Hippocampal Synaptic Transmission Research Articles

Hyperexcitable PV interneurons render hippocampal microcircuitry vulnerable to amyloid beta

AbstractBackgroundHippocampal Parvalbumin (PV) neurons are GABAergic inhibitory interneurons that provide feedback and feedforward inhibition. They control hippocampal local circuitry and are essential for spatial learning and memory. Accordingly, their dysfunction has been associated with Alzheimer’s disease (AD). Previously, we showed that an early amyloid‐beta dependent PV hyperexcitability is causally involved in hippocampal circuit dysfunction and cognitive impairment in a mouse model of AD. Here, we investigate the short‐ and long‐term effects of PV hyperexcitability on hippocampal function and test whether PV neuron hyperexcitability can render hippocampal circuits vulnerable to amyloid beta.MethodWe use chemogenetics (hM3Dq‐activating receptor with clozapine‐N‐oxide) in order to increase PV neuron activity for three weeks. We then train the mice in the Morris water maze (MWM) in order to asses hippocampus‐dependent spatial memory. Finally, using whole‐cell patch‐clamp recordings, we investigate PV and pyramidal neuron excitability and synaptic transmission in the hippocampus.ResultWe found that prolonged activation of PV neurons disrupts synaptic transmission and causes spatial memory deficits on the short‐term, while on the long‐term, natural compensatory mechanisms restore synaptic transmission and spatial memory. A single low‐dose of amyloid‐beta disrupts long‐term restoration of hippocampal synaptic transmission when PV neurons are hyperexcitable. Specifically, under these conditions, amyloid‐beta impairs PV neuron function, resulting in significant spatial memory deficits.ConclusionTaken together, our data show that an induced hyperexcitablity state of PV neurons render hippocampal circuitry vulnerable to amyloid‐beta.

Glycogen synthase kinase-3 inhibition rescues sex-dependent contextual fear memory deficit in human immunodeficiency virus-1 transgenic mice.

A significant number of HIV-1 patients on antiretroviral therapy develop HIV-associated neurocognitive disorders (HAND). Evidence indicate that biological sex may regulate HAND pathogenesis, but the mechanisms remain unknown. We investigated synaptic mechanisms associated with sex differences in HAND, using the HIV-1-transgenic 26 (Tg26) mouse model. Contextual- and cue-dependent memories of male and female Tg26 mice and littermate wild type mice were assessed in a fear conditioning paradigm. Hippocampal electrophysiology, immunohistochemistry, western blot, qRT-PCR and ELISA techniques were used to investigate cellular, synaptic and molecular impairments. Cue-dependent memory was unaltered in male and female Tg26 mice, when compared to wild type mice. Male, but not female, Tg26 mice showed deficits in contextual fear memory. Consistently, only male Tg26 mice showed depressed hippocampal basal synaptic transmission and impaired LTP induction in area CA1. These deficits in male Tg26 mice were independent of hippocampal neuronal loss and microglial activation but were associated with increased HIV-1 long terminal repeat mRNA expression, reduced hippocampal synapsin-1 protein, reduced BDNF mRNA and protein, reduced AMPA glutamate receptor (GluA1) phosphorylation levels and increased glycogen synthase kinase 3 (GSK3) activity. Importantly, selective GSK3 inhibition using 4-benzyl-2-methyl-1,2,4-thiadiazolidine-3,5-dione increased levels of synapsin-1, BDNF and phosphorylated-GluA1 proteins, restored hippocampal basal synaptic transmission and LTP, and improved contextual fear memory in male Tg26 mice. Sex-dependent impairments in contextual fear memory and synaptic plasticity in Tg26 mice are associated with increased GSK3 activity. This implicates GSK3 inhibition as a potential therapeutic strategy to improve cognition in HIV-1 patients.

NRSF/REST Deficiency Impairs Cognitive Abilities in Aged Mice But Does Not Interfere with Memory Deficits of APP/PS1 Transgenic Mice

NRSF/REST plays an important role in the neuronal homeostasis as a transcriptional repressor of neuronal genes. NRSF/REST has been linked to cognitive preservation and longevity of humans, but its specific functions in age-dependent and Alzheimer's disease-related memory deficits remain unclear. In this study, we conditionally deleted NRSF/REST in the dorsal telencephalon or neurons of wild-type and APP/PS1 transgenic mice, and evaluated their cognitive abilities at different ages. The data indicated that conditional NRSF/REST-deficient mice had an age-dependently diminished retrieval performance in a variety of memory tests and altered hippocampal synaptic transmission and activity-dependent synaptic plasticity. In addition, the NRSF/REST deficient mice were characterized by an increase of activated glial cells, complement C3 protein, and the transcription factor C/EBPβ in the cortex and hippocampus. However, reduction of NRSF/REST in APP/PS1 mice by conditional depletion did not worsen the Aβ load and memory performance. The experiments suggest an important role of NRSF/REST for the maintenance of memory and synaptic plasticity in ageing mice, and point toward its potential roles in the onset of ageing-related memory impairments. Conditional NRSF/REST knockout mice of this study could be reliable experimental models of non-Alzheimer dementia.

