Failure of delayed nonsynaptic neuronal plasticity underlies age-associated long-term associative memory impairment.
BACKGROUND
Cognitive impairment associated with subtle changes in neuron and neuronal network function rather than widespread neuron death is a feature of the normal aging process in humans and animals. Despite its broad evolutionary conservation, the etiology of this aging process is not well understood. However, recent evidence suggests the existence of a link between oxidative stress in the form of progressive membrane lipid peroxidation, declining neuronal electrical excitability and functional decline of the normal aging brain. The current study applies a combination of behavioural and electrophysiological techniques and pharmacological interventions to explore this hypothesis in a gastropod model (Lymnaea stagnalis feeding system) that allows pinpointing the molecular and neurobiological foundations of age-associated long-term memory (LTM) failure at the level of individual identified neurons and synapses.


RESULTS
Classical appetitive reward-conditioning induced robust LTM in mature animals in the first quartile of their lifespan but failed to do so in animals in the last quartile of their lifespan. LTM failure correlated with reduced electrical excitability of two identified serotonergic modulatory interneurons (CGCs) critical in chemosensory integration by the neural network controlling feeding behaviour. Moreover, while behavioural conditioning induced delayed-onset persistent depolarization of the CGCs known to underlie appetitive LTM formation in this model in the younger animals, it failed to do so in LTM-deficient senescent animals. Dietary supplementation of the lipophilic anti-oxidant α-tocopherol reversed the effect of age on CGCs electrophysiological characteristics but failed to restore appetitive LTM function. Treatment with the SSRI fluoxetine reversed both the neurophysiological and behavioural effects of age in senior animals.


CONCLUSIONS
The results identify the CGCs as cellular loci of age-associated appetitive learning and memory impairment in Lymnaea and buttress the hypothesis that lipid peroxidation-dependent depression of intrinsic excitability is a hallmark of normal neuronal aging. The data implicate both lipid peroxidation-dependent non-synaptic as well as apparently lipid peroxidation-independent synaptic mechanisms in the age-dependent decline in behavioural plasticity in this model system.
Department of Biological Sciences, Faculty of Science, University of Calgary, Calgary, AB T2N 1 N4, Canada.
Shawn N
SN
Watson
Tara E
TE
Risling
Petra M
PM
Hermann
Willem C
WC
Wildering
D000367:Age Factors; D000704:Analysis of Variance; D000818:Animals; D000975:Antioxidants / Q000008:administration & dosage; D001070:Appetitive Behavior / Q000187:drug effects / Q000502:physiology; D001362:Avoidance Learning / Q000187:drug effects; D001522:Behavior, Animal; D055592:Biophysical Phenomena / Q000187:drug effects; D003214:Conditioning, Classical / Q000187:drug effects / Q000502:physiology; D004558:Electric Stimulation; D005247:Feeding Behavior / Q000187:drug effects; D005473:Fluoxetine / Q000627:therapeutic use; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology; D008569:Memory Disorders / Q000188:drug therapy / Q000473:pathology* / Q000503:physiopathology*; D057567:Memory, Long-Term / Q000502:physiology*; D009043:Motor Activity / Q000187:drug effects / Q000502:physiology; D009473:Neuronal Plasticity / Q000187:drug effects / Q000502:physiology*; D009474:Neurons / Q000502:physiology; D000439:Pentanols / Q000494:pharmacology; D017367:Selective Serotonin Reuptake Inhibitors / Q000627:therapeutic use; D012903:Smell / Q000187:drug effects; D012908:Snails; D013395:Sucrose / Q000008:administration & dosage; D013549:Sweetening Agents / Q000008:administration & dosage; D013569:Synapses / Q000187:drug effects / Q000473:pathology / Q000502:physiology*; D024502:alpha-Tocopherol / Q000008:administration & dosage
D000975:Antioxidants; D005473:Fluoxetine; D000439:Pentanols; D017367:Selective Serotonin Reuptake Inhibitors; D013395:Sucrose; D013549:Sweetening Agents; D024502:alpha-Tocopherol; C005716:amyl acetate