14-19. Then, clinical symptoms were detected. Seizure severity was recorded by behavioral tests, serum levels of inflammatory cytokines were measured by Luminex assays, microglia and astrocyte expressions were detected by immunofluorescence, and changes in neuronal number in the hippocampal CA1 region among different groups were detected by Nissl staining., Results: Our results revealed that nicotine effectively improved fetal outcomes. Furthermore, it significantly decreased systolic blood pressure, and maternal serum levels of Th1 cytokines (TNF-α, IL-1β, IL-6 and IL-12P70) and an IL-17 cytokine (IL-17A), and dramatically increased eclampsia-like seizure threshold. Moreover, this attenuated neuronal loss and decreased the expression of microglial activation markers of the hippocampal CA1 region in the eclampsia-like group. Additionally, pretreatment with α-bungarotoxin, a selective α7-nAChR antagonist could prevent the protective effects of nicotine in eclampsia-like model rats., Conclusion: Our findings indicate that the administration of nicotine may attenuate microglial activity and increase eclampsia-like seizure threshold in rat hippocampus through the α7 nicotinic receptor., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Tian ma (Gastrodia elata, GE) is an ancient Chinese herbal medicine that has been suggested to be effective as an anticonvulsant and analgesic, and to have sedative effects against vertigo, general paralysis, epilepsy and tetanus. The primary active ingredient isolated from GE is termed gastrodin, which is the glucoside of 4-hydroxybenzyl alcohol (4-HBA). Gastrodin can abolish hypoxia-, glutamate- and N-methyl-D-aspartate (NMDA) receptor-induced toxicity in primary culture of rat cortical neurons, and reduces seizure severity in seizure-sensitive gerbils. We evaluated the effect of gastrodin on NMDA excitotoxicity in hippocampal slice cultures (HSCs) with propidium iodide (PI) fluorescence measurement. We also evaluated the effects of gastrodin for treating active in vivo temporal lobe seizures induced by lithium/pilocarpine. Seizure severity, time span to seizure onset, mortality rate and hippocampal histology for survivors were compared. The effect of gastrodin was evaluated for treating in vitro seizures induced by Mg²⁺-free medium in hippocampal slices. Frequencies and amplitudes of epileptiform discharges were compared. The effect of gastrodin on synaptic transmission was evaluated on hippocampal CA1 Schaffer collaterals. Application of 25 μM gastrodin significantly suppressed NMDA excitotoxicity in CA3 but not in CA1 hippocampus and dentate gyrus. Intraventricular gastrodin accelerated seizure onset for 12 min after intraperitoneal pilocarpine injection (P = 0.051). Three of five rats (60%) in the gastrodin group, and three of four (75%) in the dimethyl sulfoxide (DMSO) group died within 3 days after status epilepticus (SE). Gastrodin also failed to inhibit epileptiform discharges in hippocampal slices induced by Mg²⁺-free medium, believed to be NMDA receptor-mediated spontaneous activity. The frequencies of the spontaneous epileptiform discharges were similar under treatments with 25 μM gastrodin, 200 μM gastrodin and DMSO. For the evaluation of gastrodin on synaptic transmission, application of DMSO, 25 μM or 200 μM gastrodin had no significant effect on excitatory postsynaptic potential (EPSP) slopes. Gastrodin at 200 μM decreased paired-pulse facilitation (PPF) from 1.23 ± 0.04 to 1.12 ± 0.04 (P = 0.002). In conclusion, gastrodin failed to suppress in vivo and in vitro seizures in our study. Gastrodin showed no effect on hippocampal Schaffer collateral EPSP. These findings suggest that gastrodin does not interact with ionotropic glutamate receptors to inhibit NMDA receptor-facilitated seizures. However, gastrodin showed protective effects against NMDA toxicity on cultured hippocampal slices. Nevertheless, gastrodin is still a potential neuroprotective agent against NMDA excitotoxicity, with potential benefits for stroke and patients with epilepsy.

Synapse loss in Alzheimer's disease (AD) correlates with cognitive decline. Involvement of microglia and complement in AD has been attributed to neuroinflammation, prominent late in disease. Here we show in mouse models that complement and microglia mediate synaptic loss early in AD. C1q, the initiating protein of the classical complement cascade, is increased and associated with synapses before overt plaque deposition. Inhibition of C1q, C3, or the microglial complement receptor CR3 reduces the number of phagocytic microglia, as well as the extent of early synapse loss. C1q is necessary for the toxic effects of soluble β-amyloid (Aβ) oligomers on synapses and hippocampal long-term potentiation. Finally, microglia in adult brains engulf synaptic material in a CR3-dependent process when exposed to soluble Aβ oligomers. Together, these findings suggest that the complement-dependent pathway and microglia that prune excess synapses in development are inappropriately activated and mediate synapse loss in AD., (Copyright © 2016, American Association for the Advancement of Science.)

Alzheimer's disease (AD) is one of the most prevalent neurodegenerative disorder. It is characterized by the formation of amyloid plaques and neurofibrillary tangles in the brain, the degeneration of cholinergic neurons and neuronal cell death. The present study aimed to investigate the effect of luteolin, a flavonoid compound, on memory impairment in a streptozotocin (STZ)‑induced Alzheimer's rat model. Morris water maze and probe tests were performed to examine the effect of luteolin treatment on cognition and memory. The effect of luteolin on CA1 pyramidal layer thickness was also examined. The results demonstrated that luteolin significantly ameliorated the spatial learning and memory impairment induced by STZ treatment. STZ significantly reduced the thickness of CA1 pyramidal layer and treatment of luteolin completely abolished the inhibitory effect of STZ. Our results suggest that luteolin has a potentially protective effect on learning defects and hippocampal structures in AD.

Interaction between the hippocampus and the medial prefrontal cortex (mPFC) has been identified as a key target in several neuropsychiatric disorders. However, the hippocampus-mPFC (H-PFC) pathway has not been outlined in mice, which are increasingly the leading choice for new animal models for neurological disorders. Our results, establish the existence of a topographical, monosynaptic pathway originating exclusively from the ventral CA1 and subiculum to the mPFC. Functional connectivity of the H-PFC pathway, examined in vivo through field potential recordings in the prelimbic mPFC after high-frequency stimulation of the hippocampal outflow, demonstrates an induction of a significant long lasting long-term potentiation, which is stable for at least one hour and strongly impaired by exposure to acute stress. Given that stress exposure is known to have serious detrimental effects on prefrontal cortical functioning and is considered a major risk factor for several neuropsychiatric disorders, the present study provides a crucial animal model of neural interaction and response to environmental stress which could lend itself to the study of disruption of brain circuits and test for potential drug candidates.