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Emerging evidence indicates that the pathogenesis of Alzheimer's disease (AD) is not confined to neuronal disruptions but robustly communicates with the brain's immune system. Genome-wide analysis suggests that several genes, which increase the risk for AD, encode for factors that regulate the glial clearance of misfolded proteins and the inflammatory reaction. This study reappraises the amyloid hypothesis by focusing on the impact of neuroinflammation in a beta-amyloid model of AD, how this possibly exacerbates the disease's progression, and the correlation between genes regulating neuroinflammation (CD33 and TREM2) with post-training recall. Male Sprague-Dawley rats were used for this study, randomly divided into a vehicle group of rats (n = 40) that were infused with phosphate-buffered saline (PBS) and an Aβ (1-42) group (n = 40) that were infused with the neurotoxin Aβ (1-42) peptide. Fear conditioning test (FCT) to assess fear memory was conducted pre and post-lesion. The polymerase chain reaction was performed to determine the expression levels of CD33 and TREM2 genes. Our results show that Aβ (1-42) lesion of the rat CA1 hippocampal subregion significantly reduces contextual fear memory, and this reduction was exacerbated as the post-lesion days increased. We also observed an increase in the expression levels of CD33 and TREM2 genes in the Aβ (1-42) lesioned groups compared to their corresponding vehicle groups. Taken together, the behavioral and gene expression data provide inferential evidence that Aβ (1-42) infusion impairs contextual memory by disrupting cellular pattern separation processes in the hippocampus, thus linking neuroinflammation to specific neural circuit disruption and cognitive deficit., Competing Interests: Declaration of Competing Interest The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Epileptogenesis is a dynamical process that involves synaptic plasticity changes such as synaptic reorganization of excitatory and inhibitory systems and axonal sprouting in the hippocampus, which is one of the most studied epileptogenic regions in the brain. However, the early events that trigger these changes are not understood well. We investigated short-term and long-term synaptic plasticity parameters and T-type Ca 2+ channel activity changes in the early phase of a rat kindling model. Chronic pentylenetetrazole (PTZ) application was used in order to induce the kindling process in rats. The recordings were obtained from hippocampal slices in the CA1 region at 25th day of PTZ application. Tetraethylammonium was used in order to induce long-term potentiation and T-type Ca 2+ channel activity was assessed in the presence of mibefradil. We found that tetraethylammonium-induced long-term potentiation was not prevented by mibefradil in the kindling group in contrast to control group. We also found an increase in paired-pulse ratios in the PTZ-applied group. Our findings indicate an increase in the "T-type Ca 2+ channel component of LTP" in the kindling group, which may be an early mechanism in epileptogenesis., (© 2020 Wiley Periodicals, Inc.)

Rett syndrome (RTT) is a severe neurodevelopmental disease caused by mutations in the methyl-CpG binding protein 2 ( MECP2 ) gene. Although altered interneuron development and function are clearly demonstrated in RTT mice, a particular mode of inhibition, tonic inhibition, has not been carefully examined. We report here that tonic inhibition is significantly reduced in pyramidal neurons in the CA1 region of the hippocampus in mice where Mecp2 is deleted either in all cells or specifically in astrocytes. Since no change is detected in the level of GABA receptors, such a reduction in tonic inhibition is likely a result of decreased ambient GABA level in the extracellular space. Consistent with this explanation, we observed increased expression of a GABA transporter, GABA transporter 3 (GAT3), in the hippocampus of the Mecp2 KO mice, as well as a corresponding increase of GAT3 current in hippocampal astrocytes. These phenotypes are relevant to RTT because pharmacological blockage of GAT3 can normalize tonic inhibition and intrinsic excitability in CA1 pyramidal neurons, and rescue the phenotype of increased network excitability in acute hippocampal slices from the Mecp2 KO mice. Finally, chronic administration of a GAT3 antagonist improved a composite symptom score and extended lifespan in the Mecp2 KO mice. Only male mice were used in this study. These results not only advance our understanding of RTT etiology by defining a new neuronal phenotype and revealing how it can be influenced by astrocytic alterations, but also reveal potential targets for intervention. SIGNIFICANCE STATEMENT Our study reports a novel phenotype of reduced tonic inhibition in hippocampal CA1 pyramidal neurons in the Rett syndrome mice, reveal a potential mechanism of increased GABA transporter expression/activity in the neighboring astrocytes, describe a disease-relevant consequence in hyperexcitability, and provide preliminary evidence that targeting this phenotype may slow down disease progression in Rett syndrome mice. These results help our understanding of the disease etiology and identify a new therapeutic target for treating Rett syndrome., (Copyright © 2020 the authors.)

Cardiac arrest causes neuronal damage and functional impairments that can result in learning/memory dysfunction after ischemia. We previously identified a saturated fatty acid (stearic acid methyl ester, SAME) that was released from the superior cervical ganglion (sympathetic ganglion). The function of stearic acid methyl ester is currently unknown. Here, we show that SAME can inhibit the detrimental effects of global cerebral ischemia (i.e. cardiac arrest). Treatment with SAME in the presence of asphyxial cardiac arrest (ACA) revived learning and working memory deficits. Similarly, SAME-treated hippocampal slices after oxygen-glucose deprivation inhibited neuronal cell death. Moreover, SAME afforded neuroprotection against ACA in the CA1 region of the hippocampus, reduced ionized calcium-binding adapter molecule 1 expression and inflammatory cytokines/chemokines, with restoration in mitochondria respiration. Altogether, we describe a unique and uncharted role of saturated fatty acids in the brain that may have important implications against cerebral ischemia., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Inflammatory pain is commonly associated with cognitive impairment. However, its molecular mechanisms are poorly understood. Thus, this study was conducted to investigate the molecular mechanisms of behavioral changes associated with inflammatory pain. Briefly, 36 Wistar rats were randomly divided into two main groups: CFA group treated with 100 μL of Complete Freunds' Adjuvant (CFA) and CFA + Minocycline group treated with 100 μL of CFA+40 mg/kg/day of minocycline). After that, each group was divided into three subgroups based on different time points of the study. The pain was induced using CFA and subsequent behavioral changes (i.e., hyperalgesia and learning and spatial memory) were analyzed by the Morris Water Maze (MWM) task and Radiant Heat. Then, the cellular and molecular changes were assessed using Western Blotting, Immunohistochemistry, and Terminal deoxynucleotidyl transferase dUTP Nick End Labeling (TUNEL) techniques. Results of the study indicated that CFA-induced pain impaired spatial learning and memory functions. Studying the cellular changes showed that persistent inflammatory pain increased the microglial activity in CA1 and Dentate Gyrus (DG) regions. Furthermore, an increase was observed in the percentage of TUNEL-positive cells. Also, pro-Brain-Derived Neurotrophic Factor (BDNF)/BDNF ratio, Caspase3, and Receptor-Interacting Protein kinase 3 (RIP3) levels increased in the rats' hippocampus following induction of persistent inflammatory pain. These changes were reversed following the cessation of pain as well as the injection of minocycline. Taking together, the results of the current study for the first time revealed that an increase in the microglia dependent proBDNF/BDNF ratio following persistent inflammatory pain leads to cell death of the CA1 and DG neurons that subsequently causes a cognitive deficit in the learning and spatial memory functions., Competing Interests: Declaration of Competing Interest The authors declare that there are no conflicts of interest., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Channelopathies are implicated in Fragile X syndrome (FXS), yet the dysfunction of a particular ion channel varies with cell type. We previously showed that HCN channel function is elevated in CA1 dendrites of the fmr1 -/y mouse model of FXS, but reduced in L5 PFC dendrites. Using male mice, we tested whether Fragile X Mental Retardation Protein (FMRPO), the protein whose absence causes FXS, differentially modulates HCN channels in CA1 versus L5 PFC dendrites. Using a combination of viral tools, intracellular peptide, and dendritic electrophysiology, we found that FMRP regulates HCN channels via a cell-autonomous protein-protein interaction. Virally expressed FMRP restored WT HCN channel-related dendritic properties in both CA1 and L5 neurons. Rapid intracellular perfusion of the non-mRNA binding N-terminal fragment, FMRP 1-298 , similarly restored dendritic function. In support of a protein-protein interaction, we found that FMRP associated with HCN-TRIP8b complexes in both hippocampus and PFC. Finally, voltage-clamp recordings showed that FMRP modulated I h by regulating the number of functional dendritic HCN channels rather than individual channel properties. Together, these represent three novel findings as to the nature of the changes in dendritic function in CA1 and PFC neurons based on the presence or absence of FMRP. Moreover, our findings provide evidence that FMRP can regulate its targets in opposite directions depending upon the cellular milieu. SIGNIFICANCE STATEMENT Changes in dendritic function, and voltage-gated ion channels in particular, are increasingly the focus of neurological disorders. We, and others, previously identified cell type-specific channelopathies in a mouse of model of Fragile X syndrome. The present study shows that replacing Fragile X Mental Retardation Protein, which is absent in Fragile X syndrome, in adult CA1 and L5 PFC neurons regulates the number of functional dendritic HCN channels in a cell type-specific manner. These results suggest that Fragile X Mental Retardation Protein regulates dendritic HCN channels via a cell-autonomous protein--protein mechanism., (Copyright © 2020 the authors.)

