The physiological functions of endogenous amyloid-β (Aβ), which plays important role in the pathology of Alzheimer's disease (AD), have not been paid enough attention. Here, we review the multiple physiological effects of Aβ, particularly in regulating synaptic transmission, and the possible mechanisms, in order to decipher the real characters of Aβ under both physiological and pathological conditions. Some worthy studies have shown that the deprivation of endogenous Aβ gives rise to synaptic dysfunction and cognitive deficiency, while the moderate elevation of this peptide enhances long term potentiation and leads to neuronal hyperexcitability. In this review, we provide a new view for understanding the role of Aβ in AD pathophysiology from the perspective of physiological meaning.
Humans ; Alzheimer Disease/pathology* ; Amyloid beta-Peptides/metabolism* ; Long-Term Potentiation ; Synaptic Transmission/physiology* ; Hippocampus

CaMKII is essential for long-term potentiation (LTP), a process in which synaptic strength is increased following the acquisition of information. Among the four CaMKII isoforms, γCaMKII is the one that mediates the LTP of excitatory synapses onto inhibitory interneurons (LTP_E→I). However, the molecular mechanism underlying how γCaMKII mediates LTP_E→I remains unclear. Here, we show that γCaMKII is highly enriched in cultured hippocampal inhibitory interneurons and opts to be activated by higher stimulating frequencies in the 10-30 Hz range. Following stimulation, γCaMKII is translocated to the synapse and becomes co-localized with the postsynaptic protein PSD-95. Knocking down γCaMKII prevents the chemical LTP-induced phosphorylation and trafficking of AMPA receptors (AMPARs) in putative inhibitory interneurons, which are restored by overexpression of γCaMKII but not its kinase-dead form. Taken together, these data suggest that γCaMKII decodes NMDAR-mediated signaling and in turn regulates AMPARs for expressing LTP in inhibitory interneurons.
Calcium-Calmodulin-Dependent Protein Kinase Type 2/metabolism* ; Hippocampus/metabolism* ; Interneurons/physiology* ; Long-Term Potentiation/physiology* ; N-Methylaspartate/metabolism* ; Receptors, AMPA/physiology* ; Receptors, N-Methyl-D-Aspartate/metabolism* ; Synapses/physiology*

Long-Term Potentiation ; Neuronal Plasticity ; Receptors, Metabotropic Glutamate ; Synaptic Transmission

Steroid hormones play important roles in brain development and function. The signaling of steroid hormones depends on the interaction between steroid receptors and their coactivators. Although the function of steroid receptor coactivators has been extensively studied in other tissues, their functions in the central nervous system are less well investigated. In this study, we addressed the function of steroid receptor coactivator 3 (SRC3) - a member of the p160 SRC protein family that is expressed predominantly in the hippocampus. While hippocampal development was not altered in Src3
Animals ; Hippocampus ; Long-Term Potentiation ; Mice ; Neuronal Plasticity ; Nuclear Receptor Coactivator 3/genetics* ; Synapses

Formaldehyde is one of the simplest organic small molecules containing C, H and O elements in the early stage of earth's evolution; however, it has been found to be existed in every eukaryotic cell and participate in "one carbon metabolism". Recent studies have shown that formaldehyde may act as a signal molecule to regulate memory formation. After electrical stimulation or learning activity, the levels of formaldehyde in rat brains were increased instantly, and N-methyl-D-aspartate (NMDA) receptor was activated to promote the formation of long-term potentiation (LTP) or spatial memory. On the contrary, after reducing the levels of formaldehyde in the brains, NMDA receptor could not be activated, which was accompanied by the deficits in both LTP and memory. Moreover, in the brains of normal aged rats and APP/PS1 transgenic mice, the concentrations of formaldehyde were abnormally increased, which directly inhibited NMDA receptor activity and impaired spatial memory. This article reviewed the physiological and pathophysiological functions of endogenous formaldehyde in learning and memory.
Animals ; Formaldehyde ; Hippocampus ; Long-Term Potentiation ; Maze Learning ; Memory ; Memory Disorders ; Mice ; Rats ; Receptors, N-Methyl-D-Aspartate

