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Abnormal patterns of brain connectivity characterize epilepsy. However, little is known about these patterns during the stages preceding a seizure induced by pentylenetetrazol (PTZ). To investigate brain connectivity in male Wistar rats during the preictal phase of PTZ-induced seizures (60 mg/kg), we recorded local field potentials in the primary motor (M1) cortex, the ventral anterior (VA) nucleus of the thalamus, the hippocampal CA1 area, and the dentate gyrus (DG) during the baseline period and after PTZ administration. While there were no changes in power density between the baseline and preictal periods, we observed an increase in directional functional connectivity in theta from the hippocampal formation to M1 and VA, as well as in middle gamma from DG to CA1 and from CA1 to M1, and also in slow gamma from M1 to CA1. These findings are supported by increased phase coherence between DG-M1 in theta and CA1-M1 in middle gamma, as well as enhanced phase-amplitude coupling of delta-middle gamma in M1 and delta-fast gamma in CA1. Interestingly, we also noted a slight decrease in phase synchrony between CA1 and VA in slow gamma. Together, these results demonstrate increased functional connectivity between brain regions during the PTZ-induced preictal period, with this increase being particularly driven by the hippocampal formation., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Alzheimer's disease (AD) leads to progressive memory decline, and alterations in hippocampal function are among the earliest pathological features observed in human and animal studies. GABAergic interneurons (INs) within the hippocampus coordinate network activity, among which type 3 interneuron-specific (I-S3) cells expressing vasoactive intestinal polypeptide and calretinin play a crucial role. These cells provide primarily disinhibition to principal excitatory cells (PCs) in the hippocampal CA1 region, regulating incoming inputs and memory formation. However, it remains unclear whether AD pathology induces changes in the activity of I-S3 cells, impacting the hippocampal network motifs. Here, using young adult 3xTg-AD mice, we found that while the density and morphology of I-S3 cells remain unaffected, there were significant changes in their firing output. Specifically, I-S3 cells displayed elongated action potentials and decreased firing rates, which was associated with a reduced inhibition of CA1 INs and their higher recruitment during spatial decision-making and object exploration tasks. Furthermore, the activation of CA1 PCs was also impacted, signifying early disruptions in CA1 network functionality. These findings suggest that altered firing patterns of I-S3 cells might initiate early-stage dysfunction in hippocampal CA1 circuits, potentially influencing the progression of AD pathology., Competing Interests: FM, RF, DT, PI, ST, FC, LT No competing interests declared, (© 2024, Michaud, Francavilla et al.)

Competing Interests: Dr. Masurkar is a council member of the Alzheimer’s Association International Research Grant Program, he serves on the steering committee of the Alzheimer’s Disease Cooperative Study, and he serves on the editorial boards of Journal of Neuro-ophthalmology and Alzheimer’s and Dementia: Translational Research and Clinical Interventions. The other authors report no financial relationships with commercial interests.

Fragile X syndrome (FXS), the most frequent monogenic form of intellectual disability, is caused by transcriptional silencing of the FMR1 gene that could render neuronal hyperexcitability. Here we show that pyramidal cells (PCs) in the dorsal CA1 region of the hippocampus elicited a larger action potential (AP) number in response to suprathreshold stimulation in juvenile Fmr1 knockout (KO) than wild-type (WT) mice. Because Kv7/M channels modulate CA1 PC excitability in rats, we investigated if their dysfunction produces neuronal hyperexcitability in Fmr1 KO mice. Immunohistochemical and western blot analyses showed no differences in the expression of Kv7.2 and Kv7.3 channel subunits between genotypes; however, the current mediated by Kv7/M channels was reduced in Fmr1 KO mice. In both genotypes, bath application of XE991 (10 μM), a blocker of Kv7/M channels: produced an increased AP number, produced an increased input resistance, produced a decreased AP voltage threshold and shaped AP medium afterhyperpolarization by increasing mean velocities. Retigabine (10 μM), an opener of Kv7/M channels, produced opposite effects to XE991. Both XE991 and retigabine abolished differences in all these parameters found in control conditions between genotypes. Furthermore, a low concentration of retigabine (2.5 μM) normalized CA1 PC excitability of Fmr1 KO mice. Finally, ex vivo seizure-like events evoked by 4-aminopyiridine (200 μM) in the dorsal CA1 region were more frequent in Fmr1 KO mice, and were abolished by retigabine (5-10 μM). We conclude that CA1 PCs of Fmr1 KO mice exhibit hyperexcitability, caused by Kv7/M channel dysfunction, and increased epileptiform activity, which were abolished by retigabine. KEY POINTS: Dorsal pyramidal cells of the hippocampal CA1 region of Fmr1 knockout mice exhibit hyperexcitability. Kv7/M channel activity, but not expression, is reduced in pyramidal cells of the hippocampal CA1 region of Fmr1 knockout mice. Kv7/M channel dysfunction causes hyperexcitability in pyramidal cells of the hippocampal CA1 region of Fmr1 knockout mice by increasing input resistance, decreasing AP voltage threshold and shaping medium afterhyperpolarization. A Kv7/M channel opener normalizes neuronal excitability in pyramidal cells of the hippocampal CA1 region of Fmr1 knockout mice. Ex vivo seizure-like events evoked in the dorsal CA1 region were more frequent in Fmr1 KO mice, and such an epileptiform activity was abolished by a Kv7/M channel opener depending on drug concentration. Kv7/M channels may represent a therapeutic target for treating symptoms associated with hippocampal alterations in fragile X syndrome., (© 2024 The Authors. The Journal of Physiology published by John Wiley & Sons Ltd on behalf of The Physiological Society.)

Pregnancy is associated with neural and behavioral plasticity, systemic inflammation, and oxidative stress, yet the impact of inflammation and oxidative stress on maternal neural and behavioral plasticity during pregnancy is unclear. We hypothesized that healthy pregnancy transiently reduces learning and memory and these deficits are associated with pregnancy-induced elevations in inflammation and oxidative stress. Cognitive performance was tested with novel object recognition (recollective memory), Morris water maze (spatial memory), and open field (anxiety-like) behavior tasks in female Sprague-Dawley rats of varying reproductive states [nonpregnant (nulliparous), pregnant (near term), and 1-2 mo after pregnancy (primiparous); n = 7 or 8/group]. Plasma and CA1 proinflammatory cytokines were measured with a MILLIPLEX magnetic bead assay. Plasma oxidative stress was measured via advanced oxidation protein products (AOPP) assay. CA1 markers of oxidative stress, neuronal activity, and apoptosis were quantified via Western blot analysis. Our results demonstrate that CA1 oxidative stress-associated markers were elevated in pregnant compared with nulliparous rats ( P ≤ 0.017) but there were equivalent levels in pregnant and primiparous rats. In contrast, reproductive state did not impact CA1 inflammatory cytokines, neuronal activity, or apoptosis. Likewise, there was no effect of reproductive state on recollective or spatial memory. Even so, spatial learning was impaired ( P ≤ 0.007) whereas anxiety-like behavior ( P ≤ 0.034) was reduced in primiparous rats. Overall, our data suggest that maternal hippocampal CA1 is protected from systemic inflammation but vulnerable to peripartum oxidative stress. Peripartum oxidative stress elevations, such as in pregnancy complications, may contribute to peripartum neural and behavioral plasticity. NEW & NOTEWORTHY Healthy pregnancy is associated with elevated maternal systemic and brain oxidative stress. During postpregnancy, brain oxidative stress remains elevated whereas systemic oxidative stress is resolved. This sustained maternal brain oxidative stress is associated with learning impairments and decreased anxiety-like behavior during the postpregnancy period.

Impaired behavioural flexibility is a core feature of neuropsychiatric disorders and is associated with underlying dysfunction of fronto-striatal circuitry. Reduced dosage of Cyfip1 is a risk factor for neuropsychiatric disorder, as evidenced by its involvement in the 15q11.2 (BP1-BP2) copy number variant: deletion carriers are haploinsufficient for CYFIP1 and exhibit a two- to four-fold increased risk of schizophrenia, autism and/or intellectual disability. Here, we model the contributions of Cyfip1 to behavioural flexibility and related fronto-striatal neural network function using a recently developed haploinsufficient, heterozygous knockout rat line. Using multi-site local field potential (LFP) recordings during resting state, we show that Cyfip1 heterozygous rats (Cyfip1 +/- ) harbor disrupted network activity spanning medial prefrontal cortex, hippocampal CA1 and ventral striatum. In particular, Cyfip1 +/- rats showed reduced influence of nucleus accumbens and increased dominance of prefrontal and hippocampal inputs, compared to wildtype controls. Adult Cyfip1 +/- rats were able to learn a single cue-response association, yet unable to learn a conditional discrimination task that engages fronto-striatal interactions during flexible pairing of different levers and cue combinations. Together, these results implicate Cyfip1 in development or maintenance of cortico-limbic-striatal network integrity, further supporting the hypothesis that alterations in this circuitry contribute to behavioural inflexibility observed in neuropsychiatric diseases including schizophrenia and autism., (© 2024. The Author(s).)