Astrocytes play essential roles in brain function by supporting synaptic connectivity and associated circuits. How these roles are regulated by transcription factors is unknown. Moreover, there is emerging evidence that astrocytes exhibit regional heterogeneity, and the mechanisms controlling this diversity remain nascent. Here, we show that conditional deletion of the transcription factor nuclear factor I-A (NFIA) in astrocytes in the adult brain results in region-specific alterations in morphology and physiology that are mediated by selective DNA binding. Disruptions in astrocyte function following loss of NFIA are most pronounced in the hippocampus, manifested by impaired interactions with neurons, coupled with diminution of learning and memory behaviors. These changes in hippocampal astrocytes did not affect basal neuronal properties but specifically inhibited synaptic plasticity, which is regulated by NFIA in astrocytes through calcium-dependent mechanisms. Together, our studies reveal region-specific transcriptional dependencies for astrocytes and identify astrocytic NFIA as a key transcriptional regulator of hippocampal circuits., Competing Interests: Declaration of Interests The authors declare no competing interests., (Copyright © 2020 Elsevier Inc. All rights reserved.)

The ubiquitin ligase, Ube3a, plays important roles in brain development and functions, since its deficiency results in Angelman Syndrome (AS) while its over-expression increases the risk for autism. We previously showed that the lack of Ube3a-mediated ubiquitination of the Ca 2+ -activated small conductance potassium channel, SK2, contributes to impairment of synaptic plasticity and learning in AS mice. Synaptic SK2 levels are also regulated by protein kinase A (PKA), which phosphorylates SK2 in its C-terminal domain, facilitating its endocytosis. Here, we report that PKA activation restores theta burst stimulation (TBS)-induced long-term potentiation (LTP) in hippocampal slices from AS mice by enhancing SK2 internalization. While TBS-induced SK2 endocytosis is facilitated by PKA activation, SK2 recycling to synaptic membranes after TBS is inhibited by Ube3a. Molecular and cellular studies confirmed that phosphorylation of SK2 in the C-terminal domain increases its ubiquitination and endocytosis. Finally, PKA activation increases SK2 phosphorylation and ubiquitination in Ube3a-overexpressing mice. Our results indicate that, although both Ube3a-mediated ubiquitination and PKA-induced phosphorylation reduce synaptic SK2 levels, phosphorylation is mainly involved in TBS-induced endocytosis, while ubiquitination predominantly inhibits SK2 recycling. Understanding the complex interactions between PKA and Ube3a in the regulation of SK2 synaptic levels might provide new platforms for developing treatments for AS and various forms of autism.

Sleep oscillations in the neocortex and hippocampus are critical for the integration of new memories into stable generalized representations in neocortex. However, the role of the thalamus in this process is poorly understood. To determine the thalamic contribution to non-REM oscillations (sharp-wave ripples, SWRs; slow/delta; spindles), we recorded units and local field potentials (LFPs) simultaneously in the limbic thalamus, mPFC, and CA1 in rats. We report that the cycles of neocortical spindles provide a key temporal window that coordinates CA1 SWRs with sparse but consistent activation of thalamic units. Thalamic units were phase-locked to delta and spindles in mPFC, and fired at consistent lags with other thalamic units within spindles, while CA1 units that were active during spatial exploration were engaged in SWR-coupled spindles after behavior. The sparse thalamic firing could promote an incremental integration of recently acquired memory traces into neocortical schemas through the interleaved activation of thalamocortical cells., Competing Interests: CV, MW No competing interests declared, (© 2020, Varela and Wilson.)

Epilepsy is a common neurological disorder characterized by recurrent epileptic seizures. The cause of most cases of epilepsy is unknown. Although changes of calcium events in a single brain region during seizures have been reported before, there have been few studies on relations between calcium events of two different brain regions and epileptic behaviors in freely moving mice. To analyze calcium events simultaneously recorded in hippocampal CA1 (CA1) and primary motor cortex M1 (M1), and to explore their relations to various epileptic behaviors in freely moving epileptic models. Epileptic models were induced by Kainic acid (KA), a direct agonist of glutamatergic receptor, on adult male C57/BL6J mice. Calcium events of neurons and glia in CA1 and M1 labeled by a calcium indicator dye were recorded simultaneously with a multi-channel fiber photometry system. Three typical types of calcium events associated with KA-induced seizures were observed, including calcium baseline-rising, cortical spreading depression (CSD) and calcium flashing with a steady rate. Our results showed that the calcium baseline-rising occurred in CA1 was synchronized with that in M1, but the CSD waves were not. However, synchronization of calcium flashing in the two areas was uncertain, because it was only detected in CA1. We also observed that different calcium events happened with different epileptic behaviors. Baseline-rising events were accompanied by clonus of forelimbs or trembling, CSD waves were closely related to head movements (15 out of 18, 6 mice). Calcium flashing occurred definitely with drastic convulsive motor seizures (CMS, 6 mice). The results prove that the synchronization of calcium event exists in CA1 and M1, and different calcium events are related with different seizure behaviors. Our results suggest that calcium events involve in the synchronization of neural network and behaviors in epilepsy.

Amyloid-β precursor protein (APP) is central to the pathogenesis of Alzheimer's disease, yet its physiological functions remain incompletely understood. Previous studies had indicated important synaptic functions of APP and the closely related homologue APLP2 in excitatory forebrain neurons for spine density, synaptic plasticity, and behavior. Here, we show that APP is also widely expressed in several interneuron subtypes, both in hippocampus and cortex. To address the functional role of APP in inhibitory neurons, we generated mice with a conditional APP/APLP2 double knockout (cDKO) in GABAergic forebrain neurons using DlxCre mice. These DlxCre cDKO mice exhibit cognitive deficits in hippocampus-dependent spatial learning and memory tasks, as well as impairments in species-typic nesting and burrowing behaviors. Deficits at the behavioral level were associated with altered neuronal morphology and synaptic plasticity Long-Term Potentiation (LTP). Impaired basal synaptic transmission at the Schafer collateral/CA1 pathway, which was associated with altered compound excitatory/inhibitory synaptic currents and reduced action potential firing of CA1 pyramidal cells, points to a disrupted excitation/inhibition balance in DlxCre cDKOs. Together, these impairments may lead to hippocampal dysfunction. Collectively, our data reveal a crucial role of APP family proteins in inhibitory interneurons to maintain functional network activity., (© The Author(s) 2020. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Potentiation of N-methyl-D-aspartate receptor (NMDAR)-mediated excitatory synaptic plasticity around 1 h after brief exposure to anoxia/aglycemia is called ischemic long-term potentiation (iLTP), which is considered a pathological form of synaptic response during the early phase of ischemic stroke. It is known that GABAergic inhibitory transmission is also an important molecular process involved in synaptic plasticity and learning memory. However, whether GABAergic transmission is involved in iLTP and early-phase plasticity in ischemic stroke remains unknown. In this study, iLTP was found to be induced in the hippocampal Schaffer-collateral pathway by exposure to oxygen glucose deprivation (OGD). Western blot analysis was conducted to analyze excitatory synaptic receptors and inhibitory synaptic receptors following OGD. The β3 subunit of the GABA A receptor (GABA A R) was markedly reduced, whereas the GluN2B subunit of the NMDAR was increased in the hippocampal area in the OGD group. Using extracellular recording, we demonstrated that application of GABA A R agonist midazolam could abolish the hippocampal iLTP. Moreover, midazolam had no significant effect on the increase in NMDAR subunit GluN2B, but ameliorated the reduction in the β3 subunit of GABA A R after OGD. In summary, our results indicated that hippocampal GABA A R reduction promoted synaptic potentiation after OGD. Activation of GABAergic inhibitory transmission function could inhibit iLTP; thus, modulation of GABAergic function is a protective treatment method in the acute phase of synaptic plasticity in ischemic stroke., 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.)

