Long-term potentiation saturation in chronic cerebral hypoperfusion Lali H.S. Sekhon 1 MB BS PhD, lan Spence 2 BSc PhD, Michael K. Morgan I MD FRACS, Neville C. Weber 3 MSc PhD 1Department of Surgery DO6, The Universityof Sydney, Sydney,NSW 2006, Australia 2Department of Pharmacology DO5, The Universityof Sydney,Sydney,NSW 2006, Australia 3School of Mathematics and Statistics FO7, The Universityof Sydney, Sydney,NSW 2006, Australia Chronic reductions in cerebral blood flow (CBF) of between 25 and 50%, in the absence of cerebral infarction, lead to impairments in hippocampal in vitro long-term potentiation (LTP). This study set out to explore some of the properties of this impairment of LTP. LTP is an electrophysiological property known to occur in the hippocampus, a region known to be exquisitely sensitive to hypoxic or ischemic insults. Thus, assessing LTP is a novel way of assessing the effects of subtle ischemic insults. Five male Sprague-Dawley rats had arteriovenous fistulae created surgically in the neck to induce a state of chronic cerebral hypoperfnsion (CCH) with the features described above. Five rats were used as age-matched controls. Twenty-six weeks after fistula formation, the animals were prepared for in vitro hippocampal recording in a submerged tissue bath. Extracellular field potentials were recorded at the Schaffer collateral-CA1 region, with a stimulus intensity that achieved a population spike amplitude of 1 mV. After tetanic stimulation, the frequency and magnitude of LTP was compared between control and fistula animals. All animals in both these groups demonstrated LTP in contradistinction to our previous work where LTP was impaired in fistula animals when a higher intensity of stimulation was used. This indicates that the structures that are associated with the initiation and maintenance of LTP (most probably the ischemia-sensitive CA1 pyramidal cells) are saturated as the stimulus intensity is increased. Thus, at this lower intensity of stimulation LTP is preserved in the fistula animals, but found to be impaired as the stimulus intensity is increased. Consequently, this study provides further information on this newly identified subtype of chronic cerebral ischemia which, in time, after further studies in humans, may help to redefine therapeutic indicators for the management of cerebral arteriovenous malformation and severe cerebrovascular disease. Journal of Clinical Neuroscience 1998, 5 (3) : 323-328 © Harcourt Brace & Co. Ltd 1998 Keywords" arteriovenous malformation, brain slices, electrophysiology, hippocampus, ischemia, long-term potentiation Introduction Chronic reductions in cerebral blood flow (CBF) can occur in many clinical situations, best typified by the reduction in CBF that occurs as a result of venous hyper- tension and cerebrovascular 'steal '1 in brain parenchyma adjacent to cerebral arteriovenous malformations (AVMs). Numerous clinical reports have described patients who have had neurological dysfunction thought attributable to the shunting of blood from adjacent neuronal structures with cerebral AVMs, in the absence of cerebral infarc- tion3 -7 Brown et al a noted that 9 of 135 patients in their study with AVMs had a functional decline over the 4 years of follow-up, translating to a functional decline in 1.6% of patients with AVMs per year. This decline was not attributed to hemorrhage and presumably would, for the most part, be attributable to the effects of the preferential diversion of blood flow through the low resistance vessels of an AVM, creating chronic cerebral hypoperfusion (CCH) in brain regions adjacent to the AVM. CCH can also occur in severe bilateral carotid artery disease, and may be responsible for subtle personality and intellect degradations that occur in these patients without evidence of infarction on computed tomography (CT) scanning. Up until the past few years it was thought that the thresholds for neuronal dysfunction described for acute ischemic insults were applicable when hypoperfusion was sustained for a prolonged duration? -n More recently, however, we have shown that there is a new subtype of chronic cerebral ischemia which does not obey the classical thresholds for acute ischemic insults. Chronic reductions in CBF of between 25 and 50%, in the absence of cerebral infarction impair neuronal function, 12 and alter structure 13a4 with these changes present after approximately 6 months of constant hypoperfusion. The changes are not present after only 10 weeks of this degree of hypoperfusion] 5 which implies that whatever mecha- nisms are responsible for these changes take time to manifest, with a maturation process initiated prior to the induced changes becoming overt. J. Clin. Neuroscience Volume 5 Number 3 July 1998 323