Acceleration of ageing-related gliopathic changes and hippocampal dysfunction following intracerebroventricular infusion of cysteamine in adult rats.
The sulphydryl agent, cysteamine, accelerates the ageing-related accumulation of peroxidase-positive (iron-rich) cytoplasmic inclusions in rat subcortical astroglia and induces their appearance in primary neuroglial cultures. In the present study, infusion of cysteamine into the lateral ventricle of young, adult rats (1 mg/day for three weeks followed by a one-month drug "washout" period) significantly increased numbers of peroxidase-positive astrocytic granules in the stratum oriens of the CA1 hippocampus relative to saline-infused controls. In contrast to the gliopathic changes, no evidence of neuronal or myelin damage was observed in the cysteamine-exposed rats. The cysteamine-treated animals exhibited significant impairment in spatial learning as determined using a three-panel runway task. The working memory deficits were more robust at the end of the drug washout period than immediately following cessation of the cysteamine infusion. Thus, the cysteamine-related memory deficits are of long duration and are not due to any acute neuroactive properties of the drug itself. Using hippocampal slices prepared after the drug washout period, we observed attenuated paired-pulse depression, with no significant effects on basal excitatory synaptic transmission or induction of long-term potentiation, in the cysteamine-infused animals relative to controls. We propose that, in cysteamine-treated rats and in the course of normal ageing, hippocampal dysfunction and associated cognitive deficits may be secondary to fundamental pathological processes originating within the astroglial compartment.
St-Jacques
R
R
Bloomfield Centre for Research in Aging, Lady Davis Institute for Medical Research, Sir Mortimer B. Davis-Jewish General Hospital, Montréal, Québec, Canada.
Chapman
A
A
Lacaille
J C
JC
Mohr
G
G
Schipper
H M
HM
D000375:Aging / Q000502:physiology*; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D001921:Brain / Q000187:drug effects / Q000473:pathology; D003543:Cysteamine / Q000008:administration & dosage* / Q000506:poisoning; D004594:Electrophysiology; D006624:Hippocampus / Q000503:physiopathology*; D066298:In Vitro Techniques; D007276:Injections, Intraventricular; D008297:Male; D008568:Memory / Q000187:drug effects; D009457:Neuroglia / Q000473:pathology*; D051381:Rats; D017207:Rats, Sprague-Dawley
D003543:Cysteamine