Wistar Audiogenic Rats (WARs) are genetically susceptible to sound-induced seizures that start in the brainstem and, in response to repetitive stimulation, spread to limbic areas, such as hippocampus. Analysis of the distribution of interevent intervals of GABAergic inhibitory postsynaptic currents (IPSCs) in CA1 pyramidal cells showed a monoexponential trend in Wistar rats, suggestive of a homogeneous population of synapses, but a biexponential trend in WARs. Based on this, we hypothesize that there are two populations of GABAergic synaptic release sites in CA1 pyramidal neurons from WARs. To address this hypothesis, we used a well-established neuronal computational model of a CA1 pyramidal neuron previously developed to replicate physiological properties of these cells. Our simulations replicated the biexponential trend only when we decreased the release frequency of synaptic currents by a factor of six in at least 40% of distal synapses. Our results suggest that almost half of the GABAergic synapses of WARs have a drastically reduced spontaneous release frequency. The computational model was able to reproduce the temporal dynamics of GABAergic inhibition that could underlie susceptibility to the spread of seizures.

Herein field recordings were utilized to test the effects of a transient period of pentylenetetrazol (PTZ) treatment on theta-burst long-term potentiation (LTP) at the Schaffer collateral-CA1 synapses as well as RT-PCR was used to investigate the effects of the combination of the pharmacological treatment and the theta-burst LTP induction on the expression of NMDA subunit mRNA in hippocampal slices. The slope of field excitatory postsynaptic potential (fEPSP) was unaffected while the population spike amplitude and area were increased by a transient period of PTZ treatment (3 mM, 10 min). After a theta burst, a brief PTZ exposure can lead to an enhancement of LTP as documented by fEPSP recording. The effect can be blocked by a selective NMDA receptor antagonist DL-AP5. An increase in the expression of GluN2B and GluN2A subunit mRNAs was also shown due to the combined treatment. The results indicate that the combined treatment increases the degree of NMDA-dependent LTP and are in accord with literature data on the subunit alterations of the hippocampal NMDA receptors. Moreover, our experimental paradigm can be used as a new approach to study the relevance of LTP-like phenomena and epileptic mechanisms.

HCN channels regulate excitability and rhythmicity in the hippocampal CA1 pyramidal cells. Perturbation in the HCN channel current (I h ) is associated with neuropsychiatric disorders, such as autism spectrum disorders. Recently, protein arginine methyltransferase 7 (PRMT7) was shown to be highly expressed in the hippocampus, including the CA1 region. However, the physiological function of PRMT7 in the CA1 neurons and the relationship to psychiatric disorders are unclear. Here we showed that PRMT7 knockout (KO) mice exhibit hyperactivity and deficits in social interaction. The firing frequency of the CA1 neurons in the PRMT7 KO mice was significantly higher than that in the wild-type (WT) mice. Compared with the WT CA1 neurons, the PRMT7 KO CA1 neurons showed a more hyperpolarized resting potential and a higher input resistance, which were occluded by the I h -current inhibitor ZD7288; these findings were consistent with the decreased I h and suggested the contribution of I h -channel dysfunction to the PRMT7 KO phenotypes. The HCN1 protein level was decreased in the CA1 region of the PRMT7 KO mice in conjunction with a decrease in the expression of Shank3, which encodes a core scaffolding protein for HCN channel proteins. A brief application of the PRMT7 inhibitor DS437 did not reproduce the phenotype of the PRMT7 KO neurons, further indicating that PRMT7 regulates I h by controlling the channel number rather than the open probability. Moreover, shRNA-mediated PRMT7 suppression reduced both the mRNA and protein levels of SHANK3, implying that PRMT7 deficiency might be responsible for the decrease in the HCN protein levels by altering Shank3 expression. These findings reveal a key role for PRMT7 in the regulation of HCN channel density in the CA1 pyramidal cells that may be amenable to pharmacological intervention for neuropsychiatric disorders.

Human immunodeficiency virus (HIV)-1 transactivator of transcription protein (Tat) is a viral protein that promotes transcription of the HIV genome and possesses cell-signaling properties. Long-term exposure of central nervous system (CNS) tissue to HIV-1 Tat is theorized to contribute to HIV-associated neurodegenerative disorder (HAND). In the current study, we sought to directly evaluate the effect of HIV-1 Tat expression on the intrinsic electrophysiological properties of pyramidal neurons located in layer 2/3 of the medial prefrontal cortex and in area CA1 of the hippocampus. Toward that end, we drove Tat expression with doxycycline (100 mg·kg -1 ·day -1 ip) in inducible Tat (iTat) transgenic mice for 7 days and then performed single-cell electrophysiological studies in acute tissue slices made through the prefrontal cortex and hippocampus. Control experiments were performed in doxycycline-treated G-tg mice, which retain the tetracycline-sensitive promoter but do not express Tat. Our results indicated that the predominant effects of HIV-1 Tat expression are excitatory in medial prefrontal cortical pyramidal neurons yet inhibitory in hippocampal pyramidal neurons. Notably, in these two populations, HIV-1 Tat expression produced differential effects on neuronal gain, membrane time constant, resting membrane potential, and rheobase. Similarly, we also observed distinct effects on action potential kinetics and afterhyperpolarization, as well as on the current-voltage relationship in subthreshold voltage ranges. Collectively, these data provide mechanistic evidence of complex and region-specific changes in neuronal physiology by which HIV-1 Tat protein may promote cognitive deficits associated with HAND. NEW & NOTEWORTHY We drove expression of human immunodeficiency virus (HIV)-1 transactivator of transcription protein (Tat) protein in inducible Tat (iTat) transgenic mice for 7 days and then examined the effects on the intrinsic electrophysiological properties of pyramidal neurons located in the medial prefrontal cortex (mPFC) and in the hippocampus. Our results reveal a variety of specific changes that promote increased intrinsic excitability of layer II/III mPFC pyramidal neurons and decreased intrinsic excitability of hippocampal CA1 pyramidal neurons, highlighting both cell type and region-specific effects.

To understand the pathogenesis of specific neuronal circuit dysfunction in Alzheimer's disease (AD), we investigated the fate of three subclasses of "modulatory interneurons" in hippocampal CA1 using the AppNL-F/NL-F knock-in mouse model of AD. Cholecystokinin- and somatostatin-expressing interneurons were aberrantly hyperactive preceding the presence of the typical AD hallmarks: neuroinflammation and amyloid-β (Aβ) accumulation. These interneurons showed an age-dependent vulnerability to Aβ penetration and a reduction in density and coexpression of the inhibitory neurotransmitter GABA synthesis enzyme, glutamic acid decarboxylase 67 (GAD67), suggesting a loss in their inhibitory function. However, calretinin (CR) interneurons-specialized to govern only inhibition, showed resilience to Aβ accumulation, preservation of structure, and displayed synaptic hyperinhibition, despite the lack of inhibitory control of CA1 excitatory pyramidal cells from midstages of the disease. This aberrant inhibitory homeostasis observed in CA1 CR cells and pyramidal cells was "normalized" by blocking P2Y1 purinoreceptors, which were "upregulated" and strongly expressed in CR cells and astrocytes in AppNL-F/NL-F mice in the later stages of AD. In summary, AD-associated cell-type selective destruction of inhibitory interneurons and disrupted inhibitory homeostasis rectified by modulation of the upregulated purinoreceptor system may serve as a novel therapeutic strategy to normalize selective dysfunctional synaptic homeostasis during pathogenesis of AD., (© The Author(s) 2019. Published by Oxford University Press.)

Introduction: Deep brain stimulation (DBS) in drug-resistant epilepsy has been applied to several brain targets. However, its exact mechanism of action is not known, and the diversity of targets makes it difficult to know the degree of evidence that supports its use., Development: A review of the literature on DBS for drug-resistant epilepsy was conducted. The efficacy of DBS in drug-resistant epilepsy seems to be mediated by a desynchronisation of neuronal activity at the epileptogenic focus or a modulation of the «circuitopathies» that exist in epilepsy, depending on the target. In DBS multiple cortical and subcortical structures have been used, but class I evidence exists only for DBS of the anterior nucleus of the thalamus., Conclusions: DBS in epilepsy is still under investigation, with class I evidence for DBS of the anterior nucleus of the thalamus. The rest of the targets have yielded variable results that must be confirmed with randomised designs in larger series.

