Hippocampal Synaptic Activity Research Articles

5-HT6 Receptors Sex-Dependently Modulate Hippocampal Synaptic Activity through GABA Inhibition.

The subtype 6 of the serotoninergic receptors (5-HT6Rs) is highly expressed in the hippocampus, and evidence indicates the beneficial effects of 5-HT6Rs blockade on short- and long-term memory in rodents. Nevertheless, the underlying functional mechanisms still need to be established. To this end, we performed electrophysiological extracellular recordings to assess the effects of the 5-HT6Rs antagonist SB-271046 on the synaptic activity and functional plasticity at the CA3/CA1 hippocampal connections of male and female mice slices. We found that basal excitatory synaptic transmission and isolated N-methyl-D-aspartate receptors (NMDARs) activation were significantly increased by SB-271046. The NMDARs-related improvement was prevented by the GABAAR antagonist bicuculline in male but not in female mice. Regarding synaptic plasticity, neither paired-pulse facilitation (PPF) nor NMDARs-dependent long-term potentiation (LTP) (induced either by high-frequency or theta-burst stimulation) was affected by the 5-HT6Rs blockade. Taken together, our results indicate a sex-dependent 5-HT6Rs effect on synaptic activity at the CA3/CA1 hippocampal connections through changes in the excitation/inhibition balance.

Upregulation of astroglial connexin 30 impairs hippocampal synaptic activity and recognition memory.

Astrocytes crucially contribute to synaptic physiology and information processing. One of their key characteristics is to express high levels of connexins (Cxs), the gap junction-forming protein. Among them, Cx30 displays specific properties since it is postnatally expressed and dynamically upregulated by neuronal activity and modulates cognitive processes by shaping synaptic and network activities, as recently shown in knockout mice. However, it remains unknown whether local and selective upregulation of Cx30 in postnatal astrocytes within a physiological range modulates neuronal activities in the hippocampus. We here show in mice that, whereas Cx30 upregulation increases the connectivity of astroglial networks, it decreases spontaneous and evoked synaptic transmission. This effect results from a reduced neuronal excitability and translates into an alteration in the induction of synaptic plasticity and an in vivo impairment in learning processes. Altogether, these results suggest that astroglial networks have a physiologically optimized size to appropriately regulate neuronal functions.

Deubiquitinase CYLD regulates excitatory synaptic transmission and short-term plasticity in the hippocampus

The fate of proteins is determined by the addition of various forms of polyubiquitin during ubiquitin-mediated proteasomal degradation. Cylindromatosis (CYLD), a K63-specific deubiquitinase, is enriched in postsynaptic density fractions of the rodent central nervous system (CNS), but the synaptic role of CYLD in the CNS is poorly understand. Here we show that CYLD deficiency (Cyld−/−) results in reduced intrinsic hippocampal neuronal firing, a decrease in the frequency of spontaneous excitatory postsynaptic currents and a decrease in the amplitude of field excitatory postsynaptic potentials. Moreover, Cyld−/− hippocampus shows downregulated levels of presynaptic vesicular glutamate transporter 1 (vGlut1) and upregulated levels of postsynaptic GluA1, a subunit of the AMPA receptor, together with an altered paired-pulse ratio (PPR). We also found increased activation of astrocytes and microglia in the hippocampus of Cyld−/− mice. The present study suggests a critical role for CYLD in mediating hippocampal neuronal and synaptic activity.

Betaine prevents and reverses the behavioral deficits and synaptic dysfunction induced by repeated ketamine exposure in mice

