Related Experiment Videos
Age-related changes in tolerance to the marine algal excitotoxin domoic acid
D Steven Kerr1, Asheema Razak, Nicola Crawford
1Department of Pharmacology and Toxicology, University of Otago School of Medical Sciences, Dunedin, New Zealand. steve.kerr@stonebow.otago.ac.n2
Abstract:
During an incident of toxic mussel poisoning, the epileptogenic excitotoxin domoic acid (DOM) was associated with lasting neurological deficits mainly in older patients (), suggesting supersensitivity to excitotoxins is a feature of brain aging. Here, hippocampal slices from young (3 months) and aged (26-29 months) Sprague Dawley rats were assessed by CA1 field potential analysis before and after preconditioning with DOM. In naïve slices from young animals, DOM produced initial hyperexcitability followed by significant dose-dependent reductions in population spike amplitude during prolonged application. Following toxin washout, only small changes in neuronal activity were evident during a second application of DOM, suggesting that a resistance to the effects of DOM occurs in hippocampal slices which have undergone prior exposure to DOM. This inducible tolerance was not antagonized by the NMDA receptor blockers APV or MK-801, nor was it diminished by the group I, II or III mGluR blockers AIDA, CPPG and EGLU. Likewise, neither the AMPA/KA blocker CNQX nor the VSCC blocker nifedipine were effective in blocking tolerance induction in young slices. Field potential analysis revealed significant age-related reductions in CA1 EPSP strength, population spike amplitude and paired-pulse inhibition, but aged slices did not differ in sensitivity to DOM relative to young. However, aged CA1 failed to exhibit any tolerance to DOM following preconditioning, suggesting that a loss of inducible neuroprotective mechanisms may account for increased sensitivity to excitotoxins during aging.
Insights
Brain aging may increase sensitivity to excitotoxins like domoic acid (DOM). Aged rat brain slices lost the ability to develop tolerance to DOM, unlike younger slices, suggesting a loss of neuroprotective mechanisms.
Area of Science:
- Neuroscience
- Neurotoxicology
- Aging Research
Background:
- Domoic acid (DOM) exposure can cause lasting neurological deficits, particularly in older individuals.
- This suggests that brain aging may lead to increased sensitivity to excitotoxins.
Purpose of the Study:
- To investigate age-related differences in sensitivity and tolerance to domoic acid (DOM) in rat hippocampal slices.
- To explore the mechanisms underlying DOM-induced neuroprotection and its potential age-related decline.
Main Methods:
- Hippocampal slices from young and aged Sprague Dawley rats were used.
- CA1 field potential analysis was performed before and after preconditioning with DOM.
- The effects of various receptor blockers (NMDA, mGluR, AMPA/KA, VSCC) on DOM tolerance were assessed.
Main Results:
- Young slices showed inducible tolerance to DOM after initial exposure, which was not blocked by various receptor antagonists.
- Aged slices exhibited reduced CA1 synaptic function compared to young slices.
- Crucially, aged CA1 slices failed to develop tolerance to DOM following preconditioning.
Conclusions:
- Aging impairs the development of DOM tolerance in the hippocampus.
- This loss of inducible neuroprotection in aged brains may contribute to heightened susceptibility to excitotoxins.
- Findings suggest a potential mechanism for increased neurological deficits in older individuals exposed to neurotoxins.