Sleep is a circadian rhythm that is modulated by endogenous circadian clock located in the suprachiasmatic nucleus (SCN). Sleep modulates memory acquisition and promotes memory consolidation. Studies have shown that sleep deprivation (SD) impairs different types of memory including passive avoidance. Furthermore, the hippocampus plays a significant role in modulating passive avoidance memory. On the other hand, 5-HT4 receptors are expressed in the hippocampus and involved in learning and memory processes. In this study, we aimed to investigate the role of CA1 hippocampal 5-HT4 receptors in memory acquisition impairment induced by total sleep deprivation (TSD: 24 h) and REM sleep deprivation (RSD: 24 h). The water box apparatus was used to induce TSD, while multi-platform apparatus was applied to induce RSD. Passive avoidance memory test was also used to evaluate memory acquisition. The results showed that, intra-CA1 pre-training injection of RS67333 (5-HT4 agonist) and RS23597 (5-HT4 antagonist) at the doses of 0.01 and 0.1 µg/rat decreased memory acquisition, but did not alter pain perception and locomotor activity. Furthermore, TSD and RSD decreased memory acquisition; however, only TSD decreased locomotor activity and induced analgesic effect. The sub-threshold doses of RS67333 and RS23597, 0.001 and 0.0001 µg/rat, respectively, reversed the effect of TSD on memory acquisition and locomotor activity. In addition, only RS23597 reversed TSD-induced analgesia. In RSD condition, the subthreshold dose of RS23597 improved RSD-induced memory acquisition deficit. In conclusion, CA1 hippocampal 5-HT4 receptors play an important role in TSD/RSD-induced cognitive alterations., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Calcium (Ca 2+ )-permeable AMPA receptors may, in certain circumstances, contribute to normal synaptic plasticity or to neurodegeneration. AMPA receptors are Ca 2+ -permeable if they lack the GluA2 subunit or if GluA2 is unedited at a single nucleic acid, known as the Q/R site. In this study, we examined mice engineered with a point mutation in the intronic editing complementary sequence (ECS) of the GluA2 gene, Gria2. Mice heterozygous for the ECS mutation (named GluA2 +/ECS(G) ) had a ~ 20% reduction in GluA2 RNA editing at the Q/R site. We conducted an initial phenotypic analysis of these mice, finding altered current-voltage relations (confirming expression of Ca 2+ -permeable AMPA receptors at the synapse). Anatomically, we observed a loss of hippocampal CA1 neurons, altered dendritic morphology and reductions in CA1 pyramidal cell spine density. Behaviourally, GluA2 +/ECS(G) mice exhibited reduced motor coordination, and learning and memory impairments. Notably, the mice also exhibited both NMDA receptor-independent long-term potentiation (LTP) and vulnerability to NMDA receptor-independent seizures. These NMDA receptor-independent seizures were rescued by the Ca 2+ -permeable AMPA receptor antagonist IEM-1460. In summary, unedited GluA2(Q) may have the potential to drive NMDA receptor-independent processes in brain function and disease. Our study provides an initial characterisation of a new mouse model for studying the role of unedited GluA2(Q) in synaptic and dendritic spine plasticity in disorders where unedited GluA2(Q), synapse loss, neurodegeneration, behavioural impairments and/or seizures are observed, such as ischemia, seizures and epilepsy, Huntington's disease, amyotrophic lateral sclerosis, astrocytoma, cocaine seeking behaviour and Alzheimer's disease.

Temporal lobe epilepsy causes severe cognitive deficits, but the circuit mechanisms remain unknown. Interneuron death and reorganization during epileptogenesis may disrupt the synchrony of hippocampal inhibition. To test this, we simultaneously recorded from the CA1 and dentate gyrus in pilocarpine-treated epileptic mice with silicon probes during head-fixed virtual navigation. We found desynchronized interneuron firing between the CA1 and dentate gyrus in epileptic mice. Since hippocampal interneurons control information processing, we tested whether CA1 spatial coding was altered in this desynchronized circuit, using a novel wire-free miniscope. We found that CA1 place cells in epileptic mice were unstable and completely remapped across a week. This spatial instability emerged around 6 weeks after status epilepticus, well after the onset of chronic seizures and interneuron death. Finally, CA1 network modeling showed that desynchronized inputs can impair the precision and stability of CA1 place cells. Together, these results demonstrate that temporally precise intrahippocampal communication is critical for spatial processing.

Both clinical and experimental studies have reported that mild traumatic brain injury (mTBI) can result in cognitive impairments in the absence of overt brain damage. Whether these impairments result from neuronal dysfunction/altered plasticity is an area that has received limited attention. In this study, we recorded activity of neurons in the cornu Ammonis (CA)1 subfield of the hippocampus in sham and mild lateral fluid percussion injured (mFPI) rats while these animals were performing an object location task. Electrophysiology results showed that the number of excitatory neurons encoding spatial information (i.e., place cells) was reduced in mFPI rats, and that these cells had broader and less stable place fields. Additionally, the in-field firing rate of place cells in sham operated, but not in mFPI, animals increased when objects within the testing arena were moved. Immunostaining indicated no visible damage or overall neuronal loss in mFPI brain sections. However, a reduction in the number of parvalbumin-positive inhibitory neurons in the CA1 subfield of mFPI animals was observed, suggesting that this reduction could have influenced place cell physiology. Alterations in spatial information content, place cell stability, and activity in mFPI rats coincided with poor performance in the object location task. These results indicate that altered place cell physiology may underlie the hippocampus-dependent cognitive impairments that result from mTBI.

Traumatic brain injury (TBI) is a major public health concern in the USA. There are approximately 2.5 million brain injuries annually, 90% of which may be classified as mild since these individuals do not display clear morphological abnormalities following injury on imaging. The majority of individuals develop neurocognitive deficits such as learning and memory impairment and recovery occurs over 3 to 6 months after mild TBI (mTBI). The hippocampus is highly susceptible to injury from mTBI due to the anatomic localization and has been implicated in the neurocognitive impairments after mTBI. Here, we investigated whether the mTBI-induced morphological and pathophysiological alterations of GABAergic interneurons in the CA1 subfield of the hippocampus recovers after 30 days in the controlled cortical impact (CCI) model of TBI. Design-based stereology shows a significant reduction in the number of GABAergic interneurons 7 days after CCI. However, the number of GABAergic interneurons is not significantly reduced at 30 days after CCI. The total number of neurons is not altered over the course of 30 days. GABAergic inhibitory currents in the CA1 subfield also show that, although there is a significant reduction in the CCI group at 7 days, the currents are not significantly different from sham controls at 30 days. We suggest that the recovery of GABAergic function in the CA1 subfield of the hippocampus observed 30 days after CCI is one of the mechanisms associated with the recovery of memory after mTBI.

Acid-sensing ion channels (ASICs), members of the degenerin/epithelial Na+ channel superfamily, are broadly distributed in the mammalian nervous system where they play important roles in a variety of physiological processes, including neurotransmission and memory-related behaviors. In the last few years, we and others have investigated the role of ASIC1a in different forms of synaptic plasticity especially in the CA1 area of the hippocampus. This review summarizes the latest research linking ASIC1a to synaptic function either in physiological or pathological conditions. A better understanding of how these channels are regulated in brain circuitries relevant to synaptic plasticity and memory may offer novel targets for pharmacological intervention in neuropsychiatric and neurological disorders.

The alteration of hippocampal function by chronic stress impairs higher order cognitive functions such as prospective memory (PM). However, how chronic stress affects hippocampal subregions related to PM remains largely unknown. In this study, the altered functional network of hippocampal subregions related to PM in chronic stress was explored. College students (N = 21) completed PM tasks and resting-state functional magnetic resonance imaging scans one month prior to (baseline) and during the final examination week (chronic stress). Hippocampal subregions' seed-based functional connectivity (FC) and PM were compared between baseline and chronic stress. PM performance declined in chronic stress. The FC of the cornu ammonis 2, 3 and dentate gyrus (CA23DG) with the bilateral caudate and precuneus was increased in chronic stress, while the FC of the subicular complex (SUBC) with the left middle frontal gyrus, the left inferior parietal gyrus and the right supramarginal gyrus was decreased. There was a negative correlation between PM performance and the FC of hippocampal subregions. We found chronic stress impairs PM by decreasing the FC of SUBC and increasing the FC of CA23DG. These findings suggest functional changes in hippocampal subregion networks as a mechanism underlying the impairment of PM in chronic stress.