As an N-methyl-D-aspartate (NMDA) receptor inhibitor, ketamine has become a popular recreational substance and currently is used to address treatment-resistant depression. Since heavy ketamine use is associated with persisting psychosis, cognitive impairments, and neuronal damage, the safety of ketamine treatment for depression should be concerned. The nutrient supplement betaine has been shown to counteract the acute ketamine-induced psychotomimetic effects and cognitive dysfunction through modulating NMDA receptors. This study aimed to determine whether the adjunctive or subsequent betaine treatment would improve the enduring behavioral disturbances and hippocampal synaptic abnormality induced by repeated ketamine exposure. Mice received ketamine twice daily for 14 days, either combined with betaine co-treatment or subsequent betaine post-treatment for 7 days. Thereafter, three-chamber social approach test, reciprocal social interaction, novel location/object recognition test, forced swimming test, and head-twitch response induced by serotonergic hallucinogen were monitored. Data showed that the enduring behavioral abnormalities after repeated ketamine exposure, including disrupted social behaviors, recognition memory impairments, and increased depression-like and hallucinogen-induced head-twitch responses, were remarkably improved by betaine co-treatment or post-treatment. Consistently, betaine protected and reversed the reduced hippocampal synaptic activity, such as decreases in field excitatory post-synaptic potentiation (fEPSP), long-term potentiation (LTP), and PSD-95 levels, after repeated ketamine treatment. These results demonstrated that both co-treatment and post-treatment with betaine could effectively prevent and reverse the adverse behavioral manifestations and hippocampal synaptic plasticity after repeated ketamine use, suggesting that betaine can be used as a novel adjunct therapy with ketamine for treatment-resistant depression and provide benefits for ketamine use disorders.

Lentiviral Expression of Rabies Virus Glycoprotein in the Rat Hippocampus Strengthens Synaptic Plasticity.

Rabies virus (RABV) is a neurotropic virus exclusively infecting neurons in the central nervous system. RABV encodes five proteins. Among them, the viral glycoprotein (RVG) plays a key role in viral entry into neurons and rabies pathogenesis. It was shown that the nature of the C-terminus of the RABV G protein, which possesses a PDZ-binding motif (PBM), modulates the virulence of the RABV strain. The neuronal protein partners recruited by this PBM may alter host cell function. This study was conducted to investigate the effect of RVG on synaptic function in the hippocampal dentate gyrus (DG) of rat. Two μl (108T.U./ml) of the lentiviral vector containing RVG gene was injected into the DG of rat hippocampus. After 2weeks, the rat's brain was cross-sectioned and RVG-expressing cells were detected by fluorescent microscopy. Hippocampal synaptic activity of the infected rats was then examined by recording the local field potentials from DG after stimulation of the perforant pathway. Short-term synaptic plasticity was also assessed by double pulse stimulation. Expression of RVG in DG increased long-term potentiation population spikes (LTP-PS), whereas no facilitation of LTP-PS was found in neurons expressing δRVG (deleted PBM). Furthermore, RVG and δRVG strengthened paired-pulse facilitation. Heterosynaptic long-term depression (LTD) in the DG was significantly blocked in RVG-expressing group compared to the control group. This blockade was dependent to PBM motif as rats expressing δRVG in the DG-expressed LTD comparable to the RVG group. Our data demonstrate that RVG expression facilitates both short- and long-term synaptic plasticity in the DG indicating that it may involve both pre- and postsynaptic mechanisms to alter synaptic function. Further studies are needed to elucidate the underlying mechanisms.

Altered mastication adversely impacts morpho-functional features of the hippocampus: A systematic review on animal studies in three different experimental conditionsinvolving the masticatory function.

Recent results have established that masticatory function plays a role not only in the balance of the stomatognathic system and in the central motor control, but also in the trophism of the hippocampus and in the cognitive activity. These implications have been shown in clinical studies and in animal researches as well, by means of histological, biochemical and behavioural techniques. This systematic review describes the effects of three forms of experimentally altered mastication, namely soft-diet feeding, molar extraction and bite-raising, on the trophism and function of the hippocampus in animal models. Through a systematic search of PubMed, Embase, Web of Science, Scopus, OpenGray and GrayMatters, 645 articles were identified, 33 full text articles were assessed for eligibility and 28 articles were included in the review process. The comprehensiveness of reporting was evaluated with the ARRIVE guidelines and the risk of bias with the SYRCLE RoB tool. The literature reviewed agrees that a disturbed mastication is significantly associated with a reduced number of hippocampal pyramidal neurons in Cornu Ammonis (CA)1 and CA3, downregulation of Brain Derived Neurotrophic Factor (BDNF), reduced synaptic activity, reduced neurogenesis in the Dentate Gyrus (DG), glial proliferation, and reduced performances in behavioural tests, indicating memory impairment and reduced spatial orientation. Moreover, while the bite-raised condition, characterized by occlusal instability, is known to be a source of stress, soft-diet feeding and molar extractions were not consistently associated with a stress response. More research is needed to clarify this topic. The emerging role of chewing in the preservation of hippocampal trophism, neurogenesis and synaptic activity is worthy of interest and may contribute to the study of neurodegenerative diseases in new and potentially relevant ways.

