Chu Chen

Postsynaptically Synthesized Prostaglandin E2 (PGE2) Modulates Hippocampal Synaptic Transmission via a Presynaptic PGE2 EP2 Receptor

Increasing evidence suggests that cyclooxygenase-2 (COX-2) is involved in synaptic transmission and plasticity, and prostaglandin E2 (PGE2) is a key molecule in COX-2-meduated synaptic modification. However, the precise mechanisms, in particular, which subtypes of PGE2 receptors (EPs) mediate the PGE2-induced synaptic response, are not clear. Recently, we demonstrated that EPs are expressed heterogeneously in the hippocampus, and EP2/4 are mainly expressed in presynaptic terminals. Here, we report that PGE2 increased synaptic stimulus-evoked amplitudes of EPSPs in hippocampal slices and frequency of miniature EPSCs (mEPSCs) in hippocampal neurons in culture. These actions were mimicked by an EP2 agonist and attenuated by protein kinase A inhibitors. Decrease of EP2 expression through silencing the EP2 gene eliminated PGE2-induced increase of the frequency of mEPSCs. COX-2 and microsomal PGE synthase-1 (mPGES-1) and mPGES-2 are present in postsynaptic dendritic spines, because they are colocalized with PSD-95 (postsynaptic density-95), a postsynaptic marker. In addition, the frequency of mEPSCs was enhanced in neurons pretreated with interleukin-1β or lipopolysaccharide, which elevated expression of COX-2 and mPGES-1 and produced PGE2, and this enhancement was inhibited by a COX-2 inhibitor that inhibited production of PGE2. Our results suggest that PGE2 synthesized by postsynaptically localized COX-2 functions as a retrograde messenger in hippocampal synaptic signaling via a presynaptic EP2 receptor.

A mouse model of Down syndrome trisomic for all human chromosome 21 syntenic regions

Down syndrome (DS) is caused by the presence of an extra copy of human chromosome 21 (Hsa21) and is the most common genetic cause for developmental cognitive disability. The regions on Hsa21 are syntenically conserved with three regions located on mouse chromosome 10 (Mmu10), Mmu16 and Mmu17. In this report, we describe a new mouse model for DS that carries duplications spanning the entire Hsa21 syntenic regions on all three mouse chromosomes. This mouse mutant exhibits DS-related neurological defects, including impaired cognitive behaviors, reduced hippocampal long-term potentiation and hydrocephalus. These results suggest that when all the mouse orthologs of the Hsa21 genes are triplicated, an abnormal cognitively relevant phenotype is the final outcome of the elevated expressions of these orthologs as well as all the possible functional interactions among themselves and/or with other mouse genes. Because of its desirable genotype and phenotype, this mutant may have the potential to serve as one of the reference models for further understanding the developmental cognitive disability associated with DS and may also be used for developing novel therapeutic interventions for this clinical manifestation of the disorder.

AMPA‐preferring glutamate receptors in cochlear physiology of adult guinea‐pig

1 The present study was designed to determine which glutamate (Glu) receptors are involved in excitatory neurotransmission at the first auditory synapse between the inner hair cells and the spiral ganglion neurons. 2 The Glu receptors present at the membrane level were investigated on isolated spiral ganglion neuron somata from guinea‐pigs by whole‐cell voltage‐clamp measurements. Glu and AMPA induced a fast onset inward current that was rapidly desensitized, while kainate induced only a non‐desensitizing, steady‐state current. NMDA induced no detectable current. 3 To further discriminate between the AMPA and kainate receptors present, we used the receptor‐specific desensitization blockers, cyclothiazide and concanavalin A. While no effect was observed with concanavalin A, cyclothiazide greatly enhanced the Glu‐, AMPA‐ and kainate‐induced steady‐state currents and potentiated Glu‐induced membrane depolarization. 4 To extrapolate the results obtained from the somata to the events occurring in situ at the dendrites, the effects of these drugs were evaluated in vivo. Cyclothiazide reversibly increased spontaneous activity of single auditory nerve fibres, while concanavalin A had no effect, suggesting that the functional Glu receptors on the somata may be the same as those at the dendrites. 5 The combination of a moderate‐level sound together with cyclothiazide increased and subsequently abolished the spontaneous and the sound‐evoked activity of the auditory nerve fibres. Histological examination revealed destruction of the dendrites, suggesting that cyclothiazide potentiates sound‐induced Glu excitotoxicity via AMPA receptors. 6 Our results reveal that fast synaptic transmission in the cochlea is mainly mediated by desensitizing AMPA receptors.