Antiepileptic drugs (AEDs) are the primary agents prescribed for clinical management of limbic epilepsy. However, high incidence of pharmacoresistance and a limited armory of drugs for inhibiting the pathological progression of epilepsy pose major obstacles to managing epilepsy. Here, we investigated the effect of tetramethylpyrazine (TMP), the main bioactive alkaloid isolated from the oriental medicine Ligusticum chuanxiong Hort. , against the epileptogenesis progression of acute hippocampal and corneal (6 Hz) electrical kindling models of TLE. TMP dose-dependently limited the progression of seizures and reduced the after-discharge duration (ADDs) in a hippocampal mouse kindling model. Mice treated with TMP (20, 50 mg/kg, i.p.) remained in stage 1 of epileptic progression for a protracted period, requiring additional stimulation to induce stages 2-5 epileptic phenotypes. TMP (50 mg/kg) also inhibited 6 Hz corneal kindling progression. In contrast, TMP did not reverse the phenotypes induced in a generalized seizures (GS) model, or the maximal electroshock (MES) or pentylenetetrazole (PTZ)-induced models of epilepsy. Furthermore, patch clamp recordings revealed no effect of TMP (10 μM) on CA1 hippocampal neurons' intrinsic properties but suppressed the (i) frequency of spontaneous excitatory post synaptic currents (sEPSCs), (ii) paired pulse ratio (PPR), and (iii) long-term potentiation (LTP) induction in the Schaffer collateral-CA1 pathway. TMP suppressed the activity of calcium, but not sodium, channels. Taken together, these results suggest that TMP has an antiepileptogenic effect, likely through suppression of excitatory synaptic transmission by its effects on inhibition of calcium channels; these traits distinguish TMP from currently available AEDs. As mice administered TMP did not show any neurologic impairment in the object recognition and open field tests, the data support further development of TMP as a promising treatment for epilepsy.

Fragile X syndrome (FXS) is the most common source of intellectual disability and autism. Extensive studies have been performed on the network and behavioral correlates of the syndrome, but our knowledge about intrinsic conductance changes is still limited. In this study, we show a differential effect of FMRP knockout in different subsections of hippocampus using whole-cell patch clamp in mouse hippocampal slices. We observed no significant change in spike numbers in the CA1 region of hippocampus, but a significant increase in CA3, in juvenile mice. However, in adult mice we see a reduction in spike number in the CA1 with no significant difference in CA3. In addition, we see increased variability in spike numbers in CA1 cells following a variety of steady and modulated current step protocols. This effect emerges in adult mice (8 weeks) but not juvenile mice (4 weeks). This increased spiking variability was correlated with reduced spike number and with elevated AHP. The increased AHP arose from elevated SK currents (small conductance calcium-activated potassium channels), but other currents involved in medium AHP, such as I h and M, were not significantly different. We obtained a partial rescue of the cellular variability phenotype when we blocked SK current using the specific blocker apamin. Our observations provide a single-cell correlate of the network observations of response variability and loss of synchronization, and suggest that the elevation of SK currents in FXS may provide a partial mechanistic explanation for this difference., (Copyright © 2019 Dwivedi et al.)

LTP, a fundamental mechanism of learning and memory, is a highly regulated process. One form of regulation is metaplasticity (i.e., the activity-dependent and long-lasting changes in neuronal state that orchestrate the direction, magnitude, and persistence of future synaptic plasticity). We have previously described a heterodendritic metaplasticity effect, whereby strong high-frequency priming stimulation in stratum oriens inhibits subsequent LTP in the stratum radiatum of hippocampal area CA1, potentially by engagement of the enmeshed astrocytic network. This effect may occur due to neuron-glia interactions in response to priming stimulation that leads to the release of gliotransmitters. Here we found in male rats that TNFα and associated signal transduction enzymes, but not interleukin-1β (IL-1β), were responsible for mediating the metaplasticity effect. Replacing priming stimulation with TNFα incubation reproduced these effects. As TNFα levels are elevated in Alzheimer's disease, we examined whether heterodendritic metaplasticity is dysregulated in a transgenic mouse model of the disease, either before or after amyloid plaque formation. We showed that TNFα and IL-1β levels were significantly increased in aged but not young transgenic mice. Although control LTP was impaired in the young transgenic mice, it was not TNFα-dependent. In the older transgenic mice, however, LTP was impaired in a way that occluded further reduction by heterosynaptic metaplasticity, whereas LTP was entirely rescued by incubation with a TNFα antibody, but not an IL-1β antibody. Thus, TNFα mediates a heterodendritic metaplasticity in healthy rodents that becomes constitutively and selectively engaged in a mouse model of Alzheimer's disease. SIGNIFICANCE STATEMENT The proinflammatory cytokine TNFα is known to be capable of inhibiting LTP and is upregulated several-fold in brain tissue, serum, and CSF of Alzheimer's disease (AD) patients. However, the mechanistic roles played by TNFα in plasticity and AD remain poorly understood. Here we show that TNFα and its downstream signaling molecules p38 MAPK, ERK, and JNK contribute fundamentally to a long-range metaplastic inhibition of LTP in rats. Moreover, the impaired LTP in aged APP/PS1 mice is rescued by incubation with a TNFα antibody. Thus, there is an endogenous engagement of the metaplasticity mechanism in this mouse model of AD, supporting the idea that blocking TNFα might be of therapeutic benefit in the disease., (Copyright © 2019 the authors.)

Inhibitory interneurons, organized into canonical feedforward and feedback motifs, play a key role in controlling normal and pathological neuronal activity. We demonstrate prominent quantitative changes in the dynamics of feedback inhibition in a rat model of chronic epilepsy (male Wistar rats). Systematic interneuron recordings revealed a large decrease in intrinsic excitability of basket cells and oriens-lacunosum moleculare interneurons in epileptic animals. Additionally, the temporal dynamics of interneuron recruitment by recurrent feedback excitation were strongly altered, resulting in a profound loss of initial feedback inhibition during synchronous CA1 pyramidal activity. Biophysically constrained models of the complete feedback circuit motifs of normal and epileptic animals revealed that, as a consequence of altered feedback inhibition, burst activity arising in CA3 is more strongly converted to a CA1 output. This suggests that altered dynamics of feedback inhibition promote the transmission of epileptiform bursts to hippocampal projection areas. SIGNIFICANCE STATEMENT We quantitatively characterized changes of the CA1 feedback inhibitory circuit in a model of chronic temporal lobe epilepsy. This study shows, for the first time, that dynamic recruitment of inhibition in feedback circuits is altered and establishes the cellular mechanisms for this change. Computational modeling revealed that the observed changes are likely to systematically alter CA1 input-output properties leading to (1) increased seizure propagation through CA1 and (2) altered computation of synchronous CA3 input., (Copyright © 2019 the authors.)