Background: Mutations in the X-linked gene cyclin-dependent kinase-like 5 (CDKL5) cause a severe neurological disorder characterised by early-onset epileptic seizures, autism and intellectual disability (ID). Impaired hippocampal function has been implicated in other models of monogenic forms of autism spectrum disorders and ID and is often linked to epilepsy and behavioural abnormalities. Many individuals with CDKL5 deficiency disorder (CDD) have null mutations and complete loss of CDKL5 protein, therefore in the current study we used a Cdkl5 -/y rat model to elucidate the impact of CDKL5 loss on cellular excitability and synaptic function of CA1 pyramidal cells (PCs). We hypothesised abnormal pre and/or post synaptic function and plasticity would be observed in the hippocampus of Cdkl5 -/y rats., Methods: To allow cross-species comparisons of phenotypes associated with the loss of CDKL5, we generated a loss of function mutation in exon 8 of the rat Cdkl5 gene and assessed the impact of the loss of CDLK5 using a combination of extracellular and whole-cell electrophysiological recordings, biochemistry, and histology., Results: Our results indicate that CA1 hippocampal long-term potentiation (LTP) is enhanced in slices prepared from juvenile, but not adult, Cdkl5 -/y rats. Enhanced LTP does not result from changes in NMDA receptor function or subunit expression as these remain unaltered throughout development. Furthermore, Ca 2+ permeable AMPA receptor mediated currents are unchanged in Cdkl5 -/y rats. We observe reduced mEPSC frequency accompanied by increased spine density in basal dendrites of CA1 PCs, however we find no evidence supporting an increase in silent synapses when assessed using a minimal stimulation protocol in slices. Additionally, we found no change in paired-pulse ratio, consistent with normal release probability at Schaffer collateral to CA1 PC synapses., Conclusions: Our data indicate a role for CDKL5 in hippocampal synaptic function and raise the possibility that altered intracellular signalling rather than synaptic deficits contribute to the altered plasticity., Limitations: This study has focussed on the electrophysiological and anatomical properties of hippocampal CA1 PCs across early postnatal development. Studies involving other brain regions, older animals and behavioural phenotypes associated with the loss of CDKL5 are needed to understand the pathophysiology of CDD., (© 2024. The Author(s).)

Sleep fragmentation (SF) is a common sleep problem experienced during the perioperative period by older adults, and is associated with postoperative cognitive dysfunction (POCD). Increasing evidence indicates that delta-wave activity during non-rapid eye movement (NREM) sleep is involved in sleep-dependent memory consolidation and that hippocampal theta oscillations are related to spatial exploratory memory. Recovery sleep (RS), a self-regulated state of sleep homeostasis, enhances delta-wave power and memory performance in sleep-deprived older mice. However, it remains unclear whether RS therapy has a positive effect on cognitive changes following SF in older mouse models. Therefore, this study aimed to explore whether preoperative RS can alleviate cognitive deficits in aged mice with SF. A model of preoperative 24-h SF combined with exploratory laparotomy-induced POCD was established in 18-month-old mice. Aged mice were treated with preoperative 6-h RS following SF and postoperative 6-h RS following surgery, respectively. The changes in hippocampus-dependent cognitive function were investigated using behavioral tests, electroencephalography (EEG), local field potential (LFP), magnetic resonance imaging, and neuromorphology. Mice that underwent 24-h SF combined with surgery exhibited severe spatial memory impairment; impaired cognitive performance could be alleviated by preoperative RS treatment. In addition, preoperative RS increased NREM sleep; enhanced EEG delta-wave activity and LFP theta oscillation in the hippocampal CA1; and improved hippocampal perfusion, microstructural integrity, and neuronal damage. Taken together, these results provide evidence that preoperative RS may ameliorate the severity of POCD aggravated by SF by enhancing delta slow-wave activity and hippocampal theta oscillation, and by ameliorating the reduction in regional cerebral blood flow and white matter microstructure integrity in the hippocampus., Competing Interests: Declaration of Competing Interest The authors declare no competing interests., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Memories benefit from sleep 1 , and the reactivation and replay of waking experiences during hippocampal sharp-wave ripples (SWRs) are considered to be crucial for this process 2 . However, little is known about how these patterns are impacted by sleep loss. Here we recorded CA1 neuronal activity over 12 h in rats across maze exploration, sleep and sleep deprivation, followed by recovery sleep. We found that SWRs showed sustained or higher rates during sleep deprivation but with lower power and higher frequency ripples. Pyramidal cells exhibited sustained firing during sleep deprivation and reduced firing during sleep, yet their firing rates were comparable during SWRs regardless of sleep state. Despite the robust firing and abundance of SWRs during sleep deprivation, we found that the reactivation and replay of neuronal firing patterns was diminished during these periods and, in some cases, completely abolished compared to ad libitum sleep. Reactivation partially rebounded after recovery sleep but failed to reach the levels found in natural sleep. These results delineate the adverse consequences of sleep loss on hippocampal function at the network level and reveal a dissociation between the many SWRs elicited during sleep deprivation and the few reactivations and replays that occur during these events., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)

Alzheimer's Disease (AD) is characterized by a range of behavioral alterations, including memory loss and psychiatric symptoms. While there is evidence that molecular pathologies, such as amyloid beta (Aβ), contribute to AD, it remains unclear how this histopathology gives rise to such disparate behavioral deficits. One hypothesis is that Aβ exerts differential effects on neuronal circuits across brain regions, depending on the neurophysiology and connectivity of different areas. To test this, we recorded from large neuronal populations in dorsal CA1 (dCA1) and ventral CA1 (vCA1), two hippocampal areas known to be structurally and functionally diverse, in the APP/PS1 mouse model of amyloidosis. Despite similar levels of Aβ pathology, dCA1 and vCA1 showed distinct disruptions in neuronal population activity as animals navigated a virtual reality environment. In dCA1, pairwise correlations and entropy, a measure of the diversity of activity patterns, were decreased in APP/PS1 mice relative to age-matched C57BL/6 controls. However, in vCA1, APP/PS1 mice had increased pair-wise correlations and entropy as compared to age matched controls. Finally, using maximum entropy models, we connected the microscopic features of population activity (correlations) to the macroscopic features of the population code (entropy). We found that the models' performance increased in predicting dCA1 activity, but decreased in predicting vCA1 activity, in APP/PS1 mice relative to the controls. Taken together, we found that Aβ exerts distinct effects across different hippocampal regions, suggesting that the various behavioral deficits of AD may reflect underlying heterogeneities in neuronal circuits and the different disruptions that Aβ pathology causes in those circuits., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Chockanathan, Padmanabhan. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Background: The hippocampal representation of space, formed by the collective activity of populations of place cells, is considered as a substrate of spatial memory. Alzheimer's disease (AD), a widespread severe neurodegenerative condition of multifactorial origin, typically exhibits spatial memory deficits among its early clinical signs before more severe cognitive impacts develop., Objective: To investigate mechanisms of spatial memory impairment in a double transgenic rat model of AD., Methods: In this study, we utilized 9-12-month-old double-transgenic TgF344-AD rats and age-matched controls to analyze the spatial coding properties of CA1 place cells. We characterized the spatial memory representation, assessed cells' spatial information content and direction-specific activity, and compared their population coding in familiar and novel conditions., Results: Our findings revealed that TgF344-AD animals exhibited lower precision in coding, as evidenced by reduced spatial information and larger receptive zones. This impairment was evident in maps representing novel environments. While controls instantly encoded directional context during their initial exposure to a novel environment, transgenics struggled to incorporate this information into the newly developed hippocampal spatial representation. This resulted in impairment in orthogonalization of stored activity patterns, an important feature directly related to episodic memory encoding capacity., Conclusions: Overall, the results shed light on the nature of impairment at both the single-cell and population levels in the transgenic AD model. In addition to the observed spatial coding inaccuracy, the findings reveal a significantly impaired ability to adaptively modify and refine newly stored hippocampal memory patterns.

Chronic stress is a core risk factor for developing a myriad of neurological disorders, including major depression. The chronicity of such stress can lead to adaptive responses or, on the contrary, to psychological maladaptation. The hippocampus is one of the most affected brain regions displaying functional changes in chronic stress. Egr1, a transcription factor involved in synaptic plasticity, is a key molecule regulating hippocampal function, but its role in stress-induced sequels has been poorly addressed. Emotional and cognitive symptoms were induced in mice by using the chronic unpredictable mild stress (CUMS) protocol. We used inducible double-mutant Egr1-CreERT2 x R26RCE mice to map the formation of Egr1-dependent activated cells. Results show that short- (2 days) or long-term (28 days) stress protocols in mice induce activation or deactivation, respectively, of hippocampal CA1 neural ensembles in an Egr1-activity-dependent fashion, together with an associated dendritic spine pathology. In-depth characterization of these neural ensembles revealed a deep-to-superficial switch in terms of Egr1-dependent activation of CA1 pyramidal neurons. To specifically manipulate deep and superficial pyramidal neurons of the hippocampus, we then used Chrna7-Cre (to express Cre in deep neurons) and Calb1-Cre mice (to express Cre in superficial neurons). We found that specific manipulation of superficial but not deep pyramidal neurons of the CA1 resulted in the amelioration of depressive-like behaviors and the restoration of cognitive impairments induced by chronic stress. In summary, Egr1 might be a core molecule driving the activation/deactivation of hippocampal neuronal subpopulations underlying stress-induced alterations involving emotional and cognitive sequels.