Long-term consequences of early postnatal lead exposure on hippocampal synaptic activity in adult mice.

IntroductionLead (Pb) exposure yielding blood lead levels (BLL) as low as 2 µg/dl in children is an international problem. More common in US low‐income neighborhoods, childhood Pb exposure can cause behavioral and cognitive deficits, including working memory impairments, which can persist into adulthood. So far, studies characterized short‐term effects of high Pb exposure on neuronal structure and function. However, long‐term consequences of early chronic Pb exposure on neuronal activity are poorly documented.MethodsHere, we exposed male and female mice (PND [postnatal day] 0 to PND 28) to one of three Pb treatments: 0 ppm (sodium‐treated water, control), 30 ppm (low dose), and 330 ppm (high dose) lead acetate. Once the male and female mice were 9–12 months old, extracellular field recordings on hippocampal slices were performed.ResultsWe show that at CA3 to CA1 synapses, synaptic transmission was decreased and neuronal fiber activity was increased in males exposed to lowest level Pb. In contrast, both synaptic transmission and neuronal fiber activity were increased in females exposed to high Pb. The ventral hippocampus–medial prefrontal cortex (vHPC–mPFC) synapses are crucial for working memory in rodents. The lowest level Pb decreased vHPC–mPFC synaptic transmission, whereas high Pb decreased short‐term synaptic depression.ConclusionsOverall, we show for the first time that early exposure to either high or lowest level Pb has long‐term consequences on different synaptic properties of at least two hippocampal synapses. Such consequences of early Pb exposure might worsen the cognitive decline observed in aging men and women. Our results suggest that additional efforts should focus on the consequences of early Pb exposure especially in at‐risk communities.

Interleukin-16 inhibits sodium channel function and GluA1 phosphorylation via CD4- and CD9-independent mechanisms to reduce hippocampal neuronal excitability and synaptic activity

Interleukin 16 (IL-16) is a cytokine that is primarily associated with CD4+ T cell function, but also exists as a multi-domain PDZ protein expressed within cerebellar and hippocampal neurons. We have previously shown that lymphocyte-derived IL-16 is neuroprotective against excitotoxicity, but evidence of how it affects neuronal function is limited. Here, we have investigated whether IL-16 modulates neuronal excitability and synaptic activity in mouse primary hippocampal cultures. Application of recombinant IL-16 impairs both glutamate-induced increases in intracellular Ca2+ and sEPSC frequency and amplitude in a CD4- and CD9-independent manner. We examined the mechanisms underlying these effects, with rIL-16 reducing GluA1 S831 phosphorylation and inhibiting Na+ channel function. Taken together, these data suggest that IL-16 reduces neuronal excitability and synaptic activity via multiple mechanisms and adds further evidence that alternative receptors may exist for IL-16.

Impaired anandamide/palmitoylethanolamide signaling in hippocampal glutamatergic neurons alters synaptic plasticity, learning, and emotional responses