Quantitative electroencephalogram analysis has been increasingly applied to study fine changes in brain oscillations in epilepsy. Here we aimed to evaluate interictal oscillations using pilocarpine model of epilepsy to identify changes in network synchronization. We analyzed the in vivo local field potential of two cortical layers (Ctx1, Ctx2) and hippocampal CA1 (stratum oriens-Ors, pyramidale-Pyr, radiatum-Rad and lacunosum-moleculare-LM) in rats, about 5 weeks after pilocarpine injection. Animals that had status epilepticus (SE) and later spontaneous recurrent seizures (SRS) (epileptic animals) exhibited higher delta power recorded in cortical and hippocampal Ors, Rad and LM electrodes. They also had lower power of theta in Ctx1, Ctx2, Ors and LM, lower slow gamma in Ctx1, Ctx2 and Ors, and lower middle and fast gamma power in Ors. NSE animals had higher delta and lower slow gamma power in Ctx1 only, and lower theta power in Ctx1, Ctx2 and LM. Essentially, epileptic animals had higher delta coherence between Ctx1-Ors, Ctx2-Ors, Ctx2-Pyr, Pyr-Ors and stronger phase-amplitude coupling (PAC) between delta and all frequencies in Rad. NSE animals, also had higher delta coherence between Ctx1-Ors and Ctx2-Ors with no changes in PAC, suggesting some cortical network reorganization. Our data suggest an increased synchrony in cortex and CA1 of epileptic animals, particularly for delta frequency with intense delta coupling in Rad, probably an important synchronization site. Understanding the rhythms organization at non-ictal state could provide insights about network connectivity involved in ictogenesis and seizure propagation., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Background: Neurological complications may occur in patients with acute or chronic renal failure; however, in cases of acute renal failure, the signs and symptoms are usually more pronounced, and progressed rapidly. Oxidative stress and nitric oxide in the hippocampus, following kidney injury may be involved in cognitive impairment in patients with uremia. Although many women continue taking hormone therapy for menopausal symptom relief, but there are also some controversies about the efficacy of exogenous sex hormones, especially estrogen therapy alone, in postmenopausal women with kidney injury. Herein, to the best of our knowledge for the first time, spatial memory and synaptic plasticity at the CA1 synapse of a uremic ovariectomized rat model of menopause was characterized by estradiol replacement alone., Results: While estradiol replacement in ovariectomized rats without uremia, promotes synaptic plasticity, it has an impairing effect on spatial memory through hippocampal oxidative stress under uremic conditions, with no change on synaptic plasticity. It seems that exogenous estradiol potentiated the deleterious effect of acute kidney injury (AKI) with increasing hippocampal oxidative stress., Conclusions: Although, estrogen may have some positive effects on cognitive function in healthy subjects, but its efficacy in menopause subjects under uremic states such as renal transplantation, needs to be further investigated in terms of dosage and duration.

Transient global ischemia usually results in delayed neuronal death in selective brain regions, prior to which a rapid loss of dendritic spines has been widely reported in these regions. Dendritic spines are characterized by a highly branched meshwork of actin cytoskeleton (F-actin), which is extremely vulnerable to the ATP-depleted conditions such as hypoxia/ischemia. However, the ischemia-induced changes of F-actin are still not clarified in the vulnerable brain areas. This study was designed to examine the temporal and spatial alterations of F-actin in the CA1 subfield of rat hippocampus following reperfusion after global cerebral ischemia. Phalloidin staining and confocal microscopic examination showed that F-actin disappeared from the dentritic spines in the CA1 stratum radiatum, but aggregated into thread- or fiber-like structures on days 1.5-2 after ischemia. This was followed by a nearly complete loss of F-actin in the CA1 subfield on days 3-7 after ischemia. Colocalization analysis demonstrated that the F-actin threads or fibers were located mainly within the dentritic trunks. As revealed by Nissl and Fluoro-Jade B staining, the decrease of F-actin proceeded concurrently with the evolution of ischemic damage. Consistently, western blots detected a significant decrease of F-/G-actin ratio in the dissected CA1 subfield after ischemia. To our knowledge, this is the first report on the change of F-actin in the ischemic brain. Although the underlying mechanisms remain to be elucidated, our findings may provide an important structural clue for the neuronal dysfunction induced by ischemia., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Objective: To investigate the role of Eclipta prostrata (E. prostrata) extract in improving spatial learning and memory deficits in D-galactose-induced aging in rats., Methods: Rats were divided into five groups, with 10 animals in each group. Aging rats were produced by treatment with 100 mg·kg-1·d-1 of D-galactose for 6 weeks. Rats in the E. prostrata treatment groups received an aqueous extract of E. prostrata orally at a concentration of 50, 100, or 200 mg·kg-1·d-1 for 3 weeks. Animals in both the normal and model groups were treated with similar volumes of saline. Spatial memory performance was measured using the Morris water maze. The mRNA levels and enzyme activities of superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx) and glutathione reductase (GR) were analyzed using real-time quantitative PCR and spectrophotometry, respectively. The levels of induced nitric oxide synthase (iNOS), nitric oxide (NO), dopamine (DA), norepinephrine (NE), and serotonin (5-HT) were determined using enzyme-linked immunosorbent assay and spectrophotometry., Results: Compared with the normal group, rats in the D-galactose-treated model group exhibited significant memory loss. There was severe damage to the hippocampal CA1 area, and expression levels of SOD, CAT, GPx, and GR were significantly decreased in the model group compared with the normal group. In the model group, levels of iNOS and NO were significantly increased compared with the normal group. However, treatment with E. prostrata extract reversed the conditions caused by D-galactose-induced aging, especially in the groups with higher treatment concentrations. Compared with the normal group, the levels of DA, NE, and 5-HT were significantly lower in the D-galactose-treated model group. In the E. prostrata extract-treated groups, however, there was a dose-dependent upregulation of DA, NE, and 5-HT expression., Conclusion: Our results suggest that administration of E. prostrata extract can result in an improvement in the learning and memory impairments that are induced by D-galactose treatment in rats. This improvement may be the result of enhanced antioxidative ability, decreased iNOS and NO levels, and the induction of DA, NE, and 5-HT expression in the brain.

Background: Physical exercise can reduce the risk of developing chronic diseases and slow the onset of neurodegenerative diseases. Since it has not been assessed which kind of training protocol might positively modulate both synaptic and muscular plasticity in neurodegenerative diseases, we studied in a mouse model of Niemann Pick type C disease, a model of minimal Alzheimer's Disease, the effect of a short term protocol., Methods: We evaluated the effect of a short term, aerobic uniform exercise training on synaptic and muscle plasticity in three different mice groups: WT controls, NPC1+/- and NPC1-/- animals. The results were compared with those obtained in the sedentary respective groups. We analyzed the effects on synaptic plasticity by in vitro extracellular recordings in hippocampal mouse slices; moreover hippocampal and muscle tissue morphological structure have been investigated by transmission electron microscopy, to highlight any structural and functional changes due to training., Results: The results indicate a rescue of long-term potentiation in homozygous but not in heterozygous mice slices and an induction of neuronal plasticity, observed by morphological analysis, both in homozygous and in heterozygous trained mice., Conclusions: Hence this protocol is adequate to improve long term potentiation (LTP) impairment and counteract muscular deterioration in homozygous mice.

Post-traumatic stress disorder (PTSD) has been associated with anxiety, memory impairments, enhanced fear, and hippocampal volume loss, although the relationship between these changes remain unknown. Single-prolonged stress (SPS) is a model for PTSD combining three forms of stress (restraint, swim, and anesthesia) in a single session that results in prolonged behavioral effects. Using pharmacogenetic ablation of adult neurogenesis in rats, we investigated the role of new neurons in the hippocampus in the long-lasting structural and behavioral effects of SPS. Two weeks after SPS, stressed rats displayed increased anxiety-like behavior and decreased preference for objects in novel locations regardless of the presence or absence of new neurons. Chronic stress produced by daily restraint for 2 or 6 hr produced similar behavioral effects that were also independent of ongoing neurogenesis. At a longer recovery time point, 1 month after SPS, rats with intact neurogenesis had normalized, showing control levels of anxiety-like behavior. However, GFAP-TK rats, which lacked new neurons, continued to show elevated anxiety-like behavior and enhanced serum corticosterone response to anxiogenic experience. Volume loss in ventral CA1 region of the hippocampus paralleled increases in anxiety-like behavior, occurring in all rats exposed to SPS at the early time point and only rats lacking adult neurogenesis at the later time point. In chronic stress experiments, volume loss occurred broadly throughout the dentate gyrus and CA1 after 6-hr daily stress but was not apparent in any hippocampal subregion after 2-hr daily stress. No effect of SPS was seen on cell proliferation in the dentate gyrus, but the survival of young neurons born a week after stress was decreased. Together, these data suggest that new neurons are important for recovery of normal behavior and hippocampal structure following a strong acute stress and point to the ventral CA1 region as a potential key mediator of stress-induced anxiety-like behavior., (Published 2019. This article is a U.S. Government work and is in the public domain in the USA.)

