Oligomeric ß-Amyloid Suppresses Hippocampal γ-Oscillations through Activation of the mTOR/S6K1 Pathway.

Neuronal synchronization at gamma frequency (30-100 Hz: γ) is impaired in early-stage Alzheimer's disease (AD) patients and AD models. Oligomeric Aß1-42 caused a concentration-dependent reduction of γ-oscillation strength and regularity while increasing its frequency. The mTOR1 inhibitor rapamycin prevented the Aß1-42-induced suppression of γ-oscillations, whereas the mTOR activator leucine mimicked the Aß1-42-induced suppression. Activation of the downstream kinase S6K1, but not inhibition of eIF4E, was required for the Aß1-42-induced suppression. The involvement of the mTOR/S6K1 signaling in the Aß1-42-induced suppression was confirmed in Aß-overexpressing APP/PS1 mice, where inhibiting mTOR or S6K1 restored degraded γ-oscillations. To assess the network changes that may underlie the mTOR/S6K1 mediated γ-oscillation impairment in AD, we tested the effect of Aß1-42 on IPSCs and EPSCs recorded in pyramidal neurons. Aß1-42 reduced EPSC amplitude and frequency and IPSC frequency, which could be prevented by inhibiting mTOR or S6K1. These experiments indicate that in early AD, oligomer Aß1-42 impairs γ-oscillations by reducing inhibitory interneuron activity by activating the mTOR/S6K1 signaling pathway, which may contribute to early cognitive decline and provides new therapeutic targets.

High abundance of microplastics in groundwater in Jiaodong Peninsula, China.

The occurrence of microplastics (MPs, <5 mm) in drinking water has aroused extensive concerns, whereas our understanding of their presence in groundwater, a major source of drinking water, is still limited. The present study investigated the occurrence of microplastics in groundwater sampled from five sites in Jiaodong Peninsula, China. The abundance, type, and size of MPs in the groundwater samples were determined by Laser Direct Infrared following a well-established and quality-controlled analytical route. Notably, MPs were detected in groundwater across all five sampling sites, with high abundances ranging from 87 to 6832 particles/L and an average abundance of 2103 particles/L. The variation of the abundance of MPs was correlated to the distances between sampling sites and anthropogenic activities, which suggested significant impacts of aboveground industry and agriculture on the abundance of MPs in groundwater. Polyethylene terephthalate (PET) and polyurethane (PU) were the dominant polymer types detected in all groundwater samples. The MPs with a size smaller than 100 µm were found to account for >90% of the total MPs detected in four sampling sites, which was likely associated with their migratory routes through surface water runoff and infiltration into the groundwater settings. The results of this study suggest the importance of counting small MPs when determining their abundances in groundwater or their abundances would be considerably underestimated. The present study for the first time demonstrated the occurrence of MPs in groundwater in China, which improves our understanding of the MPs distribution and raises concerns about groundwater safety in terms of MPs pollution.

Region-dependent regulation of acute ethanol on γ oscillation in the rat hippocampal slices.

BACKGROUND: Ethanol use disorders are a serious medical and public health problem in the world today. Acute ethanol intoxication can lead to cognitive dysfunction such as learning and memory impairment. Gamma oscillations (γ, 30-80 Hz) are synchronized rhythmic activity generated by population of neurons within local network, and closely related to learning and memory function. The hippocampus is a critical anatomic structure that supports learning and memory. On the grounds of structure and function, hippocampus can be divided into the intermediate (IH), the dorsal (DH), and ventral hippocampus (VH). The current study is the first to investigate the effects of acute ethanol on γ oscillations in these sub-regions of rat hippocampal slices. METHODS: The sustained γ oscillations were induced by 200 nM kainate (KA) in the CA3c of IH, DH, and VH. When KA-induced γ oscillation reached the steady state, ethanol (50 mM or 100 mM) was applied and the effects of ethanol on γ oscillation power was measured in the slices sequentially sectioned from ventral to dorsal hippocampus of adult rats. RESULTS: In the intermediate hippocampal slices, compared with control (KA only), ethanol (50 mM) caused 36.1 ± 3.9% decrease in γ power (p < 0.05, n = 10), while ethanol (100 mM) caused 55.3 ± 5.5% decrease in γ power (p < 0.001, n = 14). In the dorsal hippocampus, only ethanol (100 mM) caused 18.1 ± 8.6% decrease in γ power (p < 0.05, n = 12). However, in the ventral hippocampus, neither 50 mM nor 100 mM ethanol affected γ oscillation. CONCLUSIONS: Our results demonstrate that ethanol may produce the differential suppression of γ oscillations in a dose-dependent manner in different sub-regions of hippocampus, suggesting that the modulation of ethanol on hippocampal γ oscillation is region-dependent.