Endocannabinoid signaling via anandamide (AEA) is implicated in a variety of neuronal functions and considered a promising therapeutic target for numerous emotion-related disorders. The major AEA degrading enzyme is fatty acid amide hydrolase (FAAH). Genetic deletion and pharmacological inhibition of FAAH reduce anxiety and improve emotional responses and memory in rodents and humans. Complementarily, the mechanisms and impact of decreased AEA signaling remain to be delineated in detail. In the present study, using the Cre/loxP system combined with an adeno-associated virus (AAV)-mediated delivery system, FAAH was selectively overexpressed in hippocampal CA1-CA3 glutamatergic neurons of adult mice. This approach led to specific FAAH overexpression at the postsynaptic site of CA1-CA3 neurons, to increased FAAH enzymatic activity, and, in consequence, to decreased hippocampal levels of AEA and palmitoylethanolamide (PEA), but the levels of the second major endocannabinoid 2-arachidonoyl glycerol (2-AG) and of oleoylethanolamide (OEA) were unchanged. Electrophysiological recordings revealed an enhancement of both excitatory and inhibitory synaptic activity and of long-term potentiation (LTP). In contrast, excitatory and inhibitory long-term depression (LTD) and short-term synaptic plasticity, apparent as depolarization-induced suppression of excitation (DSE) and inhibition (DSI), remained unaltered. These changes in hippocampal synaptic activity were associated with an increase in anxiety-like behavior, and a deficit in object recognition memory and in extinction of aversive memory. This study indicates that AEA is not involved in hippocampal short-term plasticity, or eLTD and iLTD, but modulates glutamatergic transmission most likely via presynaptic sites, and that disturbances in this process impair learning and emotional responses.

Blocking TNFα-driven astrocyte purinergic signaling restores normal synaptic activity during epileptogenesis.

Epilepsy is characterized by unpredictable recurrent seizures resulting from abnormal neuronal excitability. Increasing evidence indicates that aberrant astrocyte signaling to neurons plays an important role in driving the network hyperexcitability, but the underlying mechanism that alters glial signaling in epilepsy remains unknown. Increase in glutamate release by astrocytes participates in the onset and progression of seizures. Epileptic seizures are also accompanied by increase of tumor necrosis factor alpha (TNFα), a cytokine involved in the regulation of astrocyte glutamate release. Here we tested whether TNFα controls abnormal astrocyte glutamate signaling in epilepsy and through which mechanism. Combining Ca2+ imaging, optogenetics, and electrophysiology, we report that TNFα triggers a Ca2+ -dependent glutamate release from astrocytes that boosts excitatory synaptic activity in the hippocampus through a mechanism involving autocrine activation of P2Y1 receptors by astrocyte-derived ATP/ADP. In a mouse model of temporal lobe epilepsy, such TNFα-driven astrocytic purinergic signaling is permanently active, promotes glial glutamate release, and drives abnormal synaptic activity in the hippocampus. Blocking this pathway by inhibiting P2Y1 receptors restores normal excitatory synaptic activity in the inflamed hippocampus. Our findings indicate that targeting the coupling of TNFα with astrocyte purinergic signaling may be a therapeutic strategy for reducing glial glutamate release and normalizing synaptic activity in epilepsy.

Ethanol Tolerance Affects Endogenous Adenosine Signaling in Mouse Hippocampus

Ethanol has many pharmacological effects, including increases in endogenous adenosine levels and adenosine receptor activity in brain. Ethanol consumption is associated with both positive and negative health outcomes, but tolerance to the behavioral effects of ethanol can lead to increased consumption, which increases the risk of negative health outcomes. The present study was performed to test whether a 7-day treatment with ethanol is linked to reduced adenosine signaling and whether this is a consequence of reduced ecto-5′-nucleotidase activity. Wild-type (CD73+/+) and ecto-5′-nucleotidase-deficient (CD73−/−) mice were treated with ethanol (2 g/kg) or saline for 7 days. In CD73+/+ mice, repeated ethanol treatment reduced the hypothermic and ataxic effects of acute ethanol, indicating the development of tolerance to the acute effects of ethanol. In CD73+/+ mice, this 7-day ethanol treatment led to increased hippocampal synaptic activity and reduced adenosine A1 receptor activity under both basal and low Mg2+ conditions. These effects of ethanol tolerance were associated with an 18% decrease in activity of ecto-5′-nucleotidase activity in hippocampal cell membranes. In contrast, ethanol treatment was not associated with changes in synaptic activity or adenosine signaling in hippocampus from CD73−/− mice. These data indicate that ethanol treatment is associated with a reduction in adenosine signaling through adenosine A1 receptors in hippocampus, mediated, at least in part, via reduced ecto-5′-nucleotidase activity.