Effects of long-lasting social isolation and re-socialization on cognitive performance and brain activity: a longitudinal study in Octodon degus

Social isolation is considered a stressful situation that results in increased physiological reactivity to novel stimuli, altered behaviour, and impaired brain function. Here, we investigated the effects of long-term social isolation on working memory, spatial learning/memory, hippocampal synaptic transmission, and synaptic proteins in the brain of adult female and male Octodon degus. The strong similarity between degus and humans in social, metabolic, biochemical, and cognitive aspects, makes it a unique animal model that can be highly applicable for further social, emotional, cognitive, and aging studies. These animals were socially isolated from post-natal and post-weaning until adulthood. We also evaluated if re-socialization would be able to compensate for reactive stress responses in chronically stressed animals. We showed that long-term social isolation impaired the HPA axis negative feedback loop, which can be related to cognitive deficits observed in chronically stressed animals. Notably, re-socialization restored it. In addition, we measured physiological aspects of synaptic transmission, where chronically stressed males showed more efficient transmission but deficient plasticity, as the reverse was true on females. Finally, we analysed synaptic and canonical Wnt signalling proteins in the hypothalamus, hippocampus, and prefrontal cortex, finding both sex- and brain structure-dependent modulation, including transient and permanent changes dependent on stress treatment.

N,N-dimethylglycine prevents toluene-induced impairment in recognition memory and synaptic plasticity in mice

Toluene intoxication produces deleterious effects on cognitive function, which has been associated with the inhibition of N-methyl-d-aspartate receptor (NMDAR). The present study determined whether N,N-dimethylglycine (DMG), a nutrient supplement and a partial agonist for NMDAR glycine binding site, could counteract recognition memory deficits and hippocampal synaptic dysfunction after acute toluene exposure. Male ICR mice were treated with toluene (250−750 mg/kg) for monitoring the sociability and social novelty in three-chamber test and long-term potentiation (LTP) of hippocampal synaptic transmission. Moreover, the combined effects of DMG (30−100 mg/kg) pretreatment with toluene (750 mg/kg) on three-chamber test, novel location and object recognition test and synaptic function were determined. Toluene decreased the sociability, preference for social novelty, hippocampal synaptic transmission and LTP in a dose-dependent manner. DMG pretreatment significantly reduced the toluene-induced memory impairment in social recognition, object location and object recognition and synaptic dysfunction. Furthermore, NMDAR glycine binding site antagonist, 7-chlorokynurenic acid, abolished the protective effects of DMG. These results indicate that DMG could prevent toluene-induced recognition memory deficits and synaptic dysfunction and its beneficial effects might be associated with modulation of NMDAR. These findings suggest that DMG supplementation might be an effective approach to prevent memory problems for the workers at risk of high-level toluene exposure or toluene abusers.

Presynaptic L-Type Ca2+ Channels Increase Glutamate Release Probability and Excitatory Strength in the Hippocampus during Chronic Neuroinflammation.