The aim of this paper was to investigate the effect of total saponins from Panax japonicus( SPJ) on cognitive decline of natural aging rats and its mechanism. Thirty male SD rats of eighteen month old were randomly divided into three groups: aged group,10 mg·kg~(-1) SPJ-treated group and 30 mg·kg~(-1) SPJ-treated group. The SPJ-treated groups were given SPJ at the dosages of 10 mg·kg~(-1) and 30 mg·kg~(-1),respectively,from the age of 18 to 24 months. Aged group were lavaged the same amount of saline,10 six-month-old rats were used as control group,with 10 rats in each group. The open field test,novel object recognition and Morris water maze were performed to detect the changes of cognitive function in each group. The changes of synaptic transmission of long-term potentiation( LTP) in hippocampal CA1 region were detected by field potential recording. Western blot was used to detect the protein levels of NLRP3,ASC,caspase-1 and the changes of Glu A1,Glu A2,CAMKⅡ,CREB and phosphorylation of CAMKⅡ,CREB in each group.The results showed that SPJ could improve the decline of cognitive function in aging rats,reduce the damage of LTP in the hippocampal CA1 region of aged rats,and decrease the expression of NLRP3,ASC,caspase-1 in aging rats. At the same time,SPJ could enhance the membrane expression of AMPA receptor( Glu A1 and Glu A2),and increase the expression of p-CAMKⅡand p-CREB in aging rats.SPJ could improve cognitive decline of natural aging rats,and its mechanism may be related to regulating NLRP3 inflammasome,thus regulating the membrane expression of AMPA receptor,and enhancing the expression phosphorylation of CAMKⅡ and CREB.
Aging ; Animals ; CA1 Region, Hippocampal ; physiology ; Cognition ; drug effects ; Inflammasomes ; metabolism ; Long-Term Potentiation ; Male ; NLR Family, Pyrin Domain-Containing 3 Protein ; metabolism ; Panax ; chemistry ; Random Allocation ; Rats ; Rats, Sprague-Dawley ; Saponins ; pharmacology

OBJECTIVE: Although, accumulating evidence is delineating a neuroprotective and neurotrophic role for lithium (Li), inconsistent findings have also been reported in human studies especially. Moreover, the effects of Li infusion into the hippocampus are still unknown. The aims of this work were (a) to assess whether basal synaptic activity and long-term potentiation (LTP) in the hippocampus are different in regard to intrahippocampal Li infusion; (b) to assess spatial learning and memory in rats chronically treated with LiCO₃ in the Morris water maze. METHODS: Field potentials were recorded form the dentate gyrus, stimulating perforant pathways, in rats chronically (20 mg/kg for 40 days) or acutely treated with LiCO₃ and their corresponding control rats. In addition, performance of rats in a Morris water maze was measured to link behaviour of rats to electrophysiological findings. RESULTS: LiCO₃ infusion into the hippocampus resulted in enhanced LTP, especially in the late phases, but attenuated LTP was observed in rats chronically treated with Li as compared to controls. Li-treated rats equally performed a spatial learning task, but did spend less time in target quadrant than saline-treated rats in Morris water maze. CONCLUSION: Despite most data suggest that Li always yields neuroprotective effects against neuropathological conditions; we concluded that a 40-day treatment of Li disrupts hippocampal synaptic plasticity underlying memory processes, and that these effects of prolonged treatment are not associated with its direct chemical effect, but are likely to be associated with the molecular actions of Li at genetic levels, because its short-term effect preserves synaptic plasticity.
Adult ; Animals ; Dentate Gyrus ; Hippocampus ; Humans ; Learning ; Lithium ; Long-Term Potentiation ; Memory ; Neuronal Plasticity ; Neuroprotective Agents ; Perforant Pathway ; Rats ; Spatial Learning ; Spatial Memory ; Water