Endocannabinoid 2-Arachidonoylglycerol Protects Neurons by Limiting COX-2 Elevation

Endocannabinoids are involved in synaptic signaling and neuronal protection; however, our understanding of the mechanisms by which endocannabinoids protect neurons from harmful insults remains elusive. 2-Arachidonoylglycerol (2-AG), the most abundant endogenous cannabinoid and a full agonist for cannabinoid receptors (CB1 and CB2), is a substrate for cyclooxygenase-2 (COX-2) and can be metabolized by COX-2. Here we show, however, that 2-AG is also capable of suppressing elevation of hippocampal COX-2 expression in response to proinflammatory and excitotoxic stimuli. 2-AG prevents neurodegeneration from toxic assaults that elevate COX-2 expression and inhibits the COX-2 elevation-enhanced excitatory glutamatergic synaptic transmission. The action of 2-AG on suppression of COX-2 appeared to be mediated via the pertussis toxin-sensitive G protein-coupled CB1 receptor and MAPK/NF-κB signaling pathways. Our results reveal that 2-AG functions as an endogenous COX-2 inhibitor protecting neurons from harmful insults by preventing excessive expression of COX-2, which provides a mechanistic basis for opening up new therapeutic approaches for protecting neurons from inflammation- and excitotoxicity-induced neurodegeneration.

Lipid Signaling and Synaptic Plasticity

Lipids are essential components of plasma- and organelle-membranes, not only providing a frame for embedded proteins (e.g., receptors and ion channels) but also functioning as reservoirs for lipid mediators. Increasing evidence indicates that bioactive lipids such as eicosanoids, endocannabinoids, and lysophospholipids serve as intercellular and intracellular signaling molecules participating in physiological and pathological functions in the brain. The discovery of some of these lipid receptors and novel lipid signaling mediators has sparked an intense interest in lipidomic neurobiology research. Classic prostaglandins (PGD2, PGE2, PGF2α, PGI2, and TXA2), catalyzed by cyclooxygenases (COX), are synthesized from arachidonic acid (AA). Experimental studies demonstrate that prostaglandin E2 (PGE2), mainly derived from the COX-2 reaction, is an important mediator, acting as a retrograde messenger via a presynaptic PGE2 subtype 2 receptor (EP2) in modulation of synaptic events. Novel prostaglandins (prostaglandin glycerol esters and prostaglandin ethanolamides) are COX-2 oxidative metabolites of endogenous cannabinoids (2-arachidonyl glycerol and arachidonyl ethanolamide). Recent evidence suggests that these new types of prostaglandins are likely novel signaling mediators involved in synaptic transmission and plasticity. This means that COX- 2 plays a central role in metabolisms of AA and endocannabinoids (eCBs) and productions of AA- and eCB- derived prostaglandins. Thus, in the present review article, the authors will mainly discuss COX-2 regulation of prostaglandin signaling in modulation of hippocampal synaptic transmission and plasticity.

PGE2 glycerol ester, a COX-2 oxidative metabolite of 2-arachidonoyl glycerol, modulates inhibitory synaptic transmission in mouse hippocampal neurons

The oxygenation of endogenous cannabinoids (eCBs) 2‐arachidonoyl glycerol (2‐AG) and arachidonoyl ethanolamide by cyclooxygenase‐2 (COX‐2) produces novel types of prostanoids: prostaglandin glycerol esters (PG‐Gs) and prostaglandin ethanolamides (PG‐EAs). However, the physiological function of COX‐2 oxidative metabolites of eCBs is still unclear. Here we demonstrate that PGE2‐G, a COX‐2 oxidative metabolite of 2‐AG, induced a concentration‐dependent increase in the frequency of miniature inhibitory postsynaptic currents (mIPSCs) in primary cultured hippocampal neurons, an effect opposite to that of 2‐AG. This increase was not inhibited by SR141716, a CB1 receptor antagonist, but was attenuated by an IP3 or MAPK inhibitor. In addition, we also examined the effects of other prostanoids derived from COX‐2 oxygenation of eCBs on mIPSCs. PGD2‐G, PGF2α‐G and PGD2‐EA, but not PGE2‐EA or PGF2α‐EA, also increased the frequency of mIPSCs. The eCB‐derived prostanoid‐induced responses appeared to be different from those of corresponding arachidonic acid‐derived prostanoids, implying that these effects are not mediated via known prostanoid receptors. We further discovered that the inhibition of COX‐2 activity reduced inhibitory synaptic activity and augmented depolarization‐induced suppression of inhibition (DSI), whereas the enhancement of COX‐2 augmented the synaptic transmission and abolished DSI. Our results, which show that COX‐2 oxidative metabolites of eCBs exert opposite effects to their parent molecules on inhibitory synaptic transmission, suggest that alterations in COX‐2 activity will have significant impact on endocannabinoid signalling in hippocampal synaptic activity.

