Long-term homocysteine exposure induces alterations in spatial learning, hippocampal signalling and synaptic plasticity

Algaidi, Sami A.; Christie, Louisa A.; Jenkinson, A. McE.; Whalley, Lawrence J.; Riedel, Gernot; Platt, Bettina

doi:10.1016/j.expneurol.2005.07.003

Cited by 58 publications

(34 citation statements)

References 58 publications

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“…Thus the homocysteine effect was possibly enhanced. Moreover, it is ambiguous whether bolus injections, such as those administered in the work of Reis et al, can raise plasma homocysteine to a level comparable with human data (35). In our sample the mean homocysteine concentration did not reach levels of hyperhocysteinaemia after elevation and the homocysteine raise was only of a limited extent.…”

Section: Discussionsupporting

confidence: 43%

“…In a water-maze paradigm with young adult rats, Algaidi et al observed that long-term potentiation, one of the neurobiological fundaments of learning and memory processes, was influenced significantly seven weeks after termination of hyperhomocysteinaemia and not earlier. This observation indicates a delayed onset or slow progression of the homocysteine effect on cognition (35).…”

Section: Discussionmentioning

confidence: 98%

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Short-term influence of elevation of plasma homocysteine levels on cognitive function in young healthy adults

Alexopoulos

Lehrl

Richter‐Schmidinger

et al. 2010

The Journal of nutrition, health and aging

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Section: Discussionsupporting

confidence: 43%

Section: Discussionmentioning

confidence: 98%

Short-term influence of elevation of plasma homocysteine levels on cognitive function in young healthy adults

Alexopoulos

Lehrl

Richter‐Schmidinger

et al. 2010

The Journal of nutrition, health and aging

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“…These observed levels nearly double the ϳ10 M level observed in controls (ϳ15-20 M, Applebaum et al 2004;Levine et al 2002), and a 5 M increase of HCY in the blood is known to increase schizophrenia susceptibility by 70% (Muntjewerff et al 2006). Consistent with the fact that CSF HCY levels are also increased in schizophrenia (Regland et al 2004), studies on HCY-injected rats have shown that increasing HCY levels in the blood causes heightened HCY in the brain that alters NMDAR-dependent plasticity (Algaidi et al 2006). In addition, the same schizophrenia-linked molecules that produce and metabolize HCY in the blood (COMT, methyl-tetrahydrofolate reductase) also do so in brain regions where COMT is the primary clearance mechanism for synaptic DA and NE (i.e., cortex, hippocampus, superior colliculus; not the striatum; Bigl et al 1974;Muntjewerff et al 2006;Roffman et al 2008;Tunbridge et al 2006Tunbridge et al , 2008.…”

mentioning

confidence: 61%

Homocysteine reduces NMDAR desensitization and differentially modulates peak amplitude of NMDAR currents, depending on GluN2 subunit composition

Bolton

Phillips

Constantine‐Paton

2013

Journal of Neurophysiology

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Bolton AD, Phillips MA, Constantine-Paton M. Homocysteine reduces NMDAR desensitization and differentially modulates peak amplitude of NMDAR currents, depending on GluN2 subunit composition. J Neurophysiol 110: 1567-1582, 2013. First published July 17, 2013 doi:10.1152/jn.00809.2012.-N-methyl-D-aspartate receptors (NMDARs) have been linked to schizophrenia because agents that bind the receptor, like ketamine and phencyclidine, are capable of inducing schizophrenia-like symptoms. Here we show that the amino acid homocysteine (HCY), which is increased in the blood of schizophrenia patients, reduces desensitization of NMDARs in cultured mouse neurons, human embryonic kidney cells transfected with GluN1 ϩ GluN2A, GluN2B, or GluN2D subunits, and hippocampal slices. HCY also alters the peak amplitude of NMDAR currents, depending on the GluN2 subunit the receptor contains; GluN1 ϩ GluN2A-containing NMDARs show an increase in peak amplitude when exposed to HCY, while GluN1 ϩ GluN2B-containing NMDARs show a decrease in peak amplitude. Both peak amplitude and desensitization effects of HCY can be occluded by saturating the NMDAR with glycine. Since glycine concentrations are not saturating in the brain, HCY could play an NMDAR-modulating role in the nervous system. We also show that HCY shares characteristics with glutamate and suggest that HCY affects both the agonist and coagonist site of the NMDAR.