Neuroinflammation is involved in the pathogenesis of several neurologic disorders, including epilepsy. Both changes in the input/output functions of synaptic circuits and cell Ca2+ dysregulation participate in neuroinflammation, but their impact on neuron function in epilepsy is still poorly understood. Lipopolysaccharide (LPS), a toxic byproduct of bacterial lysis, has been extensively used to stimulate inflammatory responses both in vivo and in vitro LPS stimulates Toll-like receptor 4, an important mediator of the brain innate immune response that contributes to neuroinflammation processes. Although we report that Toll-like receptor 4 is expressed in both excitatory and inhibitory mouse hippocampal neurons (both sexes), its chronic stimulation by LPS induces a selective increase in the excitatory synaptic strength, characterized by enhanced synchronous and asynchronous glutamate release mechanisms. This effect is accompanied by a change in short-term plasticity with decreased facilitation, decreased post-tetanic potentiation, and increased depression. Quantal analysis demonstrated that the effects of LPS on excitatory transmission are attributable to an increase in the probability of release associated with an overall increased expression of L-type voltage-gated Ca2+ channels that, at presynaptic terminals, abnormally contributes to evoked glutamate release. Overall, these changes contribute to the excitatory/inhibitory imbalance that scales up neuronal network activity under inflammatory conditions. These results provide new molecular clues for treating hyperexcitability of hippocampal circuits associated with neuroinflammation in epilepsy and other neurologic disorders.SIGNIFICANCE STATEMENT Neuroinflammation is thought to have a pathogenetic role in epilepsy, a disorder characterized by an imbalance between excitation/inhibition. Fine adjustment of network excitability and regulation of synaptic strength are both implicated in the homeostatic maintenance of physiological levels of neuronal activity. Here, we focused on the effects of chronic neuroinflammation induced by lipopolysaccharides on hippocampal glutamatergic and GABAergic synaptic transmission. Our results show that, on chronic stimulation with lipopolysaccharides, glutamatergic, but not GABAergic, neurons exhibit an enhanced synaptic strength and changes in short-term plasticity because of an increased glutamate release that results from an anomalous contribution of L-type Ca2+ channels to neurotransmitter release.

Role of heat shock transcription factor 2 in the NMDA-dependent neuroplasticity induced by chronic ethanol intake in mouse hippocampus.

Ethanol consumption impairs learning and memory through disturbances of NMDA-type glutamate receptor-dependent synaptic plasticity (long-term depression [LTD] and long-term potentiation [LTP]) in the hippocampus. Recently, we demonstrated that two ethanol binge-like episodes in young adult rats selectively blocked NMDA-LTD in hippocampal slices, increased NMDA receptor sensitivity to a GluN2B subunit antagonist, and induced cognitive deficits. Here, using knockout adult mice, we show that a stress-responsive transcription factor of the heat shock factor family, HSF2, which is involved in the perturbation of brain development induced by ethanol, participates in these processes. In the absence of ethanol, hsf2-/- mice show a selective loss of LTD in the hippocampus, which is associated with an increased sensitivity of NMDA-field excitatory postsynaptic potentials (fEPSPs) to a GluN2B antagonist, compared with wild-type (WT) mice. These results suggest that HSF2 is required for proper glutamatergic synaptic transmission and LTD plasticity. After 1 month of chronic ethanol consumption in a two-bottle choice paradigm, WT mice showed an increase in hippocampal synaptic transmission, an enhanced sensitivity to GluN2B antagonist, and a blockade of LTD. In contrast, such modulation of synaptic transmission and plasticity were absent in hsf2-/- mice. We conclude that HSF2 is an important mediator of both glutamatergic neurotransmission and synaptic plasticity in basal conditions and also mediates ethanol-induced neuroadaptations of the hippocampus network after chronic ethanol intake.

Knockdown of Follistatin-like 1 disrupts synaptic transmission in hippocampus and leads to cognitive impairments

Follistatin-like 1 (FSTL1), also named transforming growth factor (TGF)-β1–inducible gene, is a secreted extracellular glycoprotein expressing widely in nervous system. Several recent studies have revealed that FSTL1 plays an essential role in neurological diseases including neuropathic pain and ischemic stroke. It proves that FSTL1 suppresses synaptic transmission by activating Na/K-ATPase in DRG neurons and inhibits neuronal apoptosis by phosphorylation AKT signaling. However, it is not clear whether FSTL1 can play a role in other type of neuron or neurodegenerative diseases. In this study, we found that the mice with Fstl1 genetic knockdown showed not only the impairments of learning and memory abilities, but also abnormal neural oscillations and synaptic plasticity in the hippocampus. Subsequently, we identified broad transcriptional changes including 55 up-regulated and 184 down-regulated genes in Fstl1 knockdown mice by RNA-Seq analysis, as well as neurotransmitter transport, synaptic transmission and disease-related genes. The expression changes of some DEGs were further validated via quantitative Realtime PCR (qRT-PCR). Further patch-clamp whole cell recording showed that Fstl1+/− mice displayed a significant decrease in glutamatergic synaptic transmission and increase in GABAergic synaptic transmission, which were consistent with the RNA-Seq analysis. Taken together, our results provide an evidence and a possibly underlying mechanism for the critical role of FSTL1 in the hippocampus on learning and memory and normal neural oscillations, suggesting that FSTL1 may plays an important role in neurodegenerative diseases related to cognitive impairments.