Propofol, but not etomidate, increases corticosterone levels and induces long-term alteration in hippocampal synaptic activity in neonatal rats

Animal studies provide strong evidence that general anesthetics (GAs), administered during the early postnatal period, induce long-term cognitive and neurological abnormalities. Because the brain growth spurt in rodents is delayed compared to that in humans, a fundamental question is whether the postnatal human brain is similarly vulnerable. Sevoflurane and propofol, GAs that share positive modulation of the gamma-aminobutyric acid type A receptor (GABAAR) function cause marked increase in corticosterone levels and induce long-term developmental alterations in synaptic activity in rodents. If synaptogenesis is affected, investigation of mechanisms of the synaptic effects of GAs is of high interest because synaptogenesis in humans continues for several years after birth. Here, we compared long-term synaptic effects of etomidate with those of propofol. Etomidate and propofol both positively modulate GABAAR activity, but in contrast to propofol, etomidate inhibits the adrenal synthesis of corticosterone.Postnatal day (P) 4, 5, or 6 rats received five injections of etomidate, propofol, or vehicle control during 5h of maternal separation. Endocrine effects of the anesthetics were evaluated by measuring serum levels of corticosterone immediately after anesthesia or maternal separation. The frequency and amplitude of miniature inhibitory postsynaptic currents (mIPSCs) in hippocampal CA1 pyramidal neurons were measured at P24-40 and P≥80.Only propofol caused a significant increase in serum corticosterone levels (F(4.26)=17.739, P<0.001). In contrast to increased frequency of mIPSCs in the propofol group (F(4.23)=8.731, p<0.001), mIPSC activity in the etomidate group was not different from that in the vehicle groups.The results of this study together with previously published data suggest that anesthetic-caused increase in corticosterone levels is required for GABAergic GAs to induce synaptic effects in the form of a long-term increase in the frequency of hippocampal mIPSCs.

GDF-15 Secreted from Human Umbilical Cord Blood Mesenchymal Stem Cells Delivered Through the Cerebrospinal Fluid Promotes Hippocampal Neurogenesis and Synaptic Activity in an Alzheimer's Disease Model

Our previous studies demonstrated that transplantation of human umbilical cord blood-derived mesenchymal stem cells (hUCB-MSCs) into the hippocampus of a transgenic mouse model of Alzheimer's disease (AD) reduced amyloid-β (Aβ) plaques and enhanced cognitive function through paracrine action. Due to the limited life span of hUCB-MSCs after their transplantation, the extension of hUCB-MSC efficacy was essential for AD treatment. In this study, we show that repeated cisterna magna injections of hUCB-MSCs activated endogenous hippocampal neurogenesis and significantly reduced Aβ42 levels. To identify the paracrine factors released from the hUCB-MSCs that stimulated endogenous hippocampal neurogenesis in the dentate gyrus, we cocultured adult mouse neural stem cells (NSCs) with hUCB-MSCs and analyzed the cocultured media with cytokine arrays. Growth differentiation factor-15 (GDF-15) levels were significantly increased in the media. GDF-15 suppression in hUCB-MSCs with GDF-15 small interfering RNA reduced the proliferation of NSCs in cocultures. Conversely, recombinant GDF-15 treatment in both in vitro and in vivo enhanced hippocampal NSC proliferation and neuronal differentiation. Repeated administration of hUBC-MSCs markedly promoted the expression of synaptic vesicle markers, including synaptophysin, which are downregulated in patients with AD. In addition, in vitro synaptic activity through GDF-15 was promoted. Taken together, these results indicated that repeated cisterna magna administration of hUCB-MSCs enhanced endogenous adult hippocampal neurogenesis and synaptic activity through a paracrine factor of GDF-15, suggesting a possible role of hUCB-MSCs in future treatment strategies for AD.