Burst discharges in the immature brain may contribute to its enhanced seizure susceptibility. The cellular mechanisms underlying burst discharges in the CA1 area of the immature versus adult hippocampus were investigated with simultaneous whole-cell and field-potential recordings. When GABA A receptors were blocked pharmacologically, bursts in CA1 were either graded or all-or-none (or mixed) as a function of electrical stimulation intensity. Most CA1 minislices from immature rats displayed all-or-none or mixed bursts, whereas the slices from adult rats predominantly elicited graded bursts. The frequency and amplitude of spontaneous excitatory postsynaptic currents (sEPSCs) were greater in CA1 pyramidal cells from the immature than the adult slices. The developmental differences in CA1 bursting were also detected in slices adjusted for maturational changes in brain volume (i.e., 350 µm thick for immature vs. 450 µm thick for adult rats). Neither N -methyl-d-aspartate (NMDA) nor group I metabotropic glutamate (mGlu1) receptor antagonists blocked the network-driven bursts in immature CA1, but an α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor blocker abolished them. Robust excitatory postsynaptic potentials (EPSPs) occurred after bursts in some immature CA1 slices (23%) but never in slices from the adult. The input-output (amount of current injected vs. number of action potentials generated) relationship was markedly greater in CA1 pyramidal cells in the immature compared with the adult hippocampus. These data suggest that the CA1 area of the immature brain is capable of generating network-driven bursts, which declines in adult rats. The increased propensity of burst generation in immature CA1 appears to involve a greater AMPA receptor-mediated synaptic network and an increased intrinsic spike-generating ability. NEW & NOTEWORTHY Burst discharges in the developing brain can provide valuable insights into epileptogenesis. We show that the immature hippocampal CA1 area is capable of generating all-or-none (i.e., network) bursts, which transitions to graded (i.e., nonnetwork) bursts in the mature brain via both synaptic and intrinsic mechanisms. Our results provide new clues to help understand possible mechanisms that may be shared in the immature and epileptic brain and how the normal brain becomes seizure prone (i.e., epileptogenesis).

The impacts of early-life adversity (ELA) on cognitive functions including striatal-dependent habit memory and hippocampal-dependent spatial memory were investigated in male mice. The ELA mouse model was generated via an altered cage environment with limited nesting and bedding materials during postnatal days 2-9 (P2-9). The altered cage environment affected the nesting behaviors of dams, creating a stressful condition for their offspring. The ELA mice had biased decision making and poor spatial memory when they grew into young adults (4-month-old). To explore the underlying synaptic basis of these effects, excitatory synapses represented by postsynaptic density protein-95 (PSD-95) were immunolabelled on a series of brain sections and stereologically quantified in the dorsomedial striatum (DMS) and dorsolateral striatum (DLS), as well as in area CA1 of the dorsal hippocampus. Increased PSD-95-immunoreactive synapses were observed in DLS but not DMS, whereas selective loss of PSD-95 synapses was detected in the stratum radiatum of area CA1. The spine data supported the selective effects of ELA on PSD-95 synapses. Specifically, both thin and mushroom-type spines were increased in DLS, while loss of thin spines was apparent in CA1 radiatum in ELA mice versus controls. The correlation between PSD-95 synapses and memory performances was further analyzed, and the data suggested that increased small (<0.20 μm 3 ) and large (>0.40 μm 3 ) synapses in DLS might drive ELA mice to make decisions largely relying on habit memory, while loss of small synapses in hippocampal CA1 damage the spatial memory of ELA mice., Competing Interests: Conflicts of interest None., (Copyright © 2022 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Gradual decline in cognitive and non-cognitive functions are considered clinical hallmarks of Alzheimer's Disease (AD). Post-mortem autoptic analysis shows the presence of amyloid β deposits, neuroinflammation and severe brain atrophy. However, brain circuit alterations and cellular derailments, assessed in very early stages of AD, still remain elusive. The understanding of these early alterations is crucial to tackle defective mechanisms. In a previous study we proved that the Tg2576 mouse model of AD displays functional deficits in the dorsal hippocampus and relevant behavioural AD-related alterations. We had shown that these deficits in Tg2576 mice correlate with the precocious degeneration of dopamine (DA) neurons in the Ventral Tegmental Area (VTA) and can be restored by L-DOPA treatment. Due to the distinct functionality and connectivity of dorsal versus ventral hippocampus, here we investigated neuronal excitability and synaptic functionality in the ventral CA1 hippocampal sub-region of Tg2576 mice. We found an age-dependent alteration of cell excitability and firing in pyramidal neurons starting at 3 months of age, that correlates with reduced levels in the ventral CA1 of tyrosine hydroxylase - the rate-limiting enzyme of DA synthesis. Additionally, at odds with the dorsal hippocampus, we found no alterations in basal glutamatergic transmission and long-term plasticity of ventral neurons in 8-month old Tg2576 mice compared to age-matched controls. Last, we used computational analysis to model the early derailments of firing properties observed and hypothesize that the neuronal alterations found could depend on dysfunctional sodium and potassium conductances, leading to anticipated depolarization-block of action potential firing. The present study depicts that impairment of cell excitability and homeostatic control of firing in ventral CA1 pyramidal neurons is a prodromal feature in Tg2576 AD mice., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Objectives: Global cerebral ischemia (CI) causes severe neuronal injury, mainly in the hippocampal CA1 region. This study aimed to investigate an immediate using transcranial direct current stimulation (tDCS) in reducing neuronal injury induced by CI., Materials and Methods: The 32 Wistar male rats were randomly divided into four groups (n=8 per group). In the ischemia group (I), CI was induced via the 4-vessel occlusion model. In the sham group (Sh), rats did not receive any intervention. In the ischemia+cathodal group (I+c/tDCS), the cathodal current was applied during CI. In the ischemia+anodal group (I+a/tDCS), the anodal current was applied. The current intensity of 400 μA was applied for 15-min during the ischemia. Hippocampal tissue was used to assess levels of NMDAR, IL-1β, TNF-α, MDA, SOD, NOS, and apoptosis markers. Histological assessment and TUNEL staining were performed in CA1 hippocampal region., Results: The c/tDCS significantly decreased the levels of IL-1β and TNF-α than the I and a/tDCS groups. The c/tDCS significantly reduced MDA and NOS levels, while increasing the level of SOD than the I and a/tDCS. The c/tDCS caused a significant decrease in NMDAR level than the a/tDCS. Using c/tDCS significantly reduced the Bax and Caspase-3 expressions, while increasing the Bcl-2 expression than the I group. In the c/tDCS group, DNA fragmentation and neuronal death were significantly lower than the I and a/tDCS groups., Conclusion: Using cathodal a direct current could attenuate primary pathophysiological pathways induced by CI, and it eventually reduced neurons death and apoptosis in the CA1 hippocampal region., Competing Interests: Declaration of Competing Interest The authors declare that they have no conflicts of interest., (Copyright © 2021 Elsevier Inc. All rights reserved.)

New neurons are abnormal in the adult hippocampus of Alzheimer's disease (AD) mouse models. The effects of modulating adult neurogenesis on AD pathogenesis differ from study to study. We reported recently that ablation of adult neural stem cells (aNSCs) was associated with improved memory in AD models. Here, we found that long-term potentiation (LTP) was improved in the hippocampus of APP/PS1 mice after ablation of aNSCs. This effect was confirmed in hAPP-J20 mice, a second AD mouse model. On the other hand, we found that exposure to enriched environment (EE) dramatically increased the number of DCX + neurons, promoted dendritic growth, and affected the location of newborn neurons in the dentate gyrus of APP/PS1 mice, and EE exposure significantly ameliorated memory deficits in APP/PS1 mice. Together, our data suggest that both inhibiting abnormal adult neurogenesis and enhancing healthy adult neurogenesis could be beneficial for AD, and they are not mutually exclusive., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Cognitive impairment (CI) is a disabling concomitant of multiple sclerosis (MS) with a complex and controversial pathogenesis. The cytokine interleukin-17A (IL-17A) is involved in the immune pathogenesis of MS, but its possible effects on synaptic function and cognition are still largely unexplored. In this study, we show that the IL-17A receptor (IL-17RA) is highly expressed by hippocampal neurons in the CA1 area and that exposure to IL-17A dose-dependently disrupts hippocampal long-term potentiation (LTP) through the activation of its receptor and p38 mitogen-activated protein kinase (MAPK). During experimental autoimmune encephalomyelitis (EAE), IL-17A overexpression is paralleled by hippocampal LTP dysfunction. An in vivo behavioral analysis shows that visuo-spatial learning abilities are preserved when EAE is induced in mice lacking IL-17A. Overall, this study suggests a key role for the IL-17 axis in the neuro-immune cross-talk occurring in the hippocampal CA1 area and its potential involvement in synaptic dysfunction and MS-related CI., Competing Interests: Declaration of interests M.D.F. participated on advisory boards for and received speaker or writing honoraria and funding for traveling from Bayer, Biogen Idec, Genzyme, Merck, Mylan, Novartis, Roche, and Teva. A. Mancini received speaker or writing honoraria and travel grants to attend national and international conferences from Almirall, Biogen Idec, Merck, Mylan, Novartis, Sanofi, and Teva. L.G. participated on advisory boards for and received speaker or writing honoraria and funding for traveling from Almirall, Biogen, Biogen-Idec, Genzyme, Mylan, Novartis, Roche, and Teva. E.P. served on scientific advisory board for Biogen Idec and Merck Serono and received honoraria for speaking and funding for traveling from Biogen, Genzyme, Novartis, Merck, and Teva. M.P.A. participated on advisory boards for and received speaker honoraria and research funding from Bayer, Biogen Idec, Sanofi Genzyme, Merck, Novartis, Roche, and Teva. P.C. received/receives research support from Bayer Schering, Biogen-Dompé, Boehringer Ingelheim, Eisai, Lundbeck, Merck-Serono, Novartis, Sanofi-Aventis, Sigma-Tau, and UCB Pharma. P.M., T.Z., A.L., M.T., A. Megaro, L.B., M.S., A.T., V.D., D.C., N.S., V.L., C.C., L.P., M.T.V., L.L.B., P.S., and L.R. declare no competing interests., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

The prefrontal-hippocampal dysfunction that underlies cognitive deficits in mental disorders emerges during early development. The lateral entorhinal cortex (LEC) is tightly interconnected with both prefrontal cortex (PFC) and hippocampus (HP), yet its contribution to the early dysfunction is fully unknown. Here we show that mice that mimic the dual genetic (G) -environmental (E) etiology (GE mice) of psychiatric risk have poor LEC-dependent recognition memory at pre-juvenile age and abnormal communication within LEC-HP-PFC networks throughout development. These functional and behavioral deficits relate to sparser projections from LEC to CA1 and decreased efficiency of axonal terminals to activate the hippocampal circuits in neonatal GE mice. In contrast, the direct entorhinal drive to PFC is not affected, yet the PFC is indirectly compromised, as target of the under-activated HP. Thus, the entorhinal-hippocampal circuit is already impaired from neonatal age on in GE mice., (© 2021. The Author(s).)