Neurexin1α Differentially Regulates Synaptic Efficacy within Striatal Circuits

Mutations in genes essential for shared aspects of synaptic function throughout the CNS, such as the presynaptic adhesion molecule Neurexin1α (Nrxn1α), are strongly implicated in neuropsychiatric pathophysiology. As the input nucleus of the basal ganglia, the striatum integrates diverse excitatory projections governing cognitive and motor control, and its functional impairment underlies neuropsychiatric disorders. While prior work has emphasized Neurexins’ contributions to synaptic transmission in hippocampus and brainstem, their function in striatal circuits remains unstudied. As Nrxn1α is highly expressed at striatal inputs, we employed optogenetic-mediated afferent recruitment of dorsal prefrontal cortex-dorsomedial striatal (DMS) connections, uncovering a decrease in net synaptic strength specifically onto indirect pathway spiny neurons in both Nrxn1α+/- and Nrxn1α-/- mice, driven by reductions in transmitter release probability. In contrast, thalamic excitatory inputs to DMS demonstrated relatively normal excitatory synaptic strength. These findings suggest that dysregulation of Nrxn1α modulates striatal function in an input and target-specific manner.

Aging Alters Olfactory Bulb Network Oscillations and Connectivity: Relevance for Aging-Related Neurodegeneration Studies.

The aging process eventually cause a breakdown in critical synaptic plasticity and connectivity leading to deficits in memory function. The olfactory bulb (OB) and the hippocampus, both regions of the brain considered critical for the processing of odors and spatial memory, are commonly affected by aging. Using an aged wild-type C57B/6 mouse model, we sought to define the effects of aging on hippocampal plasticity and the integrity of cortical circuits. Specifically, we measured the long-term potentiation of high-frequency stimulation (HFS-LTP) at the Shaffer-Collateral CA1 pyramidal synapses. Next, local field potential (LFP) spectra, phase-amplitude theta-gamma coupling (PAC), and connectivity through coherence were assessed in the olfactory bulb, frontal and entorhinal cortices, CA1, and amygdala circuits. The OB of aged mice showed a significant increase in the number of histone H2AX-positive neurons, a marker of DNA damage. While the input-output relationship measure of basal synaptic activity was found not to differ between young and aged mice, a pronounced decline in the slope of field excitatory postsynaptic potential (fEPSP) and the population spike amplitude (PSA) were found in aged mice. Furthermore, aging was accompanied by deficits in gamma network oscillations, a shift to slow oscillations, reduced coherence and theta-gamma PAC in the OB circuit. Thus, while the basal synaptic activity was unaltered in older mice, impairment in hippocampal synaptic transmission was observed only in response to HFS. However, age-dependent alterations in neural network appeared spontaneously in the OB circuit, suggesting the neurophysiological basis of synaptic deficits underlying olfactory processing. Taken together, the results highlight the sensitivity and therefore potential use of LFP quantitative network oscillations and connectivity at the OB level as objective electrophysiological markers that will help reveal specific dysfunctional circuits in aging-related neurodegeneration studies.

Neurotoxic effects of high-dose piperine on hippocampal synaptic transmission and synaptic plasticity in a rat model of memory impairment

In recent years, piperine has attracted much attention due to its various biological effects as a neuroprotective agent. Therefore, clarification of the possible side effects of piperine is important to identify its potential pharmacological action. Thus, the effects of piperine on the long-term plasticity of perforant pathway to dentate gyrus synapses were studied in hippocampus of an animal model of Alzheimer's disease (AD).Adult male rats were injected with intracerebroventricular (ICV) streptozotocin (STZ) bilaterally, on days 1 and 3 (3 mg/kg). The STZ-injected rats were treated with different doses of piperine for 4 weeks before being used in behavioral, electrophysiological and histopathological experiments. The passive-avoidance test was conducted on all animals in order to determine the cognitive performance. Rats were placed in a stereotaxic frame to implant a recording electrode in the hippocampal dentate gyrus and a stimulating electrode in the perforant path. Additionally, we assessed the density of survived neurons stained by cresyl violet.In this study, chronic administration of piperine low dose improved the ICV-STZ induced learning and long-term potentiation (LTP) impairments with no significant effect on baseline synaptic activity. In contrast, remarkable learning and long-term plasticity impairments were observed in rats treated by high dose of piperine in comparison to the other groups. Interestingly, this impaired hippocampal LTP was accompanied by an obvious alteration in baseline activity and significantly decreased neuronal numbers within the hippocampus. Therefore, our data provides a new understanding of the piperine supplementation effects on hippocampal electrophysiological profile although the consequences may be either beneficial or detrimental.