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“…Two responses recorded at 30-s intervals were averaged to provide a mean response per min and calculated relative to baseline (in percentage). The ex vivo recorded amplitude of the system-relevant output summed as population spike was used as a proxy for synaptic plasticity of hippocampal synapses [68][69][70].…”

Section: Ex Vivo Slice Electrophysiologymentioning

confidence: 99%

Polymeric alkylpyridinium salts permit intracellular delivery of human Tau in rat hippocampal neurons: requirement of Tau phosphorylation for functional deficits

Koss

Robinson

Mietelska‐Porowska

et al. 2015

Cell. Mol. Life Sci.

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Patients suffering from tauopathies including frontotemporal dementia (FTD) and Alzheimer's disease (AD) present with intra-neuronal aggregation of microtubule-associated protein Tau. During the disease process, Tau undergoes excessive phosphorylation, dissociates from microtubules and aggregates into insoluble neurofibrillary tangles (NFTs), accumulating in the soma. While many aspects of the disease pathology have been replicated in transgenic mouse models, a region-specific non-transgenic expression model is missing. Complementing existing models, we here report a novel region-specific approach to modelling Tau pathology. Local co-administration of the pore-former polymeric 1,3-alkylpyridinium salts (Poly-APS) extracted from marine sponges, and synthetic full-length 4R recombinant human Tau (hTau) was performed in vitro and in vivo. At low doses, Poly-APS was non-toxic and cultured cells exposed to Poly-APS (0.5 µg/ml) and hTau (1 µg/ml; ~22 µM) had normal input resistance, resting-state membrane potentials and Ca(2+) transients induced either by glutamate or KCl, as did cells exposed to a low concentration of the phosphatase inhibitor Okadaic acid (OA; 1 nM, 24 h). Combined hTau loading and phosphatase inhibition resulted in a collapse of the membrane potential, suppressed excitation and diminished glutamate and KCl-stimulated Ca(2+) transients. Stereotaxic infusions of Poly-APS (0.005 µg/ml) and hTau (1 µg/ml) bilaterally into the dorsal hippocampus at multiple sites resulted in hTau loading of neurons in rats. A separate cohort received an additional 7-day minipump infusion of OA (1.2 nM) intrahippocampally. When tested 2 weeks after surgery, rats treated with Poly-APS+hTau+OA presented with subtle learning deficits, but were also impaired in cognitive flexibility and recall. Hippocampal plasticity recorded from slices ex vivo was diminished in Poly-APS+hTau+OA subjects, but not in other treatment groups. Histological sections confirmed the intracellular accumulation of hTau in CA1 pyramidal cells and along their processes; phosphorylated Tau was present only within somata. This study demonstrates that cognitive, physiological and pathological symptoms reminiscent of tauopathies can be induced following non-mutant hTau delivery into CA1 in rats, but functional consequences hinge on increased Tau phosphorylation. Collectively, these data validate a novel model of locally infused recombinant hTau protein as an inducer of Tau pathology in the hippocampus of normal rats; future studies will provide insights into the pathological spread and maturation of Tau pathology.

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Long-term homocysteine exposure induces alterations in spatial learning, hippocampal signalling and synaptic plasticity

Cited by 58 publications

References 58 publications

Short-term influence of elevation of plasma homocysteine levels on cognitive function in young healthy adults

Short-term influence of elevation of plasma homocysteine levels on cognitive function in young healthy adults

Homocysteine reduces NMDAR desensitization and differentially modulates peak amplitude of NMDAR currents, depending on GluN2 subunit composition

Polymeric alkylpyridinium salts permit intracellular delivery of human Tau in rat hippocampal neurons: requirement of Tau phosphorylation for functional deficits

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