Aging is an irreversible biological process that involves oxidative stress, neuroinflammation, and apoptosis, and eventually leads to cognitive dysfunction. However, the underlying mechanisms are not fully understood. In this study, we investigated the role and potential mechanisms of Synaptotagmin-7, a calcium membrane transporter in cognitive impairment in aging mice. Our results indicated that Synaptotagmin-7 expression significantly decreased in the hippocampus of D-galactose-induced or naturally aging mice when compared with healthy controls, as detected by western blot and quantitative reverse transcriptase-polymerase chain reaction analysis. Synaptotagmin-7 overexpression in the dorsal CA1 of the hippocampus reversed long-term potentiation and improved hippocampus-dependent spatial learning in D-galactose-induced aging mice. Synaptotagmin-7 overexpression also led to fully preserved learning and memory in 6-month-old mice. Mechanistically, we demonstrated that Synaptotagmin-7 improved learning and memory by elevating the level of fEPSP and downregulating the expression of aging-related genes such as p53 and p16. The results of our study provide new insights into the role of Synaptotagmin-7 in improving neuronal function and overcoming memory impairment caused by aging, suggesting that Synaptotagmin-7 overexpression may be an innovative therapeutic strategy for treating cognitive impairment., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Patients with Alzheimer's disease (AD) often have fragmentation of sleep/wake cycles and disrupted 24-h (circadian) activity. Despite this, little work has investigated the potential underlying day/night disruptions in cognition and neuronal physiology in the hippocampus. The molecular clock, an intrinsic transcription-translation feedback loop that regulates circadian behavior, may also regulate hippocampal neurophysiological activity. We hypothesized that disrupted diurnal variation in clock gene expression in the hippocampus corresponds with loss of normal day/night differences in membrane excitability, synaptic physiology, and cognition. We previously reported disrupted circadian locomotor rhythms and neurophysiological output of the suprachiasmatic nucleus (the primary circadian clock) in Tg-SwDI mice with human amyloid-beta precursor protein mutations. Here, we report that Tg-SwDI mice failed to show day/night differences in a spatial working memory task, unlike wild-type controls that exhibited enhanced spatial working memory at night. Moreover, Tg-SwDI mice had lower levels of Per2, one of the core components of the molecular clock, at both mRNA and protein levels when compared to age-matched controls. Interestingly, we discovered neurophysiological impairments in area CA1 of the Tg-SwDI hippocampus. In controls, spontaneous inhibitory post-synaptic currents (sIPSCs) in pyramidal cells showed greater amplitude and lower inter-event interval during the day than the night. However, the normal day/night differences in sIPSCs were absent (amplitude) or reversed (inter-event interval) in pyramidal cells from Tg-SwDI mice. In control mice, current injection into CA1 pyramidal cells produced more firing during the night than during the day, but no day/night difference in excitability was observed in Tg-SwDI mice. The normal day/night difference in excitability in controls was blocked by GABA receptor inhibition. Together, these results demonstrate that the normal diurnal regulation of inhibitory transmission in the hippocampus is diminished in a mouse model of AD, leading to decreased daytime inhibition onto hippocampal CA1 pyramidal cells. Uncovering disrupted day/night differences in circadian gene regulation, hippocampal physiology, and memory in AD mouse models may provide insight into possible chronotherapeutic strategies to ameliorate Alzheimer's disease symptoms or delay pathological onset., (Copyright © 2021. Published by Elsevier Inc.)

Hypoxia typically accompanies acute inflammatory responses in patients and animal models. However, a limited number of studies have examined the effect of hypoxia in combination with inflammation (Hypo-Inf) on neural function. We previously reported that neuronal excitability in hippocampal CA1 neurons decreased during hypoxia and greatly rebounded upon reoxygenation. We attributed this altered excitability mainly to the dynamic regulation of hyperpolarization-activated cyclic nucleotide-gated cation (HCN) channels and input resistance. However, the molecular mechanisms underlying input resistance changes by Hypo-Inf and reperfusion remained unclear. In the present study, we found that a change in the density of the delayed rectifier potassium current (I DR ) can explain the input resistance variability. Furthermore, voltage-dependent inactivation of A-type potassium (I A ) channels shifted in the depolarizing direction during Hypo-Inf and reverted to normal upon reperfusion without a significant alteration in the maximum current density. Our results indicate that changes in the input resistance, and consequently excitability, caused by Hypo-Inf and reperfusion are at least partially regulated by the availability and voltage dependence of K V channels. Moreover, these results suggest that selective K V channel modulators can be used as potential neuroprotective drugs to minimize hypoxia- and reperfusion-induced neuronal damage., (© 2021. The Author(s).)

Autism spectrum disorder (ASD) is a severe life-long neuropsychiatric disorder. Alterations and imbalance of several neurochemical systems may be involved in ASD pathophysiology, of them, serotonergic neurotransmission dysfunction and deficiency may underlie behavioral abnormalities associated with ASD. However, the functional importance of serotonergic receptors, particularly 5HT7 receptors in ASD pathology remains poorly defined. Serotonin receptor subtype 7 (5-HT7R) plays a direct regulatory role in the development and also for the mature function of the brain, therefore, further studies are necessary to elucidate the role of these receptors in the etiology of autism. To address this issue, we combined here behavioral, electrophysiological methods to further characterize the contribution of 5-HT7Rs in the prenatal valproic acid (VPA) exposure-induced impairment in synaptic plasticity and their impact on the associated behavioral changes. This may help to unravel the underlying cellular mechanisms involved in ASD and can lead to new treatment and/or prevention therapies based on the role of the serotonergic system for autism. Findings revealed that compared to control, autistic-like offspring showed increased anxiety-like behavior, reduced social interaction, decreased locomotor activity, and impaired identification of the novel object. However, administration of 5-HT7Rs agonist, LP-211, for 7 consecutive days before testing from postnatal day 21 to 27 reversed all behavioral deficits induced by prenatal exposure to VPA in offspring. Also, both short-term depression and long-term potentiation were impaired in the autistic-like pups, but activation of 5-HT7Rs rescued the LTP impairment in the autistic-like group so that there was no significant difference between the two groups. Blockade of 5-HT7Rs caused LTP impairment following HFS in the autistic-like group. Besides, there was a significant difference in LTD induction following SB-269970 application between the control and the autistic-like groups measured at first 10 min following TPS. Moreover, both the number and the size of retrograde fast blue-labelled neurons in the raphe nuclei were reduced. Overall, these results provide for the first time, as far as we know, functional evidence for the restorative role of 5-HT7Rs activation against prenatal VPA exposure induced behavioral deficits and hippocampal synaptic plasticity impairment. Therefore, these receptors could be a potential and promising pharmacotherapy target for the treatment of autism., (Copyright © 2021 Elsevier Inc. All rights reserved.)