Nicotine abolishes memory-related synaptic strengthening and promotes synaptic depression in the neurogenic dentate gyrus of miR-132/212 knockout mice.

Micro‐RNAs (miRNAs) are highly evolutionarily conserved short‐length/noncoding RNA molecules that modulate a wide range of cellular functions in many cell types by regulating the expression of a variety of targeted genes. miRNAs have also recently emerged as key regulators of neuronal genes mediating the effects of psychostimulant drugs and memory‐related neuroplasticity processes. Smoking is a predominant addictive behaviour associated with millions of deaths worldwide, and nicotine is a potent natural psychoactive agonist of cholinergic receptors, highly abundant in cigarettes. The influence of miRNAs modulation on cholinergic signalling in the nervous system remains however poorly explored. Using miRNA knockout mice and biochemical, electrophysiological and pharmacological approaches, we examined the effects of miR‐132/212 gene disruption on the levels of hippocampal nicotinic acetylcholine receptors, total ERK and phosphorylated ERK (pERK) and MeCP2 protein levels, and studied the impact of nicotine stimulation on hippocampal synaptic transmission and synaptic depression and strengthening. miR‐132/212 deletion significantly altered α7‐nAChR and pERK protein levels, but not total ERK or MeCP2, and resulted in both exacerbated synaptic depression and virtually abolished memory‐related synaptic strengthening upon nicotine stimulation. These observations reveal a functional miRNAs/nicotinergic signalling interplay critical for nicotinic‐receptor expression and neuroplasticity in brain structures relevant for drug addiction and learning and memory functions.

Activation of nicotinic acetylcholine receptors induces potentiation and synchronization within in vitro hippocampal networks

Nicotinic acetylcholine receptors (nAChRs) are known to play a role in cognitive functions of the hippocampus, such as memory consolidation. Given that they conduct Ca2+ and are capable of regulating the release of glutamate and γ‐aminobutyric acid (GABA) within the hippocampus, thereby shifting the excitatory‐inhibitory ratio, we hypothesized that the activation of nAChRs will result in the potentiation of hippocampal networks and alter synchronization. We used nicotine as a tool to investigate the impact of activation of nAChRs on neuronal network dynamics in primary embryonic rat hippocampal cultures prepared from timed‐pregnant Sprague‐Dawley rats. We perturbed cultured hippocampal networks with increasing concentrations of bath‐applied nicotine and performed network extracellular recordings of action potentials using a microelectrode array (MEA). We found that nicotine modulated network dynamics in a concentration‐dependent manner; it enhanced firing of action potentials as well as facilitated bursting activity. In addition, we used pharmacological agents to determine the contributions of discrete nAChR subtypes to the observed network dynamics. We found that β4‐containing nAChRs are necessary for the observed increases in spiking, bursting and synchrony, while the activation of α7 nAChRs augments nicotine‐mediated network potentiation but is not necessary for its manifestation. We also observed that antagonists of N‐methyl‐D‐aspartate receptors (NMDARs) and group I metabotropic glutamate receptors (mGluRs) partially blocked the effects of nicotine. Furthermore, nicotine exposure promoted autophosphorylation of Ca2+/calmodulin‐dependent kinase II (CaMKII) and serine 831 phosphorylation of the α‐amino‐3‐hydroxy‐5‐methyl‐4‐isoxazolepropionic acid receptor (AMPAR) subunit GluA1. These results suggest that nicotinic receptors induce potentiation and synchronization of hippocampal networks and glutamatergic synaptic transmission. Findings from this work highlight the impact of cholinergic signaling in generating network‐wide potentiation in the form of enhanced spiking and bursting dynamics that coincide with molecular correlates of memory such as increased phosphorylation of CaMKII and GluA1.Support or Funding InformationNational Science Foundation (PHY‐1205919 and IOS‐ 1755033), National Institutes of Health (RF1 AG056603‐01) and the Georgetown‐MedStar CERSI Scholars program.

Brainstem catecholaminergic neurons mediate cognitive impairment in heart failure rats through regulation of hippocampal synaptic‐related gene expression.