Aim: To investigate the effect of crocin on the learning and memory acquisition of AD rats and its underlying mechanisms., Methods: A total of 48 healthy male SD rats were randomly divided into control group, AD model group, resveratrol group, and crocin group, with 12 rats per group. AD model was established by injecting A β 25-35 to the lateral ventricle of rats, and thereafter the rats were administrated with resveratrol (40 mg/kg), crocin (40 mg/kg), or PBS daily for 14 days. Y-maze test and sucrose preference test were used to detect the learning and memory acquisition of rats. Neuronal apoptosis was detected by TUNEL staining and Western blot for apoptosis-related proteins Bax, Bcl-2, and Caspase-3. Immunofluorescence staining and Western blot tests were used to detect the expression of glucose regulated protein 78 (GRP78) and C/EBP homologous protein (CHOP) in hippocampal CA1 region (Hippo) and prefrontal cortical neurons (PFC)., Results: The learning and memory abilities of AD rats were significantly decreased, which was significantly rescued by resveratrol and crocin. The apoptotic cell number of Hippo and PFC neurons in AD model group was significantly higher than that in control group ( P <0.01), while resveratrol and crocin significantly decreased the apoptotic cell number in AD group ( P <0.01). Compared with the control group, the expression of Bcl2 in PFC and hippo of AD model group was significantly decreased ( P <0.01), while those of Bax, Caspase3, GRP78, and CHOP were significantly increased ( P <0.01). Resveratrol and crocin could significantly reverse the expression of these proteins in AD rats ( P <0.05)., Conclusion: Crocin can improve the learning and memory ability of AD rats possibly by reducing endoplasmic reticulum stress and neuronal apoptosis., Competing Interests: The authors declare that there are no conflicts of interest regarding the publication of this paper.

This study aimed to explore the relationship between autophagy and synaptic plasticity in the pathogenesis of vascular dementia (VD). The autophagy inhibitor 3-methyladenine (3-MA) and the autophagy agonist rapamycin (Rap) were injected into the lateral ventricles of rats, and a rat VD model was established using a modified four-vessel occlusion method. The expression of LC3-II, synaptophysin (Syn), and postsynaptic density protein 95 (PSD-95) in the CA1 area of the rat hippocampus were detected using western blotting. Decreased Syn and PSD-95 expression in the VD group was accompanied by an increased LC3-II/LC3-I ratio. The expression of Syn and PSD-95 increased after 3-MA application, but decreased following Rap application. The LC3-II/LC3-I ratio was negatively correlated with Syn and PSD-95 expression. These findings suggest that autophagy may regulate synaptic plasticity in the hippocampus in a VD model of rats. Inhibition of autophagy is beneficial to the remodeling of synapses in the hippocampal CA1 area of the VD rat model, and this may provide a theoretical basis for the treatment and prevention of VD., (Copyright © 2019. Published by Elsevier B.V.)

β-amyloid (Aβ)-dependent neuronal hyperactivity is believed to contribute to the circuit dysfunction that characterizes the early stages of Alzheimer's disease (AD). Although experimental evidence in support of this hypothesis continues to accrue, the underlying pathological mechanisms are not well understood. In this experiment, we used mouse models of Aβ-amyloidosis to show that hyperactivation is initiated by the suppression of glutamate reuptake. Hyperactivity occurred in neurons with preexisting baseline activity, whereas inactive neurons were generally resistant to Aβ-mediated hyperactivation. Aβ-containing AD brain extracts and purified Aβ dimers were able to sustain this vicious cycle. Our findings suggest a cellular mechanism of Aβ-dependent neuronal dysfunction that can be active before plaque formation., (Copyright © 2019 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.)

Depression and transient ischaemic attack represent the common psychological and neurological diseases, respectively, and are tightly associated. However, studies of depression-affected ischaemic attack have been limited to epidemiological evidences, and the neural circuits underlying depression-modulated ischaemic injury remain unknown. Here, we find that chronic social defeat stress (CSDS) and chronic footshock stress (CFS) exacerbate CA1 neuron loss and spatial learning/memory impairment after a short transient global ischaemia (TGI) attack in mice. Whole-brain mapping of direct outputs of locus coeruleus (LC)-tyrosine hydroxylase (TH, Th:) positive neurons reveals that LC-CA1 projections are decreased in CSDS or CFS mice. Furthermore, using designer receptors exclusively activated by designer drugs (DREADDs)-based chemogenetic tools, we determine that Th:LC-CA1 circuit is necessary and sufficient for depression-induced aggravated outcomes of TGI. Collectively, we suggest that Th:LC-CA1 pathway plays a crucial role in depression-induced TGI vulnerability and offers a potential intervention for preventing depression-related transient ischaemic attack.

Gastrin-releasing peptide (GRP) has been confirmed to exhibit a variety of physiological functions in the brain and play a role in many neurological diseases. Our previous research found that GRP could restore the impaired synaptic plasticity and the spatial learning and memory impairments induced by vascular dementia (VD). However, the specific mechanisms of GRP affecting hippocampus, especially the effects on the neuronal oscillations were still poorly understood. In this study, we examined the effects of GRP on the changes of the interactions between theta and gamma oscillations in the hippocampal CA3-CA1 pathway of VD rats and explored the potential electrophysiological mechanism. To this purpose, local field potentials (LFPs) simultaneously collected from hippocampal CA3 and CA1 were measured by the power spectrum, phase synchronization, phase-phase coupling (PPC) and phase-amplitude coupling (PAC). We found that GRP substantially restored the phase synchronization of the theta and gamma oscillations. The GRP also significantly improved the strength of theta-gamma cross-frequency coupling (including theta-gamma PPC and theta-gamma PAC) in the CA3-CA1 network. The results indicated that GRP could alleviate the changes of neural activities in hippocampal CA3-CA1 pathway induced by VD. This might be an electrophysiological mechanism for GRP preventing cognitive impairments induced by VD.

In the central nervous system, Tropomyosin-receptor-kinase B (TrkB) signaling is involved in neuronal survival, differentiation as well as in regulation of synaptic transmission and excitability. As its powerful potential to modulate neuronal functions, TrkB pathway is an attractive target for novel drugs and treatment of common neurological disorders. 7,8-Dihydroxyflavone (DHF), a TrkB receptor agonist, has similar properties with neurotrophin Brain Derived Neurotropic Factor (BDNF). DHF is reported to have a number of beneficial effects in neuroprotection, against depression and improving learning and memory. However, the outcome of acute application of DHF on the excitability of neuronal circuits is not clear. Especially the effects of DHF on synchronized epileptiform activity are not known. In this study, we investigated whether DHF induces epileptiform activity in brain slices and DHF has any effect on already initiated epileptiform discharges. We used acute horizontal hippocampal-entorhinal cortex slices obtained from 30 to 35 days of mice. Extracellular field potential recordings were obtained from entorhinal cortex (EC) and hippocampus CA1 region. DHF did not initiate any epileptiform activity or abnormal discharges. However, DHF increased the frequency of 4 aminopyridine (4AP) induced ictal and interictal events in both EC and CA1. The duration of induced ictal charges were also prolonged upon DHF application. In a number of slices, both EC and CA1, DHF led to ictogenesis. These results suggest that the acute activation of TrkB by DHF has a powerful potential on synchronized neuronal discharges which should be considered in future therapeutical approaches., (Copyright © 2019 Elsevier B.V. All rights reserved.)

N-methyl-D-aspartate receptors (NMDARs) have been highly implicated in the pathogenesis and treatment of depression. While NMDARs can be found inside and outside glutamate synapses, it remains unclear if NMDARs at synaptic (sNMDAR) and extrasynaptic locations (exNMDAR) play different roles in the formation of depression-related behaviors. Using chronic social defeat stress (CSDS), an animal model for anxiety- and depression-related behaviors, we found that mice susceptible to CSDS exhibited low hippocampal exNMDAR function. Raising exNMDAR function by enhancing the release of glutamate from astrocytic cystine-glutamate antiporters or targeting extrasynaptic receptors with agonist-coated gold nanoparticles that cannot enter the synaptic cleft prevented social avoidance behavior in stressed mice. Interestingly, ketamine, which is a fast-acting antidepressant, exhibited stronger blockade to sNMDARs than to exNMDARs. These findings suggest that the susceptibility and resilience of mice toward CSDS is related to low and high exNMDAR function in the hippocampus, respectively. Enhancing exNMDAR function could be a novel treatment approach for mood and anxiety disorders.