The developmental period is critical in delineating plastic response to internal and external events. However, neurobehavioural effects of global cerebral ischemia (GCI) in the maturing brain remain largely unknown. This study characterised the effects of GCI experienced at puberty on adulthood (1) hippocampus CA1 neuronal damage, (2) cognitive and emotional impairments, and (3) glucocorticoid receptor (GR) expression. Effects of adolescent exposure to the phenol vanillic acid (VA) on post-ischemic outcomes were also determined. Male Long Evans rats (n = 35) were supplemented for 21 consecutive days (postnatal days 33-53) with VA (91 mg/kg) or nut paste vehicle (control) prior to a 10-min GCI or sham surgery. As adults, rats were tested in the Open Field Test (OFT), Elevated-Plus Maze (EPM), and Barnes Maze (BM). GR expression was determined in the basolateral amygdala (BLA), CA1, and paraventricular nucleus (PVN), and brain injury assessed via CA1 neuronal density. Adolescent GCI exposure induced extensive hippocampal CA1 injury, which was not prevented by VA supplementation. Behaviourally, GCI increased EPM exploration while having no impact on spatial memory. VA intake increased OFT peripheral exploration. Notably, while no delayed changes in CA1 and PVN GR immunoreactivity were noted, both treatments separately increased BLA GR expression when compared with sham-nut paste rats. Age at GCI occurrence plays a critical role on post-ischemic impairments. The observation of minimal functional impairments despite important CA1 neuronal damage supports use of compensatory mechanisms. Our findings also show daily VA supplementation during adolescence to have no protective effects on post-ischemic outcomes, contrasting adult intake., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Cardiac arrest (CA) is the leading cause of death in humans. Research has shown that mild therapeutic hypothermia (MTH) can reduce neurological sequelae and mortality after CA. Nevertheless, the mechanism remains unclear. This study aimed to determine whether MTH promotes neurogenesis, attenuates neuronal damage, and inhibits apoptosis of neurons in rats after CA. Sprague-Dawley rats were divided into the normothermia and mild hypothermia groups. The rats in the normothermia and hypothermia groups were exposed to 2 h of normothermia (36-37℃) and hypothermia (32-33℃), respectively, immediately after resuscitation from 5 min of asphyxial CA. Corresponding control groups not subjected to CA were included. On days 1-6, 5-bromodeoxyuridine (BrdU) 100 mg/kg/day was administered intraperitoneally. The animals were euthanized 1 week after CA. Compared with the normothermia group, the hypothermia group showed a significant increase in the number of doublecortin (DCX) immune-positive cells in the subgranular zone of the hippocampus 1 week after CA. Neurogenesis was assessed using double immunofluorescent labeling of BrdU with neuronal-specific nuclear protein (NeuN)/DCX. There was no marked change in the number of newborn mature (BrdU+-NeuN+) neurons, though there was a significant increase in the number of newborn immature (BrdU+-DCX+) neurons in the hypothermia than in the normothermia group 1 week after CA. Neuronal injury and apoptosis in the CA1 region of the hippocampus, assessed using NeuN immunofluorescence and terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling assays, were significantly reduced in the hypothermia group 1 week after CA. Moreover, mild hypothermia increased the expression of cold-shock protein RNA-binding motif protein 3 (RBM3) in the early stage (24 h/48 h) after CA. These results suggested that mild hypothermia promotes generation of neuronal cells, reduces neuronal injury, and inhibits apoptosis of neurons, which may be related to RBM3 expression., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Taste recognition memory is evident in rodents because the initial neophobia to novel tastes attenuates across exposures as the taste becomes familiar and safe. This attenuation of taste neophobia (AN) is context-dependent and an auditory background change could induce the recovery of the neophobic response. The AN auditory context-dependency requires the hippocampal integrity but the neurochemical mechanisms underlying the interaction with the taste memory circuit remain unexplored. We have applied pharmacological intervention by 6-hidroxydopamine (6-OHDA) hippocampal lesion for assessing the role of catecholamines in the hippocampal system to Wistar rats that drank a novel 3% vinegar solution for several consecutive days. Additionally, we manipulated the auditory background as a context that could either change or remain constant across all the drinking sessions. We found that a disruption of the context-dependent AN was induced by intracerebral administration of 6-OHDA targeted to the ventral CA1 hippocampus (vCA1). We conclude that the ability of the auditory context to modulate taste recognition memory involves the catecholaminergic activity in the ventral hippocampal circuit for the proper acquisition of safe taste memory., (Copyright © 2021 Elsevier B.V. All rights reserved.)

This study examines changes in synaptic transmission with progression of the chronic epileptic state. Male Sprague-Dawley rats (P40-45) were injected with either saline or pilocarpine. In rats injected with pilocarpine, status epilepticus ensued. Hippocampal slices were cut 20-60 days or 80-110 days post-treatment. Evoked and miniature EPSCs (mEPSCs) were recorded from CA1 pyramidal neurons using whole-cell voltage-clamp. Fiber volleys were also recorded from stratum radiatum. Evoked EPSCs from the pilocarpine-treated cohort showed enhanced amplitudes 20-60 days post-treatment compared to the saline-treated cohort, whereas mEPSCs recorded from the same age group showed no change in event frequency and a slight but significant decrease in mEPSC amplitude distribution. In contrast, comparing evoked EPSCs and mEPSCs recorded 80-110 days after treatment indicated reduced amplitudes from pilocarpine-treated animals compared to controls. mEPSC inter-event interval decreased. This could be explained by a partial depletion of the ready releasable pool of neurotransmitter vesicles in Schaffer collateral presynaptic terminals of the pilocarpine-treated rats. In both saline- and pilocarpine-treated cohorts, concomitant decreases in mEPSC amplitudes as time after treatment progressed suggest that age-related changes in CA1 circuitry may be partially responsible for changes in synaptic transmission that may influence the chronic epileptic state., (Copyright © 2021 The Author(s). Published by Elsevier Inc. All rights reserved.)

Findings from recent studies have revealed that microRNAs (miRNAs) are related to numerous neurological disorders. However, whether miRNAs regulate neuronal anomalies involved in the pathogenesis of depression remain unclear. In the present study, we screened miRNA expression profiles in the CA1 hippocampus of a rat model of depression and found that a specific miRNA, microRNA-211-5p, was significantly down-regulated in depressed rats. When miR-211-5p was up-regulated in these rats, neuronal apoptosis within the CA1 area was suppressed, effects which were accompanied with an amelioration of depression-like behaviours in these rats. These neuroprotective effects of miR-211-5p in depressed rats appear to result through suppression of the Dyrk1A/ASK1/JNK signalling pathway within the CA1 area. In further support of this proposal are the findings that knock-down of miR-211-5p within the CA1 area of normal rats activated the Dyrk1A/ASK1/JNK pathway, resulting in the promotion of neuronal apoptosis and display of depression-like behaviours in these rats. Taken together, these results demonstrate that deficits in miR-211-5p contribute to neuronal apoptosis and thus depression-like behaviours in rats. Therefore, the miR-211-5p/Dyrk1A pathway may be critically involved in the pathogenesis of depression and serve as a potential therapeutic target for the treatment of depression., (© 2021 The Authors. Journal of Cellular and Molecular Medicine published by Foundation for Cellular and Molecular Medicine and John Wiley & Sons Ltd.)

Alzheimer's Disease (AD) is characterized by progressive neurodegeneration and cognitive impairment. Synaptic dysfunction is an established early symptom, which correlates strongly with cognitive decline, and is hypothesised to mediate the diverse neuronal network abnormalities observed in AD. However, how synaptic dysfunction contributes to network pathology and cognitive impairment in AD remains elusive. Here, we present a grid-cell-to-place-cell transformation model of long-term CA1 place cell dynamics to interrogate the effect of synaptic loss on network function and environmental representation. Synapse loss modelled after experimental observations in the APP/PS1 mouse model was found to induce firing rate alterations and place cell abnormalities that have previously been observed in AD mouse models, including enlarged place fields and lower across-session stability of place fields. Our results support the hypothesis that synaptic dysfunction underlies cognitive deficits, and demonstrate how impaired environmental representation may arise in the early stages of AD. We further propose that dysfunction of excitatory and inhibitory inputs to CA1 pyramidal cells may cause distinct impairments in place cell function, namely reduced stability and place map resolution., Competing Interests: The authors have declared that no competing interests exist.

Both environmental stress and immune challenge can induce abnormal neurobehavior. However, the impact of chronic stress on immune challenge-related neurobehavioral abnormalities is still controversial. Hence, we aimed to investigate the effects of chronic stress on immune challenge-related neurobehavioral abnormalities and explore the possible underlying mechanisms. During the first set of experiments, mice were reared under normal condition (NC) or chronic stress (CS) for 4 consecutive weeks. They were allocated to the following four groups: NC + normal saline (NS) group, CS + NS group, NC + lipopolysaccharide (LPS) group, and CS + LPS group. Open field, elevated plus maze, fear conditioning, novel object recognition, and forced swimming tests were performed, and their tissues were harvested. During the second set of experiments, after rearing the mice under the above conditions for 3 weeks, microelectrodes were implanted into the CA1 of the hippocampus. After recovery for 1 week under the respective environmental conditions, the mice were allocated to four groups, as in the first experiments. The basal (home cage) and task (fear conditioning)-related local field potential (LFP) were recorded. In the present study, LPS significantly induced a decrease in the freezing to context and discrimination ratio. However, only the freezing to context was further reduced by prior chronic stress. This suggested that chronic stress worsened fear memory impairment induced by acute LPS challenge. Consistent with the change in fear memory, LPS significantly decreased the expression of PV in the CA1, which was further downregulated by prior chronic stress. On the other hand, LPS inhibited the power of both basal and task-related θ oscillations in the CA1. Only the task-related θ power was further decreased by chronic stress. In conclusion, our study showed that the phenotypic loss of PV interneurons and the decrease in the power of the θ oscillation in the CA1 aggravated by chronic stress may mediate, at least in part, the deterioration of fear memory impairment induced by LPS., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Temporal lobe epilepsy (TLE) is the most common form of focal epilepsies. Pharmacoresistance and comorbidities pose significant challenges to its treatment necessitating the development of non-pharmacological approaches. In an earlier study, exposure to enriched environment (EE) reduced seizure frequency and duration and ameliorated chronic epilepsy-induced depression in rats. However, the cellular basis of beneficial effects of EE remains unknown. Accordingly, in the current study, we evaluated the effects of EE in chronic epilepsy-induced changes in behavioral hyperexcitability, synaptic transmission, synaptophysin (SYN), and calbindin (CB) expression, hippocampal subfield volumes and cell density in male Wistar rats. Epilepsy was induced by lithium-pilocarpine-induced status epilepticus. Chronic epilepsy resulted in behavioral hyperexcitability, decreased basal synaptic transmission, increased paired-pulse facilitation ratio, decreased hippocampal subfields volumes. Moreover, epileptic rats showed decreased synaptophysin and CB expression in the hippocampus. Six weeks post-SE, epileptic rats were exposed to EE for 2 weeks, 6 hr/day. EE significantly reduced the behavioral hyperexcitability and restored basal synaptic transmission correlating with increased expression of SYN and CB. Our results reaffirm the beneficial effects of EE on behavior in chronic epilepsy and establishes some of the putative cellular mechanisms. Since drug resistance and comorbidities are a major concern in TLE, we propose EE as a potent non-pharmacological treatment modality to mitigate these changes in chronic epilepsy., (© 2021 Wiley Periodicals LLC.)