Heart failure (HF) is common in elder population and it is highly associated with cognitive impairment (CI). Several studies suggest that autonomic imbalance contribute to age‐related CI. We previously showed that catecholaminergic neurons (C1) from the rostral ventrolateral medulla (RVLM) displayed chronic activation in HF. In addition, we also shown that HF rats showed CI. Whether RVLM‐C1 neurons contribute to CI in the setting of HF is completely unknown. Therefore, we aimed to study the contribution of RVLM‐C1 neurons on cognitive function in HF. Adult male Sprague‐Dawley rats underwent volume overload to induce HF. Anti‐dopamine β‐hydroxylase‐saporin (DβH–SAP: 5ng/150nl) was used to selectively destroy RVLM‐C1 neurons. Morris water maze (MWM) test was used to assess learning and memory performance. Micropunches containing the hippocampus were dissected to measure the expression of several synaptic‐related genes using a custom 12‐gene array by qRT‐PCR. HF rats displayed learning and memory impairment compared to control animals. Indeed, HF showed an increased traveled distance to the target platform along 5 trial/days during MWM test (15.1±0.5 vs. 30.7±2.1 m; Control vs. HF, respectively; p<.05). In addition, when the platform was changed daily to a different quadrant (i.e. to evaluate reference memory) HF rats showed an increase in the number of trials required to reach the platform compared to control rats (4.2±0.1 ± vs. 8.2±1.2 trials; Control vs. HF, respectively; p<.05). Partial ablation of RVLM‐C1 neurons in HF rats decreased traveled distance to reach the target platform compared to HF rats without treatment (18.1±1 vs 30.7±2.1 m; HFDβH–SAP vs. HF, respectively; p<.05). Also, during memory testing HF untreated rats needed almost twice the number of trials to accomplish the task when compared to HF+DβH–SAP rats (4.4±0.4 vs. 8.2±1.2 trials; HFDβH–SAP vs. HF, respectively; p<.05). Finally, compared to control rats, HF rats display (Ctrl vs. HF, in AU) decreased levels of PSD‐95 (1.0±0.2 vs. 0.4±0.3), Hommer1 (1.0±0.2 vs. 0.6±0.3), CaMKIV (1.0±0.2 vs. 0.5±0.3), Piccolo (1.0±0.3 vs. 0.4±0.2), Erc2 (1.0±0.3 vs. 0.2±0.1), RIM (1.0±0.5 vs. 0.3±0.2), Neuroligin 3 (1.0±0.4 vs. 0.5±0.3), Neuroxin 1 (1.0±0.3 vs. 0.6±0.4) and Synaptotagmin‐1 (1.0±0.3 vs. 0.6±0.1). Importantly, DβH–SAP treatment in HF significantly restored the expression levels of Hommer1, Piccolo, Erc2, RIM and Synaptotagmin‐1 to levels observed in control rats. Taken together, our results show that catecholaminergic RVLM neurons contribute to CI in HF rats. In addition, our results suggest that RVLM‐C1 may regulate hippocampal synaptic transmission in the setting of HF through the regulation of gene expression in the hippocampus.Support or Funding InformationSupported by FONDECYT 1180172 and 3190659 and the basal Center of Excellence in Aging and Regeneration (AFB 170005).

Dietary intake of polyunsaturated fatty acids alleviates cognition deficits and depression-like behaviour via cannabinoid system in sleep deprivation rats

Sleep deprivation (SD) is a common feature in modern society. Prolonged sleep deprivation causes cognition deficits and depression-like behavior in the model of animal experiments. Endocannabinoid system are key modulators of synaptic function, which were related to memory and mood. Although the underlying mechanism remains unknown, several studies indicated the benefits of polyunsaturated fatty acids (PUFAs, linolenic acid, 39.7 %; linoleic acid, 28 %; and oleic acid, 22 %) on brain function through the endocannabinoid system. The present study aimed to evaluate the influence of dietary PUFAs on cognition deficits induced by sleep deprivation in Sprague Dawley rats. The rats were sleep deprivation continuously for 7 days and fed with PUFAs at three different dosages (2, 4 and 8 μl/g body weight) at the meantime. The effect of PUFAs on cognition was investigated by object recognition test while depressive-like behavior were detected using sucrose preference test and forced swim test. The mechanism of PUFAs was elucidated by hippocampal synaptic transmission analyses. The resluts revealed that SD led to the disorder of cognition and mood which was improved by the supplement of PUFAs. SD significantly increased the mEPSC frequency, and decreased the protein level of cannabinoid type-1 receptors (CB1R). These changes were restored by supplement of PUFAs, which showed a similar level to the control group. Behaviour tests showed that the positive effects on repairing cognition and anxiety disorders were almost completely abolished when the CB1R receptor antagonist rimonabant was applied to the SD rats. These findings indicated that PUFAs are a factor regulating cognition deficits and depression induced by SD via cannabinoid type-1 receptors.