Developmental effects of wheel running on hippocampal glutamate receptor expression in young and mature adult rats

Recent evidence suggests that the behavioral benefits associated with voluntary wheel running in rodents may be due to modulation of glutamatergic transmission in the hippocampus, a brain region implicated in learning and memory. However, the expression of the glutamatergic ionotropic N-methyl-d-aspartate receptor (GluN) in the hippocampus in response to chronic sustained voluntary wheel running has not yet been investigated. Further, the developmental effects during young and mature adulthood on wheel running output and GluN expression in hippocampal subregions has not been determined, and therefore is the main focus of this investigation. Eight-week-old and 16-week-old male Wistar rats were housed in home cages with free access to running wheels and running output was monitored for 4weeks. Wheel access was terminated and tissues from the dorsal and ventral hippocampi were processed for Western blot analysis of GluN subunit expression. Young adult runners demonstrated an escalation in running output but this behavior was not evident in mature adult runners. In parallel, young adult runners demonstrated a significant increase in total GluN (1 and 2A) subunit expression in the dorsal hippocampus (DH), and an opposing effect in the ventral hippocampus (VH) compared to age-matched sedentary controls; these changes in total protein expression were not associated with significant alterations in the phosphorylation of the GluN subunits. In contrast, mature adult runners demonstrated a reduction in total GluN2A expression in the DH, without producing alterations in the VH compared to age-matched sedentary controls. In conclusion, differential running activity-mediated modulation of GluN subunit expression in the hippocampal subregions was revealed to be associated with developmental effects on running activity, which may contribute to altered hippocampal synaptic activity and behavioral outcomes in young and mature adult subjects.

Role of Steroids in Hyperexcitatory Adverse and Anesthetic Effects of Sevoflurane in Neonatal Rats

Recent studies have demonstrated that long-term developmental effects of neonatal anesthesia were more prominent in males. We tested whether steroids, in general, and sex steroids, in particular, are involved in the mediation of sevoflurane-caused paradoxical cortical seizures during the early postnatal period. Methods: Cortical electroencephalograms, hippocampal synaptic activity, serum levels of steroids and the loss of the righting reflex (LORR), a marker of anesthetic effect, were measured on postnatal days 4-6 in Sprague Dawley rats of both genders exposed to 2.1% sevoflurane. Results: Episodes of seizures, persistent spikes in electroencephalograms and increases in serum corticosterone were similar in both genders. In the order of increasing potency, the corticosteroid receptor antagonist RU 28318, the estradiol receptor antagonist ICI 182780 and the estradiol synthesis inhibitor formestane decreased sevoflurane-induced seizures. Exogenous estradiol increased sevoflurane-caused seizures, spikes and serum levels of corticosterone. These estradiol-enhanced seizures and spikes were depressed by ICI 182780 and the NKCC1 inhibitor, bumetanide, while RU 28318 decreased seizures only. In hippocampal CA1 neurons, estradiol increased the amplitude, rise time and area under the curve of gamma-aminobutyric acid type A receptor (GABA_AR)-mediated miniature postsynaptic currents. Exogenous estradiol shortened, while ICI 182780 and formestane lengthened the time needed for sevoflurane to induce LORR. Conclusion: These findings provide evidence for gender-independent acute electroencephalographic effects of sevoflurane at this age. Corticosterone and estradiol are involved in the mediation of sevoflurane-induced seizures. Estradiol, but not corticosterone, also contributes to sevoflurane-caused spikes, by enhancing GABA_AR-mediated excitation in the cortex. By increasing GABA_AR-mediated inhibition in more mature caudal regions of the brain, estradiol contributes to sevoflurane-induced LORR.

Transcriptional regulation of the neuropeptide VGF by the neuron-restrictive silencer factor/neuron-restrictive silencer element.