Rabies is a life-threatening viral infection of the brain. Rabies virus (RABV) merely infects excitable cells including neurons provoking drastic behaviors including negative emotional memories. RABV glycoprotein (RVG) plays a critical role in RABV pathogenesis. RVG interacts with various cytoplasmic PDZ (PSD-95/Dlg/ZO-1) containing proteins through its PDZ binding motif (PBM). PTZ domains have crucial role in formation and function of signal transduction. Hippocampus is one of the cerebral regions that contain high load of viral antigens. We examined impact of RVG expression in the dorsal hippocampus on aversive as well as spatial learning and memory performance in rats. Two microliter of the lentiviral vector (~10 8  T.U./ml) encoding RVG or ∆RVG (deleted PBM) genomes was microinjected into the hippocampal CA1. After 1 week, rat's brain was cross-sectioned and RVG/∆RVG-expressing neuronal cells were confirmed by fluorescent microscopy. Passive avoidance and spatial learning and memory were assessed in rats by Shuttle box and Morris water maze (MWM). In the shuttle box, both RVG and ∆RVG decreased the time spent in the dark compartment compared to control (p < 0.05). In MWM, RVG and ∆RVG did not affect the acquisition of spatial task. In the probe test, RVG-expressing rats spent more time in the target quadrant, and also reached the platform position sooner than control group (p < 0.05). Rats expressing ∆RVG significantly swam farther from the hidden platform than RVG group (p < 0.05). Our data indicate RVG expression in the hippocampus strengthens aversive and spatial learning and memory performance. The boosting effect on spatial but not avoidance memory is mediated through PBM.

The high mortality rate associated with acute kidney injury (AKI) is commonly due to progressive, inflammatory multiple organ dysfunction, which often involves neurological complications. The AKI-stimulated mechanisms leading to brain dysfunction are not well understood, which hinders development of new therapeutic avenues to minimize AKI-mediated neural effects. The hippocampal CA1 area is a particularly vulnerable region during AKI but the electrophysiological and inflammatory mechanisms involved in this vulnerability remain largely unknown. Here, we used immunohistochemistry to quantitatively investigate the number of astrocytes expressing glial fibrillary acidic protein (GFAP) as an indicator of inflammation, and whole cell patch clamp to evaluate electrophysiological changes in CA1 at different time points following induction of bilateral renal ischemia (BRI) in male Wistar rats. Further we evaluated the effectiveness of erythropoietin (EPO, 1000 U/kg i.p.) in mitigating BRI-associated changes. Plasma concentrations of blood urea nitrogen (BUN) were significantly enhanced at 24 h, 72 h and 1 week, and creatinine (Cr) was increased at 24 h after reperfusion, which were changes reduced by EPO. BRI led to an increase in CA1 GFAP-positive cells 24 h and 72 h, but not 1 week, after reperfusion, and EPO reversed this effect of BRI at 24 h. Additionally, BRI caused an increase in the peak amplitude and coefficient of variation of CA1 pyramidal neuronal action potentials, which were changes not seen in presence of EPO. When taken together, altered neuronal electrophysiological properties and astrogliosis could contribute to the neurological complications induced by AKI, and EPO offers hope as a potential neuroprotective agent., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Synapse loss and altered synaptic strength are thought to underlie cognitive impairment in Alzheimer's disease (AD) by disrupting neural activity essential for memory. While synaptic dysfunction in AD has been well characterized in anesthetized animals and in vitro, it remains unknown how synaptic transmission is altered during behavior. By measuring synaptic efficacy as mice navigate in a virtual reality task, we find deficits in interneuron connection strength onto pyramidal cells in hippocampal CA1 in the 5XFAD mouse model of AD. These inhibitory synaptic deficits are most pronounced during sharp-wave ripples, network oscillations important for memory that require inhibition. Indeed, 5XFAD mice exhibit fewer and shorter sharp-wave ripples with impaired place cell reactivation. By showing inhibitory synaptic dysfunction in 5XFAD mice during spatial navigation behavior and suggesting a synaptic mechanism underlying deficits in network activity essential for memory, this work bridges the gap between synaptic and neural activity deficits in AD., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

For a better translation from treatment designs of schizophrenia to clinical efficiency, there is a crucial need to refine preclinical animal models. In order to consider the multifactorial nature of the disorder, a new mouse model associating three factors (genetic susceptibility-partial deletion of the MAP6 gene, early-life stress-maternal separation, and pharmacological treatment-chronic Δ-9-tetrahydrocannabinol during adolescence) has recently been described. While this model depicts a schizophrenia-like phenotype, the neurobiological correlates remain unknown. Synaptic transmission and functional plasticity of the CA1 hippocampal region of male and female 3-hit mice were therefore investigated using electrophysiological recordings on the hippocampus slice. While basal excitatory transmission remained unaffected, NMDA receptor (NMDAr)-mediated long-term potentiation (LTP) triggered by theta-burst (TBS) but not by high-frequency (HFS) stimulation was impaired in 3-hit mice. Isolated NMDAr activation was not affected or even increased in female 3-hit mice, revealing a sexual dimorphism. Considering that the regulation of LTP is more prone to inhibitory tone if triggered by TBS than by HFS, the weaker potentiation in 3-hit mice suggests a deficiency of intrinsic GABA regulatory mechanisms. Indeed, NMDAr activation was increased by GABA A receptor blockade in wild-type but not in 3-hit mice. This electrophysiological study highlights dysregulations of functional properties and plasticity in hippocampal networks of 3-hit mice, one of the mechanisms suspected to contribute to the pathophysiology of schizophrenia. It also shows differences between males and females, supporting the sexual dimorphism observed in the disorder. Combined with the previously reported study, the present data reinforce the face validity of the 3-hit model that will help to consider new therapeutic strategies for psychosis.

Background: Although studies have reported an increased risk for cognitive disorders in Hashimoto's thyroiditis (HT) patients, even in the euthyroid state, the mechanisms involved remain unclear. The hippocampus is a classic brain region associated with cognitive function, among which the formation of long-term potentiation (LTP) in the Schaffer collateral-CA1 pathway plays an important role in the process of learning and memory. Therefore, this study established a euthyroid HT model in mice and investigated whether and how HT itself has the ability to trigger LTP alterations accompanied by learning and memory abnormality. Methods: An experimental euthyroid HT model was established in NOD mice through immunization with porcine thyroglobulin (Tg). Morris water maze was measured to determine mice spatial learning and memory. We investigated the effect of HT on synaptic transmission and high-frequency stimulation-induced LTP in the Schaffer collateral-CA1 synapse of mice hippocampus in vivo . Then, animals were sacrificed for thyroid-related parameter measure as well as detection of cellular and molecular events associated with the induction of LTP. Results: HT mice showed intrathyroidal lymphocyte infiltration and rising serum thyroid autoantibody levels accompanied by normal thyroid function. The HT mice had poorer performance in Morris water maze than controls. These alterations were mirrored by abnormalities in synaptic plasticity in the Schaffer collateral-CA1 synapses of the hippocampus in vivo . The integrity of the synaptic structure is the premise for the production of LTP. As detected by transmission electron microscopy, the ultrastructure of synapse and astrocyte in the hippocampus were impaired in euthyroid HT mice. Additionally, Western blot and real-time polymerase chain reaction analyses confirmed that in HT mice, GS, GLAST, and GLT-1, key elements in glutamate-glutamine circulation located in astrocyte, were downregulated, accompanied by elevated levels of glutamate in the hippocampus, which impaired the material basis for LTP induction. NMDR2B expression in the hippocampus was also downregulated. Conclusion: HT can induce damage of LTP in the hippocampal Schaffer collateral-CA1 pathway in the euthyroid state, and this can be attributed, at least partly, to astrocytes impairment, which may underlie the deleterious effects of HT itself on hippocampal-dependent learning and memory function.

Background: Accumulating evidences have demonstrated the roles of several long non-coding RNAs (lncRNAs) in depression. We aim to examine the capabilities of lncRNA growth arrest-specific transcript 5 (GAS5) on mice with depression-like behaviors and the mechanism of action., Methods: Fifty-six healthy mice were selected for model establishment. Morris water maze test and trapeze test were performed for evaluating learning and memory ability. The binding relationship between lncRNA GAS5 and microRNA-26a (miR-26a) and the target relationship between miR-26a and EGR1 were verified by dual-luciferase reporter gene assay. The apoptosis of neurons in the hippocampal CA1 region of mice was detected by TUNEL staining. The expression of inflammatory factors, lncRNA GAS5, miR-26a, early growth response gene 1 (EGR1), phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT) pathway- and apoptosis-related factors in hippocampal tissues was tested by RT-qPCR and western blot analysis., Results: miR-26a expression was down-regulated while EGR1 and lncRNA GAS5 expression were up-regulated in hippocampal tissues of mice with depression-like behaviors. LncRNA GAS5 specifically bound to miR-26a and miR-26a targeted EGR1. Silencing of lncRNA GAS5 curtailed the release of inflammatory factors and the apoptosis of hippocampal neuron of mice with depression-like behaviors. EGR1 suppressed PI3K/AKT pathway activation to promote the release of inflammatory factors and the apoptosis of hippocampal neurons in mice with depression-like behaviors., Conclusion: Our study provides evidence that silencing of lncRNA GAS5 could activate PI3K/AKT pathway to protect hippocampal neurons against damage in mice with depression-like behaviors by regulating the miR-26a/EGR1 axis., Competing Interests: Declaration of Competing Interest The authors declare there to be no conflicts of interest., (Copyright © 2020 Elsevier Inc. All rights reserved.)

