Exp Brain Res (1991) 85 : 559-564 E Br' n Research 9 Springer-Verlag1991 Neonatal hyperthyroidism disrupts hippocampal LTP and spatial learning C. Pavlides, A.I. Westlind-Danielsson, H. Nyborg, and B.S. McEwen The Rockefeller University, 1230 York Ave., New York, NY 10021, USA Received October 18, 1990/Accepted February 12, 1991 Summary. Excess thyroid hormone at an early stage of development produces marked neurochemical and mor- phological alterations in the rat hippocampal formation. In order to better understand the functional significance of these changes, we tested adult rats treated neonatally with triiodothyronine (T3), and their control litter mates, in a spatial learning task and for the induction of long- term potentiation (LTP) in the dentate gyrus (DG) of the hippocampal formation. The T3-treated rats were signifi- cantly impaired in their performance on the spatial task in comparison to their matched controls. Similarly, the effi- cacy of LTP induction was significantly attenuated in the T3-treated animals. Further, a significant correlation was obtained between LTP induction and performance on the spatial learning task. Thus, a brief neonatal excess of thyroid hormone produces impairments in spatial learn- ing along with decreases in LTP, long held as a model of learning and memory. This relationship provides a unique opportunity to study associations between behavioral, physiological, pharmacological and morphological pro- cesses intimately associated with the hippocampal forma- tion Key words: Thyroid hormone Development - Hip- pocampus - Dentate gyrus - LTP - Learning Memory - Rat and Mugnaini 1980; Rabie et al. 1979; Rami et al. 1986ab; Westlind-Danielsson et al. 1990) and neurochemical (Meaney et al. 1987; Rabie et al. 1979; Westlind-Daniel- sson et al. 1990) aberrations in the hippocampus which are detectable in the adult animal. There is a scarcity of studies, however, investigating the functional significance of these alterations. The hippocampus and closely related structures are believed to play a crucial role in learning and memory processes (Squire 1986). Using simple learn- ing paradigms (i.e., conditioned avoidance, closed field test, Lashley-III maze and Y Water maze), a number of studies have reported that hyperthyroidism disrupts learning and memory in these tasks (Davenport et al. 1975; Eayrs 1964; Lipp et al. 1984; Lipp et al. 1988; Schapiro 1968). Recent theories of hippocampal function have stressed the role of this structure in spatial learning and memory (O'Keefe and Nadel 1978; Olton and Papas 1979). In the present study, rats neonatally treated with TH were tested on a spatial discrimination task. In addi- tion, long-term potentiation (LTP), in the dentate gyrus of the hippocampus, was studied in these animals. LTP is characterized by an increase in synaptic efficacy following brief high frequency stimulation of afferent fibers and has been postulated as a model of neuronal plasticity. In the present study we demonstrated the deleterious effects of brief neonatal triidothyronine (T3) treatment on both the spatial learning and memory task as well as the efficacy of LTP induction. Introduction The late ontogenesis of the rodent hippocampal formation allows relatively simple experimental manipulations, carried out within the first few postnatal weeks, to inter- fere with neuronal (cell acquisition, migration and differ- entiation) and glial cell development in the hippocampus. For example, neonatal thyroid hormone (TH) administra- tion produces morphological (Gould et al. 1990; Lauder Offprint requests to: C. Pavlides (address see above) Material and Methods Thyroid hormone administration Twenty two newborn male and 12 female Sprague-Dawley rats (Charles River Labs) pooled from 9-11 dams were randomly as- signed to each dam. The pups from each litter were injected either with a dose of 3,5,3'-triiodo- L- thyronine (T3) (0.5 #g/g body weight in 25 #1 sesame oil, s.c., on P1, P2 and P4) or received the vehicle. Following weaning (P26), all rats were housed in groups of 3 and given water and Purina lab chow ad libitum. The animals were then allowed to mature to approximately 2-3 months of age.