Metformin Ameliorates Synaptic Defects in a Mouse Model of AD by Inhibiting Cdk5 Activity.

Cyclin-dependent kinase 5 (Cdk5) is a serine/threonine kinase that is activated by the neuron-specific activators p35/p39 and plays important roles in neuronal development, synaptic plasticity, and cognitive behavior. However, the proteolytic cleavage of p35 to p25 leads to prolonged and aberrant Cdk5 activation and results in synaptic depression, highly mimicking the early pathology of Alzheimer's disease (AD). Therefore, Cdk5 inhibition is a potential promising strategy for AD drug development. Here in the present study, we showed that metformin, the most widely used drug for type 2 diabetes, suppressed Cdk5 hyper-activation and Cdk5-dependent tau hyper-phosphorylation in the APP/PS1 mouse hippocampus. We also identified the underlying molecular and cellular mechanism that metformin prevented Cdk5 hyper-activation by inhibiting the calpain-dependent cleavage of p35 into p25. Moreover, chronic metformin treatment rescued the core phenotypes in APP/PS1 mice as evidenced by restored spine density, surface GluA1 trafficking, Long-term potentiation (LTP) expression, and spatial memory. Altogether our study discovered an unidentified role of metformin in suppressing Cdk5 hyper-activation and thus preventing AD pathogenesis and suggested that metformin is a potential promising AD therapeutic drug.

Dopamine D4 receptor activation restores CA1 LTP in hippocampal slices from aged mice.

Normal aging is characterized with a decline in hippocampal memory functions that is associated with changes in long-term potentiation (LTP) of the CA3-to-CA1 synapse. Age-related deficit of the dopaminergic system may contribute to impairment of CA1 LTP. Here we assessed how the modulation of CA1 LTP by dopamine is affected by aging and how it is dependent on the Ca2+ source. In slices from adult mice, the initial slope of the field potential showed strong LTP, but in slices from aged mice LTP was impaired. Dopamine did not affect LTP in adult slices, but enhanced LTP in aged slices. The dopamine D1/D5 receptor (D1R/D5R) agonist SKF-81297 did not affect LTP in adult but caused a relative small increase in LTP in aged slices; however, although there was no difference in dopamine D4 receptor (D4R) expression, the D4R agonist PD168077 increased LTP in aged slices to a magnitude similar to that in adult slices. The N-Methyl-D-aspartate receptor antagonist D-AP5 reduced LTP in adult slices, but not in aged slices. However, in the presence of D-AP5, PD168077 completely blocked LTP in aged slices. The voltage-dependent calcium channel (VDCC) blocker nifedipine reduced LTP in adult slices, but surprisingly enhanced LTP in aged slices. Furthermore, in the presence of nifedipine, PD168077 caused a strong enhancement of LTP in aged slices to a magnitude exceeding LTP in adult slices. Our results indicate that the full rescue of impaired LTP in aging by the selective D4R activation and that a large potentiation role on LTP by co-application of D4R agonist and VDCC blocker may provide novel strategies for the intervention of cognitive decline of aging and age-related diseases.

Selective dopamine receptor 4 activation mediates the hippocampal neuronal calcium response via IP3 and ryanodine receptors.

Intracellular calcium is a key factor in most cellular processes, including cell growth, differentiation, proliferation and neurotransmitter release. Dopamine (DA) mediates synaptic transmission by regulating the intracellular calcium content. It is not clear, however, which specific subunit of the DA receptor contributes to DA modulation of intracellular calcium content changes. Through the traditional technique of Fura-2 calcium imaging, this study demonstrated that the DA can induce transient calcium in cultured hippocampal neurons and that this response can be mimicked by a selective dopamine receptor 4 (DR4) agonist PD168077 (PD). PD-induced calcium transience can be blocked by a calcium chelator, such as BAPTA-AM, or by pre-treatment of neurons with thapsigargin, a IP3 receptor antagonist, or a micromolar concentration of ryanodine, a ryanodine receptor (RyR) antagonist. However PD-induced calcium transience cannot be blocked by pre-treatment of neurons with a free-calcium medium or a cocktail of NMDA receptor, L-type calcium channel and alpha7 nicotinic acetylcholine receptor blockers. These results indicate that the calcium response induced by DR4 activation is mainly through activation of IP3 receptor in internal stores, which is likely to contribute to the DA modulation of synaptic transmission and cognitive function.