The neurotrophin-inducible gene VGF plays an important role in the maintenance of organismal energy balance and in the mediation of hippocampal synaptic activity. The regulatory mechanism of VGF transcription is not fully understood. The neuron-restrictive silencer factor (NRSF) binds with the neuron-restrictive silencer element (NRSE), thereby suppressing the transcription of NRSE-containing genes. In this study, we show that the NRSE sequence of the VGF gene critically regulates the repression of VGF expression in NMB cells. Sequence analysis also establishes the presence of two putative NRSEs (NRSE-1 and NRSE-2) in the promoter region of the VGF gene. In reporter gene experiments, a more than eight-fold increase in the promoter activity was observed when both NRSE-1 and NRSE-2 were deleted. Deletion of NRSE-2 alone did not affect the promoter activity, thus indicating that NRSE-1 could be solely responsible for the repression of VGF gene expression. Mutations in the NRSE-1 sequence increased promoter activity. However, no change in activity was observed when NRSE-1 was coexpressed with dominant-negative NRSF, thereby suggesting that endogenous NRSF interacts with NRSE-1. Binding of NRSF to NRSE in a sequence-specific manner was confirmed with chromatin immunoprecipitation assays, respectively. Furthermore, the overexpressed NRSF in PC12 cells significantly suppressed the VGF gene expression by interacting with the NRSE located in the VGF promoter region. Our results indicate that NRSF plays an important role as a repressor of VGF gene regulation in NMB cells through a mechanism that is dependent on VGF-NRSE.

α-TLR2 antibody attenuates the Aβ-mediated inflammatory response in microglia through enhanced expression of SIGIRR.

The immunoregulatory function of single-Ig-interleukin-1 related receptor (SIGIRR) is derived from its ability to constrain the inflammatory consequences of interleukin (IL)-1R and toll-like receptor (TLR)4 activation. This role extends to the brain, where SIGIRR deficiency increases the synaptic and cognitive dysfunction associated with IL-1R- and TLR4-mediated signalling. The current study set out to investigate the interaction between SIGIRR and TLR2 in brain tissue and the data demonstrate that the response to the TLR2 agonist, Pam3CysSK4 (Pam3Cys4), is enhanced in glial cells from SIGIRR(-/-) animals. Consistent with the view that β-amyloid peptide (Aβ) signals through activation of TLR2, the data also show that Aβ-induced changes are exaggerated in glia from SIGIRR(-/-) animals. We report that microglia, rather than astrocytes, are the primary glial cell expressing both TLR2 and SIGIRR. While Aβ increased TLR2 expression, it decreased SIGIRR expression in microglia. This was mimicked by direct activation of TLR2 with Pam3Cys4. We investigated the effect of an anti-TLR2 antibody (αTLR2) on the Aβ-induced inflammatory responses and demonstrate that it prevented the expression and release of the pro-inflammatory cytokines TNFα and IL-6 from microglia. In addition, application of αTLR2 alleviated the Aβ-mediated impairment in long-term potentiation (LTP) of hippocampal synaptic activity. The protective effects of αTLR2 were accompanied by an up-regulation in SIGIRR expression. We propose that a mechanism involving activation of PI3 kinase/Akt and the transcription factor peroxisome proliferator-activated receptor (PPAR)γ may facilitate this increase in SIGIRR. These findings highlight a novel role of SIGIRR as a negative regulator of TLR2-mediated inflammation in the brain.

Anti-VEGF alter cognitive functions and the CA1-CA3 hippocampal activity in mice: The first reported “Chemofog” with a targeted cancer therapy