Animals ; Brain ; physiology ; Extinction, Psychological ; physiology ; Humans ; Long-Term Potentiation ; Long-Term Synaptic Depression ; Neural Pathways ; physiology ; Neuronal Plasticity ; Neurons ; physiology ; Receptors, AMPA ; physiology

Mounting evidence supports an important role of chemokines, produced by spinal cord astrocytes, in promoting central sensitization and chronic pain. In particular, CCL2 (C-C motif chemokine ligand 2) has been shown to enhance N-methyl-D-aspartate (NMDA)-induced currents in spinal outer lamina II (IIo) neurons. However, the exact molecular, synaptic, and cellular mechanisms by which CCL2 modulates central sensitization are still unclear. We found that spinal injection of the CCR2 antagonist RS504393 attenuated CCL2- and inflammation-induced hyperalgesia. Single-cell RT-PCR revealed CCR2 expression in excitatory vesicular glutamate transporter subtype 2-positive (VGLUT2) neurons. CCL2 increased NMDA-induced currents in CCR2/VGLUT2 neurons in lamina IIo; it also enhanced the synaptic NMDA currents evoked by dorsal root stimulation; and furthermore, it increased the total and synaptic NMDA currents in somatostatin-expressing excitatory neurons. Finally, intrathecal RS504393 reversed the long-term potentiation evoked in the spinal cord by C-fiber stimulation. Our findings suggest that CCL2 directly modulates synaptic plasticity in CCR2-expressing excitatory neurons in spinal lamina IIo, and this underlies the generation of central sensitization in pathological pain.
Animals ; Benzoxazines ; pharmacology ; therapeutic use ; Chemokine CCL2 ; antagonists & inhibitors ; genetics ; metabolism ; pharmacology ; Excitatory Amino Acid Agents ; pharmacology ; Excitatory Amino Acid Agonists ; pharmacology ; Female ; Freund's Adjuvant ; toxicity ; Hyperalgesia ; chemically induced ; metabolism ; prevention & control ; Long-Term Potentiation ; drug effects ; physiology ; Luminescent Proteins ; genetics ; metabolism ; Male ; Mice ; Mice, Inbred C57BL ; Mice, Transgenic ; Myelitis ; chemically induced ; drug therapy ; metabolism ; Neurons ; drug effects ; Pain Management ; Somatostatin ; genetics ; metabolism ; Spinal Cord ; cytology ; Spiro Compounds ; pharmacology ; therapeutic use ; Vesicular Glutamate Transport Protein 2 ; genetics ; metabolism ; Vesicular Inhibitory Amino Acid Transport Proteins ; genetics ; metabolism

Circadian rhythms are driven by circadian oscillators, and these rhythms result in the biological phenomenon of 24-h oscillations. Previous studies suggest that learning and memory are affected by circadian rhythms. One of the genes responsible for generating the circadian rhythm is Rev-erbα. The REV-ERBα protein is a nuclear receptor that acts as a transcriptional repressor, and is a core component of the circadian clock. However, the role of REV-ERBα in neurophysiological processes in the hippocampus has not been characterized yet. In this study, we examined the time-dependent role of REV-ERBα in hippocampal synaptic plasticity using Rev-erbα KO mice. The KO mice lacking REV-ERBα displayed abnormal NMDAR-dependent synaptic potentiation (E-LTP) at CT12~CT14 (subjective night) when compared to their wild-type littermates. However, Rev-erbα KO mice exhibited normal E-LTP at CT0~CT2 (subjective day). We also found that the Rev-erbα KO mice had intact late LTP (L-LTP) at both subjective day and night. Taken together, these results provide evidence that REV-ERBα is critical for hippocampal E-LTP during the dark period.
Animals ; Biological Phenomena ; Circadian Clocks ; Circadian Rhythm ; Hippocampus ; Learning ; Long-Term Potentiation ; Memory ; Mice ; Neuronal Plasticity