The role that thyroid hormone deficiency plays in depression and synaptic plasticity in adults has only begun to be elucidated. This paper analyzes the possible link between depression and hypothyroidism in cognitive function alterations, using Wistar-Kyoto (WKY-an animal model of depression) rats and control Wistar rats under standard and thyroid hormone deficiency conditions (propylthiouracil administration-PTU). A weakening of memory processes in the WKY rats is shown behaviorally, and in the reduction of long-term potentiation (LTP) in the dentate gyrus (DG) and CA1 hippocampal regions. PTU administration decreased LTP and increased basal excitatory transmission in the DG in Wistar rats. A decrease in short-term synaptic plasticity is shown by the paired-pulse ratio measurement, occurring during hypothyroidism in DG and CA1 in WKY rats. Differences between the strains may result from decreases in the p-CaMKII, p-AKT, and the level of acetylcholine, while in the case of the co-occurrence of depression and hypothyroidism, an increase in the p-ERK1-MAP seemed to be important. Obtained results show that thyroid hormones are less involved in the inhibition of glutamate release and/or excitability of the postsynaptic neurons in WKY rats, which may indicate a lower sensitivity of the hippocampus to the action of thyroid hormones in depression.

Objective: Many antiseizure drugs (ASDs) act on voltage-dependent sodium channels, and the molecular basis of these effects is well established. In contrast, how ASDs act on the level of neuronal networks is much less understood., Methods: In the present study, we determined the effects of eslicarbazepine (S-Lic) on different types of inhibitory neurons, as well as inhibitory motifs. Experiments were performed in hippocampal slices from both sham-control and chronically epileptic pilocarpine-treated rats., Results: We found that S-Lic causes an unexpected reduction of feed-forward inhibition in the CA1 region at high concentrations (300 µM), but not at lower concentrations (100 µM). Concurrently, 300 but not 100 μM S-Lic significantly reduced maximal firing rates in putative feed-forward interneurons located in the CA1 stratum radiatum of sham-control and epileptic animals. In contrast, feedback inhibition was not inhibited by S-Lic. Instead, application of S-Lic, in contrast to previous data for other drugs like carbamazepine (CBZ), resulted in a lasting potentiation of feedback inhibitory post-synaptic currents (IPSCs) only in epileptic and not in sham-control animals, which persisted after washout of S-Lic. We hypothesized that this plasticity of inhibition might rely on anti-Hebbian potentiation of excitatory feedback inputs onto oriens-lacunosum moleculare (OLM) interneurons, which is dependent on Ca 2+ -permeable α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors. Indeed, we show that blocking Ca 2+ -permeable AMPA receptors completely prevents upmodulation of feedback inhibition., Significance: These results suggest that S-Lic affects inhibitory circuits in the CA1 hippocampal region in unexpected ways. In addition, ASD actions may not be sufficiently explained by acute effects on their target channels, rather, it may be necessary to take plasticity of inhibitory circuits into account., (© 2021 The Authors. Epilepsia published by Wiley Periodicals LLC on behalf of International League Against Epilepsy.)

Alzheimer's disease (AD) is a multifaceted neurodegenerative disorder characterized by progressive and irreversible cognitive decline, with no disease-modifying therapy until today. Spike timing-dependent plasticity (STDP) is a Hebbian form of synaptic plasticity, and a strong candidate to underlie learning and memory at the single neuron level. Although several studies reported impaired long-term potentiation (LTP) in the hippocampus in AD mouse models, the impact of amyloid-β (Aβ) pathology on STDP in the hippocampus is not known. Using whole cell patch clamp recordings in CA1 pyramidal neurons of acute transversal hippocampal slices, we investigated timing-dependent (t-) LTP induced by STDP paradigms at Schaffer collateral (SC)-CA1 synapses in slices of 6-month-old adult APP/PS1 AD model mice. Our results show that t-LTP can be induced even in fully developed adult mice with different and even low repeat STDP paradigms. Further, adult APP/PS1 mice displayed intact t-LTP induced by 1 presynaptic EPSP paired with 4 postsynaptic APs (6× 1:4) or 1 presynaptic EPSP paired with 1 postsynaptic AP (100× 1:1) STDP paradigms when the position of Aβ plaques relative to recorded CA1 neurons in the slice were not considered. However, when Aβ plaques were live stained with the fluorescent dye methoxy-X04, we observed that in CA1 neurons with their somata <200 µm away from the border of the nearest Aβ plaque, t-LTP induced by 6× 1:4 stimulation was significantly impaired, while t-LTP was unaltered in CA1 neurons >200 µm away from plaques. Treatment of APP/PS1 mice with the anti-inflammatory drug fingolimod that we previously showed to alleviate synaptic deficits in this AD mouse model did not rescue the impaired t-LTP. Our data reveal that overexpression of APP and PS1 mutations in AD model mice disrupts t-LTP in an Aβ plaque distance-dependent manner, but cannot be improved by fingolimod (FTY720) that has been shown to rescue conventional LTP in CA1 of APP/PS1 mice.

Stress may promote emotional and cognitive disturbances, which differ by sex. Adverse outcomes, including memory disturbances, are typically observed following chronic stress, but are now being recognized also after short events, including mass shootings, assault, or natural disasters, events that consist of concurrent multiple acute stresses (MAS). Prior work has established profound and enduring effects of MAS on memory in males. Here we examined the effects of MAS on female mice and probed the role of hormonal fluctuations during the estrous cycle on MAS-induced memory problems and the underlying brain network and cellular mechanisms. Female mice were impacted by MAS in an estrous cycle-dependent manner: MAS impaired hippocampus-dependent spatial memory in early-proestrous mice, characterized by high levels of estradiol, whereas memory of mice stressed during estrus (low estradiol) was spared. As spatial memory requires an intact dorsal hippocampal CA1, we examined synaptic integrity in mice stressed at different cycle phases and found a congruence of dendritic spine density and spatial memory deficits, with reduced spine density only in mice stressed during high estradiol cycle phases. Assessing MAS-induced activation of brain networks interconnected with hippocampus, we identified differential estrous cycle-dependent activation of memory- and stress-related regions, including the amygdala. Network analyses of the cross-correlation of fos expression among these regions uncovered functional connectivity that differentiated impaired mice from those not impaired by MAS. In conclusion, the estrous cycle modulates the impact of MAS on spatial memory, and fluctuating physiological levels of sex hormones may contribute to this effect. SIGNIFICANCE STATEMENT: Effects of stress on brain functions, including memory, are profound and sex-dependent. Acute stressors occurring simultaneously result in spatial memory impairments in males, but effects on females are unknown. Here we identified estrous cycle-dependent effects of such stresses on memory in females. Surprisingly, females with higher physiological estradiol experienced stress-induced memory impairment and a loss of underlying synapses. Memory- and stress-responsive brain regions interconnected with hippocampus were differentially activated across high and low estradiol mice, and predicted memory impairment. Thus, at functional, network, and cellular levels, physiological estradiol influences the effects of stress on memory in females, providing insight into mechanisms of prominent sex differences in stress-related memory disorders, such as post-traumatic stress disorder., (Copyright © 2021 Hokenson et al.)

Dravet syndrome (Dravet) is a rare, severe childhood-onset epilepsy, caused by heterozygous de novo mutations in the SCN1A gene, encoding for the alpha subunit of the voltage-gated sodium channel, Na V 1.1. The neuronal basis of Dravet is debated, with evidence favoring reduced function of inhibitory neurons, that might be transient, or enhanced activity of excitatory cells. Here, we utilized Dravet mice to trace developmental changes in the hippocampal CA1 circuit, examining the properties of CA1 horizontal stratum-oriens (SO) interneurons and pyramidal neurons, through the pre-epileptic, severe and stabilization stages of Dravet. Our data indicate that reduced function of SO interneurons persists from the pre-epileptic through the stabilization stages, with the greatest functional impairment observed during the severe stage. In contrast, opposing changes were detected in CA1 excitatory neurons, with a transient increase in their excitability during the pre-epileptic stage, followed by reduced excitability at the severe stage. Interestingly, alterations in the function of both inhibitory and excitatory neurons were more pronounced when the firing was evoked by synaptic stimulation, implying that loss of function of Na V 1.1 may also affect somatodendritic functions. These results suggest a complex pathophysiological mechanism and indicate that the developmental trajectory of this disease is governed by reciprocal functional changes in both excitatory and inhibitory neurons., (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)

Objective: Neuromodulatory anterior thalamic deep brain stimulation (DBS) is an effective therapy for intractable epilepsy, but few patients achieve complete seizure control with thalamic DBS. Other stimulation sites may be considered for anti-seizure DBS. We investigated bilateral low-frequency stimulation of the endopiriform nuclei (LFS-EPN) to control seizures induced by intracortically implanted cobalt wire in rats., Methods: Chronic epilepsy was induced by cobalt wire implantation in the motor cortex unilaterally. Bipolar-stimulating electrodes were implanted into the EPN bilaterally. Continuous electroencephalography (EEG) was recorded using electrodes placed into bilateral motor cortex and hippocampus CA1 areas. Spontaneous seizures were monitored by long-term video-EEG, and behavioral seizures were classified based on the Racine scale. Continuous 1-Hz LFS-EPN began on the third day after electrode implantation and was controlled by a multi-channel stimulator. Stimulation continued until the rats had no seizures for three consecutive days., Results: Compared with the control and sham stimulation groups, the LFS-EPN group experienced significantly fewer seizures per day and the mean Racine score of seizures was lower due to fewer generalized seizures. Ictal discharges at the epileptogenic site had significantly reduced theta band power in the LFS-EPN group compared to the other groups., Interpretation: Bilateral LFS-EPN attenuates cobalt wire-induced seizures in rats by modulating epileptic networks. Reduced ictal theta power of the EEG broadband spectrum at the lesion site may be associated with the anti-epileptogenic mechanism of LFS-EPN. Bilateral EPN DBS may have therapeutic applications in human partial epilepsies., (© 2020 The Authors. Annals of Clinical and Translational Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.)