C patients treated with chemotherapy may show impaired cognition (Chemofog) long-term after the treatment completion. Recently, targeted therapies have been developed and have been also associated with the appearance of leukoencephalopathy and major asthenia in cancer patients. Our previous work has identified a direct link between chemotherapy and impaired long-term behavioral flexibility associated with a decreased proliferation within the hippocampus and no cognitive dysfunctions after the cancer treatment everolimus in mice. In this study, we evaluated the impact of the systemic administration of an anti-VEGF antibody on cognitive function, hippocampal vascularization, cerebral metabolic activity and hippocampal synaptic activity in mice as well as on proliferation of neural stem and endothelial cells in vitro. Antibodies against the mouse VEGF (B20-4.1.1, MTA Genentech) and human VEGF (bevacizumab, Genentech, MTA, Roche) were administered to adult C57/Bl6 mice (1.5 mg/kg) every 4 days for 24 days. Note that B20-4.1.1 treatment caused a slowing of weight gain. During/or after treatment, emotional reactivity, spontaneous activity, learning and spatial memory, behavioral flexibility and object recognition memory were assessed. The selective cognitive impairments observed in B20-treated mice (spatial learning in the Morris water maze and memory consolidation in the object recognition test), were predictive of hippocampal dysfunctions. In addition, we detected modifications of the cytochrome oxidase activity in CA1-CA3 hippocampal area and markers involved in long term potentiation. However, proliferation of neural hippocampal precursors (BrdU labeling) and vascular density (Collagen IV) in vivo as well as neurosphere growth and Bend.3 endothelial cell proliferation in vitro were unaltered. Together, these data indicate that the inhibition of endogenous systemic VEGF levels does not drastically change the plasticity of the hippocampal vascular niche, but selectively alters the spatial learning dependent on the long-term potentiation in the hippocampus.

Dexmedetomidine suppresses long-term potentiation in the hippocampal CA1 field of anesthetized rats.

The aim of this study was to evaluate the effect of dexmedetomidine (DEX) on hippocampal synaptic activity in vivo. The adult rats used for this study received a intraperitoneal bolus injection of 3, 10, 30, or 100 μg/kg of DEX or an equivalent volume of saline. Electrophysiological recording of the hippocampal CA1 region was initiated 20 min after drug administration. The results are expressed as the percentages of the population spike amplitude measured just before high-frequency stimulation (HFS). The electrophysiological data were analyzed with an area under the curve (AUC) of 10-60 min after HFS. Moreover, to investigate the sedative dose of DEX in rats, we recorded the duration of loss of spontaneous movement after the administration of each dose of DEX. Intraperitoneal administration of DEX at doses of 30 and 100 μg/kg induced a range of sedative effects. The AUC measurements were significantly lower in the 30 and 100 μg/kg groups than in those injected with vehicle (vehicle: 8.81 ± 0.49, n = 7; DEX 30 µg/kg: 6.02 ± 0.99, n = 6; DEX 100 µg/kg: 5.10 ± 0.43, n = 5; P < 0.05). The results of our in vivo study reveal that sedative doses of DEX impaired the induction of hippocampal long-term potentiation (LTP). These findings may signify a causal link between DEX-induced sedative action and hippocampal LTP suppression, providing a better understanding of the mechanisms underlying the DEX-induced sedative and/or amnestic effect.

Interaction of DHPG‐LTD and synaptic‐LTD at senescent CA3‐CA1 hippocampal synapses

The susceptibility, but not the magnitude, of long-term depression (LTD) induced by hippocampal CA3-CA1 synaptic activity (synaptic-LTD) increases with advanced age. In contrast, the magnitude of LTD induced by pharmacological activation of CA3-CA1 group I metabotropic glutamate receptors (mGluRs) increases during aging. This study examined the signaling pathways involved in induction of LTD and the interaction between paired-pulse low frequency stimulation-induced synaptic-LTD and group I mGluR selective agonist, (RS)-3,5-dihydroxyphenylglycine (DHPG, 100 µM)-induced DHPG-LTD in hippocampal slices obtained from aged (22-24 months) male Fischer 344 rats. Prior induction of synaptic-LTD did not affect induction of DHPG-LTD; however, prior induction of the DHPG-LTD occluded synaptic-LTD suggesting that expression of DHPG-LTD may incorporate synaptic-LTD mechanisms. Application of individual antagonist for the group I mGluR (AIDA), the N-methyl-d-aspartate receptor (NMDAR) (AP-5), or L-type voltage-dependent Ca(2+) channel (VDCC) (nifedipine) failed to block synaptic-LTD and any two antagonists severely impaired synaptic-LTD induction, indicating that activation of any two mechanisms is sufficient to induce synaptic-LTD in aged animals. For DHPG-LTD, AIDA blocked DHPG-LTD and individually applied NMDAR or VDCC attenuated but did not block DHPG-LTD, indicating that the magnitude of DHPG-LTD depends on all three mechanisms.