Multiple Kinases Involved in the Nicotinic Modulation of Gamma Oscillations in the Rat Hippocampal CA3 Area.

Neuronal synchronization at gamma band frequency (20-80 Hz, γ oscillations) is closely associated with higher brain function, such as learning, memory and attention. Nicotinic acetylcholine receptors (nAChRs) are highly expressed in the hippocampus, and modulate hippocampal γ oscillations, but the intracellular mechanism underlying such modulation remains elusive. We explored multiple kinases by which nicotine can modulate γ oscillations induced by kainate in rat hippocampal area CA3 in vitro. We found that inhibitors of cyclic AMP dependent kinase (protein kinase A, PKA), protein kinase C (PKC), N-methyl-D-aspartate receptor (NMDA) receptors, Phosphoinositide 3-kinase (PI3K) and extracellular signal-related kinases (ERK), each individually could prevent the γ oscillation-enhancing effect of 1 µM nicotine, whereas none of them affected baseline γ oscillation strength. Inhibition of the serine/threonine kinase Akt increased baseline γ oscillations and partially blocked its nicotinic enhancement. We propose that the PKA-NMDAR-PI3K-ERK pathway modifies cellular properties required for the nicotinic enhancement of γ oscillations, dependent on a PKC-ERK mediated pathway. These signaling pathways provide clues for restoring γ oscillations in pathological conditions affecting cognition. The suppression of γ oscillations at 100 µM nicotine was only dependent on PKA-NMDAR activation and may be due to very high intracellular calcium levels.

Acute Ethanol Inhibition of γ Oscillations Is Mediated by Akt and GSK3ß.

Hippocampal network oscillations at gamma band frequency (γ, 30-80 Hz) are closely associated with higher brain functions such as learning and memory. Acute ethanol exposure at intoxicating concentrations (≥50 mM) impairs cognitive function. This study aimed to determine the effects and the mechanisms of acute ethanol exposure on γ oscillations in an in vitro model. Ethanol (25-100 mM) suppressed kainate-induced γ oscillations in CA3 area of the rat hippocampal slices, in a concentration-dependent, reversible manner. The ethanol-induced suppression was reduced by the D1R antagonist SCH23390 or the PKA inhibitor H89, was prevented by the Akt inhibitor triciribine or the GSk3ß inhibitor SB415286, was enhanced by the NMDA receptor antagonist D-AP5, but was not affected by the MAPK inhibitor U0126 or PI3K inhibitor wortmanin. Our results indicate that the intracellular kinases Akt and GSk3ß play a critical role in the ethanol-induced suppression of γ oscillations and reveal new cellular pathways involved in the ethanol-induced cognitive impairment.

Nicotinic modulation of Ca2+ oscillations in rat cortical neurons in vitro.

The roles of nicotine on Ca(2+) oscillations [intracellular Ca(2+) ([Ca(2+)]i) oscillation] in rat primary cultured cortical neurons were studied. The spontaneous [Ca(2+)]i oscillations (SCO) were recorded in a portion of the neurons (65%) cultured for 7-10 days in vitro. Application of nicotine enhanced [Ca(2+)]i oscillation frequency and amplitude, which were reduced by the selective α4ß2-nicotinic acetylcholine receptors (nAChRs) antagonist dihydro-ß-erythroidine (DHßE) hydrobromide, and the selective α7-nAChRs antagonist methyllycaconitine citrate (MLA, 20 nM). DHßE reduced SCO frequency and prevented the nicotinic increase in the frequency. DHßE somewhat enhanced SCO amplitude and prevented nicotinic increase in the amplitude. MLA (20 nM) itself reduced SCO frequency without affecting the amplitude but blocked nicotinic increase in [Ca(2+)]i oscillation frequency and amplitude. Furthermore, coadministration of both α4ß2- and α7-nAChRs antagonists completely prevented nicotinic increment in [Ca(2+)]i oscillation frequency and amplitude. Thus, our results indicate that both α4ß2- and α7-nAChRs mediated nicotine-induced [Ca(2+)]i oscillations, and two nAChR subtypes differentially regulated SCO.