Aim: To clarify whether long-term potentiation (LTP) is the mechanism underpinning mnemonic processes. Mathrials and methods: We studied LTP in hippocampal slices from rats whose spatial memory deficit was produced by either olfactory bulbectomy (OBX) or pretreatment with an ergot alkaloid, agroclavine. OBX is accompanied by cholinergic system inhibition whereas agroclavine predominantly activates dopaminergic mediation. The both have been shown to be involved in learning/memory and LTP mechanisms. Results: In OBX- vs. sham-operated rat, we have revealed significant reduction of LTP in hippocampal CA1 region. In contrast, no LTP differences in agroclavine- vs. vehicle-treated rats were observed. Conclusions: These results demonstrate that LTP expression in the hippocampus is dependent on the origin of spatial memory impairment. Furthermore, they suggest that pharmacological and neurodegenerative models of AD might be useful approach for discovery of both AD mechanisms and mixed pathology dementias.

Cannabidiol (CBD) is a major phytocannabinoid in Cannabis sativa. CBD is being increasingly reported as a clinical treatment for neurological diseases. Febrile seizure is one of the most common diseases in children with limited therapeutic options. We investigated possible therapeutic effects of CBD on febrile seizures and the underlying mechanism. Use of a hyperthermia-induced seizures model revealed that CBD significantly prolonged seizure latency and reduced the severity of thermally-induced seizures. Hippocampal neuronal excitability was significantly decreased by CBD. Further, CBD significantly reduced the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) mediated evoked excitatory postsynaptic currents (eEPSCs) and the amplitude and frequency of miniature EPSCs (mEPSCs). Furthermore, CBD significantly accelerated deactivation in GluA1 and GluA2 subunits. Interestingly, CBD slowed receptor recovery from desensitization of GluA1, but not GluA2. These effects on kinetics were even more prominent when AMPAR was co-expressed with γ-8, the high expression isoform 8 of transmembrane AMPAR regulated protein (TARPγ8) in the hippocampus. The inhibitory effects of CBD on AMPAR depended on its interaction with the distal N-terminal domain of GluA1/GluA2. CBD inhibited AMPAR activity and reduced hippocampal neuronal excitability, thereby improving the symptoms of febrile seizure in mice. The putative binding site of CBD in the N-terminal domain of GluA1/GluA2 may be a drug target for allosteric gating modulation of AMPAR., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Microgravity can cause body fluids to accumulate in the brain, resulting in brain damage. There are few studies that focus on the detection of electrophysiological signals in simulated microgravity rats, and the precise mechanisms are unknown. In this study, a new device was established to investigate the influence of microgravity on hippocampal neurons. A 16-channel microelectrode array was fabricated for in vivo multichannel electrophysiological recordings. In these experiments, microelectrode array was inserted into normal, 28-day tail suspension model, and 3-day recovered after modulation rats to record electrophysiological signals in the CA1 and DG regions of the hippocampus. Through analysis of electrophysiological signals, we obtained the following results: (1) spike signals of model rats sporadically showed brief periods of suspension involving most of the recorded neurons, which corresponded to slow and smooth peaks in local field potentials. For model rats, the firing rate was reduced, and the power in the frequency spectrum was concentrated in the slow frequency band (0-1 Hz); (2) after the detected hippocampal cells divided into pyramidal cells and interneurons, the spike duration of pyramidal cells showed remarkable latency, and their average firing rates showed a more significant decrease compared to interneurons. These results demonstrate that the hippocampal neurons were impaired after modulation in the cellular dimension, and pyramidal cells were more susceptible than interneurons., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier Inc. All rights reserved.)

This study examined the effects of delivery mode on the response to inflammatory pulpal pain and pain-induced changes in cognitive performance in adult rats. Experiments were done on rats born by vaginal or caesarean section (C-section) delivery. Dental pulp was irritated by intradental capsaicin (100 μg) application and then nociceptive scores were recorded for 40 min. Spatial and passive avoidance learning and memory were assessed using the Morris water maze (MWM) and shuttle box tools, respectively. Additionally, in vivo recording of field excitatory postsynaptic potential (fEPSP) in the CA1 of the hippocampus was used to verify synaptic plasticity. Capsaicin produced more significant nociceptive behavior in vaginally delivered rats compared to C-section rats ( P < 0.01). C-section-delivered rats show better performance in both MWM and shuttle box tests. Likewise, C-section rats had greater fEPSP slopes compared to the vaginally delivered group ( P < 0.05). Capsaicin impairs cognitive performance in rats born by each delivery route. However, capsaicin effects were more significant in rats delivered vaginally than by C-section. Overall, C-section-delivered rats show lower sensitivity to capsaicin-evoked pulpal nociception and better cognitive performance than vaginally delivered rats. These effects are in part mediated by reduced neuroinflammation and enhanced neuronal synaptic plasticity following C-section delivery.

Patients with Alzheimer's disease (AD) suffer from spatial memory impairment and wandering behavior, but the brain circuit mechanisms causing such symptoms remain largely unclear. In healthy brains, spatially tuned hippocampal place cells and entorhinal grid cells exhibit distinct spike patterns in different environments, a circuit function called "remapping." We tested remapping in amyloid precursor protein knockin (APP-KI) mice with impaired spatial memory. CA1 neurons, including place cells, showed disrupted remapping, although their spatial tuning was only mildly diminished. Medial entorhinal cortex (MEC) neurons severely lost their spatial tuning and grid cells were almost absent. Fast gamma oscillatory coupling between the MEC and CA1 was also impaired. Mild disruption of MEC grid cells emerged in younger APP-KI mice, although the spatial memory and CA1 remapping of the animals remained intact. These results point to remapping impairment in the hippocampus, possibly linked to grid cell disruption, as circuit mechanisms underlying spatial memory impairment in AD., Competing Interests: Declaration of Interests The authors declare no competing interests., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Long-lasting confusion and memory difficulties during the postictal state remain a major unmet problem in epilepsy that lacks pathophysiological explanation and treatment. We previously identified that long-lasting periods of severe postictal hypoperfusion/hypoxia, not seizures per se, are associated with memory impairment after temporal lobe seizures. While this observation suggests a key pathophysiological role for insufficient energy delivery, it is unclear how the networks that underlie episodic memory respond to vascular constraints that ultimately give rise to amnesia. Here, we focused on cellular/network level analyses in the CA1 of hippocampus in vivo to determine if neural activity, network oscillations, synaptic transmission, and/or synaptic plasticity are impaired following kindled seizures. Importantly, the induction of severe postictal hypoperfusion/hypoxia was prevented in animals treated by a COX-2 inhibitor, which experimentally separated seizures from their vascular consequences. We observed complete activation of CA1 pyramidal neurons during brief seizures, followed by a short period of reduced activity and flattening of the local field potential that resolved within minutes. During the postictal state, constituting tens of minutes to hours, we observed no changes in neural activity, network oscillations, and synaptic transmission. However, long-term potentiation of the temporoammonic pathway to CA1 was impaired in the postictal period, but only when severe local hypoxia occurred. Lastly, we tested the ability of rats to perform object-context discrimination, which has been proposed to require temporoammonic input to differentiate between sensory experience and the stored representation of the expected object-context pairing. Deficits in this task following seizures were reversed by COX-2 inhibition, which prevented severe postictal hypoxia. These results support a key role for hypoperfusion/hypoxia in postictal memory impairments and identify that many aspects of hippocampal network function are resilient during severe hypoxia except for long-term synaptic plasticity.

Chronic early life stress (ELS) increases vulnerability to psychopathologies and cognitive deficits in adulthood by disrupting the function of related neural circuits. However, whether this disruption emerges early in the developing brain remains largely unexplored. In the current study, using an established limited-bedding and nesting model of ELS in postnatal day (P)2-10 mice, we provide direct evidence that ELS caused early modification of hippocampal glutamatergic synapses in the developing brain. We demonstrated that ELS induced rapid enhancement of AMPA receptor function in hippocampal CA1 pyramidal neurons through a postsynaptic mechanism, and importantly, this was associated with premature unsilencing of NMDA receptor-only silent hippocampal synapses. These results suggest that potentiation of AMPAR function may represent an early mediator of ELS-induced alterations of neural networks in the developing brain and may potentially contribute to subsequent cognitive impairments later in life. NEW & NOTEWORTHY Early life stress (ELS) is known to increase the risk of later life cognitive deficits by disrupting neural circuit function. However, whether this disruption emerges early in the developing brain remains largely unexplored. The current study presents direct evidence that ELS prematurely unsilences hippocampal synapses to enhance AMPA receptor functions in a limited-bedding and nesting model, revealing an early mediator of ELS-induced neural circuit reorganizations.