Abstracts

Prior studies in rodents have demonstrated that recurrent seizures are associated with cognitive impairment. While there are a myriad of morphological and physiological changes in the brain following seizures, the mechanisms responsible for seizure-induced cognitive impairment remain unclear. In this study we examined seizure-induced physiological changes that occurred following serial seizures that might account for post-seizure memory impairment. Adult male rats were subjected to twice daily flurothyl-induced generalized tonic-clonic seizures (n=15) or sham seizures (n=15) for 5 days. In one group of animals we examine long-term potentiation (LTP) in freely behaving rats induced by a single 100 Hz high frequency stimulation train (1 sec duration). Synaptic transmission efficacy was assessed by measuring the field EPSP slope and population spikes amplitude from averaged waveforms before and after high frequency stimulation. In a second group of animals we performed place cell recordings prior to and following each seizure. A place cell is a single neuron which fires action potentials only in a well-circumscribed, cell-specific region of the environment, and is virtually silent elsewhere. Place cells form a map-like representation of space which can be used in long term storage of spatial memory. Moreover, firing fields are stable over long times (weeks or months) in a constant environment, implying that the across-cell representation is remembered and not created de novo each time the rat enters the environment. We designed the study to permit us to look at changes in place cell firing over the five days the rats were having seizures. We were successful in recording from more than 100 cells in the control and seizure animals. Recurrent flurothyl-induced seizures were associated with a progressive decline in LTP whereas control animals demonstrated robust LTP daily. After 10 seizures LTP could not be elicited. Place cell firing patterns also changed dramatically with repetitive seizures with alterations in the stability and precision of the firing fields. In addition, seizures were associated with the emergence of new firing fields in some rats, suggesting a [ldquo]re-mapping[rdquo] of the environment as a result of the on-going seizure activity. The impairment of place cell precision and stability progressively increased with increased seizure number. Both the alteration in LTP and place cell firing patterns parallel impaired visual-spatial memory of rats studied in the water maze. Recurrent seizures result in impaired performance in the water maze, impaired LTP, and aberrant place cell firing patterns. Our findings suggest that altered synaptic efficiency and selectivity may underlie the disturbances in visual-spatial memory. Furthermore, these results demonstrate that recurrent seizures are associated with progressive changes in critical physiological processes. (Supported by NINDS (R01NS044296).)