COX-2 oxidative metabolite of endocannabinoid 2-AG enhances excitatory glutamatergic synaptic transmission and induces neurotoxicity

Neuroinflammation has been implicated in the pathogenesis of neurodegenerative diseases. Cyclooxygenase‐2 (COX‐2), an inducible enzyme converting arachidonic acid (AA) to prostaglandins, is the key player in neuroinflammation. It has been long thought that the COX‐2‐mediated neuronal injury/degeneration is attributed to the increased production of AA‐derived prostaglandins. Recent studies show that endogenous cannabinoid 2‐arachidonoylglycerol (2‐AG) is a natural substrate for COX‐2, and it can be oxygenated by COX‐2 to form prostaglandin glyceryl esters. In this study, we demonstrate that prostaglandin E2 glyceryl ester (PGE2‐G), a major COX‐2 oxidative metabolite of 2‐arachidonoylglycerol, enhanced hippocampal glutamatergic synaptic transmission indicated by the increased frequency of miniature excitatory post‐synaptic currents, and induced neuronal injury/death revealed by the terminal transferase dUTP nick end labeling staining and caspase 3 activation. The actions of PGE2‐G are not mediated via a cannabinoid receptor 1, but mediated through ERK, p38 mitogen‐activated protein kinase, IP3, and NF‐κB signal transduction pathways. In addition, the PGE2‐G‐induced neurotoxicity is attenuated by blockade of the NMDA receptors. Our results suggest that the COX‐2 oxidative metabolism of endocannabinoids is an important mechanism contributing to the inflammation‐induced neurodegeneration.

Effects of individual segmental trisomies of human chromosome 21 syntenic regions on hippocampal long-term potentiation and cognitive behaviors in mice

As the genomic basis for Down syndrome (DS), human trisomy 21 is the most common genetic cause of intellectual disability in children and young people. The genomic regions on human chromosome 21 (Hsa21) are syntenic to three regions in the mouse genome, located on mouse chromosome 10 (Mmu10), Mmu16, and Mmu17. Recently, we have developed three new mouse models using chromosome engineering carrying the genotypes of Dp(10)1Yey/+, Dp(16)1Yey/+, or Dp(17)1Yey/+, which harbor a duplication spanning the entire Hsa21 syntenic region on Mmu10, Mmu16, or Mmu17, respectively. In this study, we analyzed the hippocampal long-term potentiation (LTP) and cognitive behaviors of these models. Our results show that, while the genotype of Dp(17)1Yey/+ results in abnormal hippocampal LTP, the genotype of Dp(16)1Yey/+ leads to both abnormal hippocampal LTP and impaired learning/memory. Therefore, these mutant mice can serve as powerful tools for further understanding the mechanism underlying cognitively relevant phenotypes associated with DS, particularly the impacts of different syntenic regions on these phenotypes.

Reduced expression of glutamate receptors and phosphorylation of CREB are responsible for in vivo Δ9-THC exposure-impaired hippocampal synaptic plasticity

J. Neurochem. (2010) 112, 691–702.

Synaptic and Cognitive Improvements by Inhibition of 2-AG Metabolism Are through Upregulation of MicroRNA-188-3p in a Mouse Model of Alzheimer's Disease

Abnormal accumulation of β-amyloid (Aβ) is the major neuropathological hallmark of Alzheimers disease (AD). However, the mechanisms underlying aberrant Aβ formation in AD remain unclear. We showed previously that inhibition of monoacylglycerol lipase (MAGL), the primary enzyme that metabolizes the endocannabinoid 2-arachidonoylglycerol (2-AG) in the brain, robustly reduces Aβ by inhibiting β-site amyloid precursor protein cleaving enzyme 1 (BACE1), a key enzyme responsible for Aβ formation. However, the molecular mechanisms responsible for suppression of BACE1 by inhibition of 2-AG metabolism are largely unknown. We demonstrate here that expression of the noncoding small RNA miR-188-3p that targets BACE1 was significantly downregulated both in the brains of AD humans and APP transgenic (TG) mice, a mouse model of AD. The downregulated miR-188-3p expression was restored by MAGL inhibition. Overexpression of miR-188-3p in the hippocampus reduced BACE1, Aβ, and neuroinflammation and prevented deteriorations in hippocampal basal synaptic transmission, long-term potentiation, spatial learning, and memory in TG mice. 2-AG-induced suppression of BACE1 was prevented by miR-188-3p loss of function. Moreover, miR-188-3p expression was upregulated by 2-AG or peroxisome proliferator-activated receptor-γ (PPARγ) agonists and suppressed by PPARγ antagonism or NF-κB activation. Reducing Aβ and neuroinflammation by MAGL inhibition was occluded by PPARγ antagonism. In addition, BACE1 suppression by 2-AG and PPARγ activation was eliminated by knockdown of NF-κB. Our study provides a novel molecular mechanism underlying improved synaptic and cognitive function in TG mice by 2-AG signaling, which upregulates miR-188-3p expression through PPARγ and NF-κB signaling pathway, resulting in suppressions of BACE1 expression and Aβ formation.