Amelioration of hippocampal dysfunction by adipose tissue-targeted stem cell transplantation in a mouse model of type 2 diabetes.

There is growing evidence that type 2 diabetes or insulin resistance is linked to cognitive impairment. We recently confirmed altered lipid composition, down-regulation of insulin receptor expression and impaired basal synaptic transmission in the hippocampus ofour transgenic murine model of adipocyte insulin resistance (AtENPP1-Tg). Here we evaluated whether the correction of adipose tissue dysfunction [via the subcutaneous transplantation of mesenchymal stem cells (MSC)] can improve the hippocampal synaptic transmission in AtENPP1-Tg mice versus their wildtype littermates. Animals were simply randomized to receive MSC, then weighed weekly for 12weeks. At euthanasia, we assessed leptin in the collected serum and hippocampal synaptic high-frequency stimulation long-term potentiation (HFS-LTP) using brain slices. MSC transplantation normalized AtENPP1-Tg body and epididymal fat weights and was associated with increased leptin levels, a sign of adipocyte maturation. More importantly, transplantation restored the deficiency observed in AtENPP1-Tg HFS-LTP, the cellular readout of memory. Our results further corroborate the role of adipocyte maturation arrest in adipose tissue and highlight a role for the adipose tissue in modulating hippocampal cellular mechanisms. Further studies are warranted to explore the mechanisms for the MSC-induced improvement of hippocampal HFS-LTP.

Dorsoventral-Specific Effects of Nerve Agent Surrogate Diisopropylfluorophosphate on Synaptic Transmission in the Mouse Hippocampus.

Although there has been an increasing appreciation for functional differences between the dorsal (dH) and ventral (vH) hippocampal sectors, there is a lack of information characterizing the cholinergic and noncholinergic mechanisms of acetylcholinesterase inhibitors on synaptic transmission along the hippocampal dorsoventral axis. Diisopropylfluorophosphate (DFP) is an organophosphate (OP) that is commonly employed as a nerve agent surrogate in vitro as well as in rodent models of disease states, such as Gulf War Illness. The present study investigated the cholinergic and noncholinergic mechanisms responsible for the effects of acute DFP exposure on dH and vH synaptic transmission in a hippocampal slice preparation. A paired-pulse extracellular recording protocol was used to monitor the population spike (PS) amplitude as well as the PS paired-pulse ratio (PS-PPR) in the CA1 subfield of the dH and the vH. We observed that DFP-induced PS1 inhibition was produced by a cholinergic mechanism in the dH, whereas a noncholinergic mechanism was indispensable in mediating the inhibitory effect of DFP on the PS1 in the vH. PS-PPR in both dH and vH sectors was increased by acute DFP exposure, an effect that was blocked by an N-methyl-D-aspartate receptor antagonist but not by cholinergic antagonists. Clinical reports have indicated dorsoventral-specific hippocampal abnormalities in cases of OP intoxications. Therefore, the observed dorsoventral-specific noncholinergic mechanisms underlying the effects of DFP on hippocampal synaptic transmission may have important implications for the treatment of OP overexposures. SIGNIFICANCE STATEMENT: It is unknown if acetylcholinesterase inhibitors differentially impact dorsal and ventral hippocampal synaptic transmission. The data in the present study show that an organophosphate, diisopropylfluorophosphate, impacts glutamatergic transmission along the dorsoventral axis in a hippocampal slice preparation via distinct cholinergic and noncholinergic mechanisms. These findings may provide insight into investigations of therapeutic agents that target noncholinergic mechanisms in cases of organophosphate overexposures.

Early Cognitive Impairment Behind Nigrostriatal Circuit Neurotoxicity: Are Astrocytes Involved?