It is commonly recognized that physical exercise positively affects several CNS regions and improves cognitive abilities. For example, exercise is associated with an increase in neurogenesis and facilitation of long-term potentiation in the hippocampus. Conversely, animal models for depression are associated with a decrease in neurogenesis and a reduction of long-term potentiation in the hippocampus. Although exercise could be a viable option in the treatment of some forms of depression, the mechanisms responsible for such improvements have not been elucidated. In this study, we examine hippocampal function using electrophysiological field recordings in CA1 and dentate gyrus to study baseline synaptic transmission and long-term potentiation in adolescent and adult rats prenatally exposed to the glucocorticoid dexamethasone. One group of animals was allowed to run voluntarily for 10 or 21 days using an exercise wheel before the experiments, and the control group was prevented from running (i.e. the exercise wheel was locked). In adult saline-exposed animals, exercise was associated with increased long-term potentiation in the dentate gyrus. Unexpectedly, in dexamethasone-exposed animals, dentate gyrus long-term potentiation was facilitated, whereas long-term potentiation in CA1 was unaffected by prenatal dexamethasone or by 10 or 21 days of voluntary running. Irrespective of age, prenatal dexamethasone and running had limited effects on synaptic transmission and presynaptic release in CA1 and dentate gyrus. In summary, running facilitates dentate gyrus long-term potentiation in adult animals that resembles the effects of prenatal dexamethasone., (Copyright © 2019 IBRO. Published by Elsevier Ltd. All rights reserved.)

Mesial temporal lobe epilepsy (TLE) is a common neurological disorder affecting the hippocampus and surrounding medial temporal lobe (MTL). Although prior studies have analyzed whole-brain network distortions in TLE patients, the functional network architecture of the MTL at the subregion level has not been examined. In this study, we utilized high-resolution 7T T2-weighted magnetic resonance imaging (MRI) and resting-state BOLD-fMRI to characterize volumetric asymmetry and functional network asymmetry of MTL subregions in unilateral medically refractory TLE patients and healthy controls. We subdivided the TLE group into mesial temporal sclerosis patients (TLE-MTS) and MRI-negative nonlesional patients (TLE-NL). Using an automated multi-atlas segmentation pipeline, we delineated 10 MTL subregions per hemisphere for each subject. We found significantly different patterns of volumetric asymmetry between the two groups, with TLE-MTS exhibiting volumetric asymmetry corresponding to decreased volumes ipsilaterally in all hippocampal subfields, and TLE-NL exhibiting no significant volumetric asymmetries other than a mild decrease in whole-hippocampal volume ipsilaterally. We also found significantly different patterns of functional network asymmetry in the CA1 subfield and whole hippocampus, with TLE-NL patients exhibiting asymmetry corresponding to increased connectivity ipsilaterally and TLE-MTS patients exhibiting asymmetry corresponding to decreased connectivity ipsilaterally. Our findings provide initial evidence that functional neuroimaging-based network properties within the MTL can distinguish between TLE subtypes. High-resolution MRI has potential to improve localization of underlying brain network disruptions in TLE patients who are candidates for surgical resection., (© 2019 Wiley Periodicals, Inc.)

This paper aims to present computer modeling of synaptic plasticity and memory in the CA3-CA1 hippocampal formation microcircuit. The computer simulations showed a comparison of a pathological model in which Alzheimer's disease (AD) was simulated by synaptic degradation in the hippocampus and control model (healthy) of CA3-CA1 networks with modification of weights for the memory. There were statistically higher spike values of both CA1 and CA3 pyramidal cells in the control model than in the pathological model (p = 0.0042 for CA1 and p = 0.0033 for CA3). A similar outcome was achieved for frequency (p = 0.0002 for CA1 and p = 0.0001 for CA3). The entropy of pyramidal cells of the healthy CA3 network seemed to be significantly higher than that of AD (p = 0.0304). We need to study a lot of physiological parameters and their combinations of the CA3-CA1 hippocampal formation microcircuit to understand AD. High statistically correlations were obtained between memory, spikes and synaptic deletion in both CA1 and CA3 cells.

Post-translational modification (PTM) plays a critical role in increasing proteome complexity and diversifying protein functions. O-GlcNAc modification is a reversible, dynamic and highly abundant PTM catalyzed by a single pair of enzymes, O-GlcNAc transferase (OGT) and O-GlcNAcase (OGA), regardless of substrates. The two enzymes are particularly enriched in the brain, and recent proteomic studies identified that a large number of neuron-specific proteins undergo O-GlcNAc modification. In addition, pathological conditions with aberrant O-GlcNAcylation such as diabetes and obesity are associated with the higher risk of cognitive decline and memory impairment. However, despite its prevalence in the brain, functional significance of O-GlcNAcylation in regulating neuronal properties remains unclear at the molecular level. Here, we report that an acute increase in O-GlcNAcylation induced by pharmacological inhibition of OGA significantly reduces the intrinsic excitability of hippocampal CA1 neurons through the cooperative modulation of multiple voltage-gated ion channels. Moreover, elevated O-GlcNAcylation also suppresses excitatory synaptic transmission at Schaffer collateral-CA1 synapses through the removal of GluA2-containing AMPA receptors from postsynaptic densities. Collectively, our findings demonstrate that a change in O-GlcNAcylation levels dynamically regulates hippocampal activity at both intrinsic and synaptic levels, providing a mechanistic link between dysregulated O-GlcNAcylation and hippocampal dysfunction.

Microglia are in a privileged position to both affect and be affected by neuroinflammation, neuronal activity and injury, which are all hallmarks of seizures and the epilepsies. Hippocampal microglia become activated after prolonged, damaging seizures known as status epilepticus (SE). However, since SE causes both hyperactivity and injury of neurons, the mechanisms triggering this activation remain unclear, as does the relevance of the microglial activation to the ensuing epileptogenic processes. In this study, we use electroconvulsive shock (ECS) to study the effect of neuronal hyperactivity without neuronal degeneration on mouse hippocampal microglia. Unlike SE, ECS did not alter hippocampal CA1 microglial density, morphology, or baseline motility. In contrast, both ECS and SE produced a similar increase in ATP-directed microglial process motility in acute slices, and similarly upregulated expression of the chemokine C-C motif chemokine ligand 2 (CCL2). Whole-cell patch-clamp recordings of hippocampal CA1 sr microglia showed that ECS enhanced purinergic currents mediated by P2X7 receptors in the absence of changes in passive properties or voltage-gated currents, or changes in receptor expression. This differs from previously described alterations in intrinsic characteristics which coincided with enhanced purinergic currents following SE. These ECS-induced effects point to a "seizure signature" in hippocampal microglia characterized by altered purinergic signaling. These data demonstrate that ictal activity per se can drive alterations in microglial physiology without neuronal injury. These physiological changes, which up until now have been associated with prolonged and damaging seizures, are of added interest as they may be relevant to electroconvulsive therapy (ECT), which remains a gold-standard treatment for depression.

Polychlorinated biphenyls (PCBs) are toxic environmental pollutants. Humans are exposed to PCB mixtures via contaminated food or water. PCB exposure causes adverse effects in adults and after exposure in utero. PCB toxicity depends on the congener mixture and CYP1A2 gene activity. For coplanar PCBs, toxicity depends on ligand affinity for the aryl hydrocarbon receptor (AHR). Previously, we found that perinatal exposure of mice to a three-coplanar/five-noncoplanar PCB mixture induced deficits in novel object recognition and trial failures in the Morris water maze in Cyp1a2 -/- ::Ahr b1 C57BL6/J mice compared with wild-type mice (Ahr b1  = high AHR affinity). Here we exposed gravid Cyp1a2 -/- ::Ahr b1 mice to a PCB mixture on embryonic day 10.5 by gavage and examined the F 1 and F 3 offspring (not F 2 ). PCB-exposed F 1 mice exhibited increased open-field central time, reduced acoustic startle, greater conditioned contextual freezing and reduced CA1 hippocampal long-term potentiation with no change in spatial learning or memory. F 1 mice also had inhibited growth, decreased heart rate and cardiac output, and impaired fertility. F 3 mice showed few effects. Gene expression changes were primarily in F 1 PCB males compared with wild-type males. There were minimal RNA and DNA methylation changes in the hippocampus from F 1 to F 3 with no clear relevance to the functional effects. F 0 PCB exposure during a period of rapid DNA de-/remethylation in a susceptible genotype produced clear F 1 effects with little evidence of transgenerational effects in the F 3 generation. While PCBs show clear developmental neurotoxicity, their effects do not persist across generations for effects assessed herein., (© 2018 John Wiley & Sons, Ltd.)