Long-term homocysteine exposure induces alterations in spatial learning, hippocampal signalling and synaptic plasticity.
Abnormally high levels of homocysteine (HCY) have been linked to neurodegenerative diseases, but it remains unclear whether this is the cause or effect of degenerative processes. Here, we investigated the effects of prolonged HCY exposure on cognitive abilities and physiological parameters by injecting rats daily with either 20 or 200 mg/kg HCY over a period of up to 14 weeks. Notwithstanding a significant weight reduction in the 200 mg HCY group, HCY-exposed animals did not show a behavioural deficit when tested repeatedly (in weeks 1, 3, 5, 7 and 13) in a reference memory version of the water maze. Unexpectedly, some improvement in repeated reversal learning was observed in HCY exposed animals compared to controls. Pre-treatment with HCY for 3 weeks before water maze training did not uncover any cognitive alterations. Increased plasma concentrations of HCY were revealed only for the 200 mg HCY group after 14 weeks of injections, but no evidence for DNA damage was obtained. Immunocytochemically, HCY was detected in the brain after 14 weeks of treatment (both 20 and 200 mg/kg), but not after 5 weeks. Bidirectional changes in basic synaptic transmission and long-term potentiation of hippocampal CA1 pyramidal cells were observed at 5, 7 and 14 weeks in both HCY groups, indicative of complex, multifactorial time- and concentration-dependent changes. Overall, it is concluded that healthy adult rats are able to cope with continuous exposure to HCY. While HCY affects growth and neuronal excitability, this does not precipitate into an immediate impairment of cognitive function.
Algaidi
S A
SA
School of Medical Sciences, College of Life Sciences and Medicine, University of Aberdeen, Institute of Medical Sciences, Foresterhill, Aberdeen AB25 2ZD, Scotland, UK.
Christie
L A
LA
Jenkinson
A McE
AM
Whalley
L
L
Riedel
G
G
Platt
B
B
D000818:Animals; D002469:Cell Separation; D020552:Comet Assay; D004594:Electrophysiology; D006624:Hippocampus / Q000187:drug effects*; D006710:Homocysteine / Q000097:blood / Q000633:toxicity*; D007150:Immunohistochemistry; D066298:In Vitro Techniques; D008214:Lymphocytes / Q000187:drug effects; D008297:Male; D018782:Maze Learning / Q000187:drug effects*; D008568:Memory / Q000187:drug effects*; D009419:Nerve Tissue Proteins / Q000378:metabolism; D009473:Neuronal Plasticity / Q000187:drug effects*; D051381:Rats; D012193:Reversal Learning / Q000187:drug effects; D015398:Signal Transduction / Q000187:drug effects*; D013028:Space Perception / Q000187:drug effects; D013569:Synapses / Q000187:drug effects*; D015430:Weight Gain / Q000187:drug effects
D009419:Nerve Tissue Proteins; D006710:Homocysteine