Cognitive dysfunction is one of the most severe nonmotor symptoms of nigrostriatal impairment. This occurs as a result of profound functional and morphological changes of different neuronal circuits, including modifications in the plasticity and architecture of hippocampal synapses. Such alterations can be implicated in the genesis and progression of dementia associated with neurodegenerative diseases including Parkinson-like symptoms. There are few studies regarding cognitive changes in nigrostriatal animal models. The aim of this study was to characterize the onset of memory deficit after induction of neurotoxicity with 6-hydroxydopamine (6-OHDA) and its correlation with hippocampal dysfunction. For this, we bilaterally microinjected 6-OHDA in dorsolateral Caudate-Putamen unit (CPu) and then, animals were tested weekly for working memory, spatial short-term memory, and motor performance. We evaluated tyrosine hydroxylase (TH) as a dopamine marker, aldehyde dehydrogenase 2 (ALDH2), a mitochondria detoxification enzyme and astrocyte glial fibrillar acid protein (GFAP) an immunoreactivity marker involved in different areas: CPu, substantia nigra, prefrontal cortex, and hippocampus. We observed a specific prefrontal cortex and nigrostriatal pathway TH reduction while ALDH2 showed a decrease-positive area in all the studied regions. Moreover, GFAP showed a specific CPu decrease and hippocampus increase of positively stained area on the third week after toxicity. We also evaluated the threshold to induce long-term potentiation in hippocampal excitability. Our findings showed that reduced hippocampal synaptic transmission was accompanied by deficits in memory processes, without affecting motor performance on the third-week post 6-OHDA administration. Our results suggest that 3 weeks after neurotoxic administration, astrocytes and ALDH2 mitochondrial enzyme modifications participate in altering the properties that negatively affect hippocampal function and consequently cognitive behavior.

Activation of nicotinic acetylcholine receptors induces potentiation and synchronization within in vitro hippocampal networks.

Nicotinic acetylcholine receptors (nAChRs) are known to play a role in cognitive functions of the hippocampus, such as memory consolidation. Given that they conduct Ca2+ and are capable of regulating the release of glutamate and γ-aminobutyric acid (GABA) within the hippocampus, thereby shifting the excitatory-inhibitory ratio, we hypothesized that the activation of nAChRs will result in the potentiation of hippocampal networks and alter synchronization. We used nicotine as a tool to investigate the impact of activation of nAChRs on neuronal network dynamics in primary embryonic rat hippocampal cultures prepared from timed-pregnant Sprague-Dawley rats. We perturbed cultured hippocampal networks with increasing concentrations of bath-applied nicotine and performed network extracellular recordings of action potentials using a microelectrode array. We found that nicotine modulated network dynamics in a concentration-dependent manner; it enhanced firing of action potentials as well as facilitated bursting activity. In addition, we used pharmacological agents to determine the contributions of discrete nAChR subtypes to the observed network dynamics. We found that β4-containing nAChRs are necessary for the observed increases in spiking, bursting, and synchrony, while the activation of α7 nAChRs augments nicotine-mediated network potentiation but is not necessary for its manifestation. We also observed that antagonists of N-methyl-D-aspartate receptors (NMDARs) and group I metabotropic glutamate receptors (mGluRs) partially blocked the effects of nicotine. Furthermore, nicotine exposure promoted autophosphorylation of Ca2+ /calmodulin-dependent kinase II (CaMKII) and serine 831 phosphorylation of the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) subunit GluA1. These results suggest that nicotinic receptors induce potentiation and synchronization of hippocampal networks and glutamatergic synaptic transmission. Findings from this work highlight the impact of cholinergic signaling in generating network-wide potentiation in the form of enhanced spiking and bursting dynamics that coincide with molecular correlates of memory such as increased phosphorylation of CaMKII and GluA1. OPEN SCIENCE BADGES: This article has received a badge for *Open Materials* because it provided all relevant information to reproduce the study in the manuscript. More information about the Open Practices badges can be found at https://cos.io/our-services/open-science-badges/.

Sex-specific Difference of Hippocampal Synaptic Plasticity in Response to Sex Neurosteroids.

Numerous studies provide increasing evidence, which supports the ideas that every cell in the brain of males may differ from those in females due to differences in sex chromosome complement as well as in response to hormonal effects. In this study, we address the question as to whether actions of neurosteroids, thus steroids, which are synthesized and function within the brain, contribute to sex-specific hippocampal synaptic plasticity. We have previously shown that predominantly in the female hippocampus, does inhibition of the conversion of testosterone to estradiol affect synaptic transmission. In this study, we show that testosterone and its metabolite dihydrotestosterone are essential for hippocampal synaptic transmission specifically in males. This also holds true for the density of mushroom spines and of spine synapses. We obtained similar sex-dependent results using primary hippocampal cultures of male and female animals. Since these cultures originated from perinatal animals, our findings argue for sex-dependent differentiation of hippocampal neurons regarding their responsiveness to sex neurosteroids up to birth, which persist during adulthood. Hence, our in vitro findings may point to a developmental effect either directly induced by sex chromosomes or indirectly by fetal testosterone secretion during the perinatal critical period, when developmental sexual priming takes place.