Although the effects of long-term experimental dysthyroidism on long-term potentiation (LTP) and long-term depression (LTD) have been documented, the relationship between LTP/LTD and acute administration of L-thyroxine (T4) has not been described. Here, we investigated the effects of intra-hippocampal administration of T4 on synaptic plasticity in the dentate gyrus of the hippocampal formation. After a 15-minute baseline recording, LTP and LTD were induced by application of high- and low-frequency stimulation protocols, respectively. Infusions of saline or T4 and tetraiodothyroacetic acid (tetrac), a T4 analog that inhibits binding of iodothyronines to the integrin αvβ3 receptor, either alone or together, were made during the stimulation protocols. The averages of the excitatory postsynaptic potential (EPSP) slopes and population spike (PS) amplitudes, between 55 to 60 minutes, were used as a measure of the LTP/LTD magnitude and were analyzed by two-way univariate ANOVA with T4 and tetrac as between-subjects factors. The input-output curves of the infusion groups were comparable to each other, as shown by the non significant interaction observed between stimulus intensity and infused drug. The magnitude of the LTP in T4-infused rats was significantly lower as compared to saline-infused rats. Both the PS amplitude and the EPSP slope were depressed more markedly with T4 infusion than with saline, tetrac, and T4 + tetrac infusion. Data of this study provide in vivo evidence that T4 can promote LTD over LTP via the integrin αvβ3 receptor, and that the effect of endogenous T4 on this receptor can be suppressed by tetrac in the hippocampus. © 2016 Wiley Periodicals, Inc.

Objective Hypoxic-ischemic (HI) brain injury in the human perinatal period often leads to significant long-term neurobehavioral dysfunction in the cognitive and sensory-motor domains. Using a neonatal HI injury model (unilateral carotid ligation followed by hypoxia) in postnatal day seven rats, the present study investigated the long-term effects of HI and potential behavioral protective effect of pentoxifylline. Methods Seven-day-old rats underwent right carotid ligation, followed by hypoxia (F i O 2 = 0.08). Rats received pentoxifylline immediately after and again 2 hours after hypoxia (two doses, 60–100 mg/kg/dose), or serum physiologic. Another set of seven-day-old rats was included to sham group exposed to surgical stress but not ligated. These rats were tested for spatial learning and memory on the simple place task in the Morris water maze from postnatal days 77 to 85. Results HI rats displayed significant tissue loss in the right hippocampus, as well as severe spatial memory deficits. Low-dose treatment with pentoxifylline resulted in significant protection against both HI-induced hippocampus tissue losses and spatial memory impairments. Beneficial effects are, however, negated if pentoxifylline is administered at high dose. Conclusion These findings indicate that unilateral HI brain injury in a neonatal rodent model is associated with cognitive deficits, and that low dose pentoxifylline treatment is protective against spatial memory impairment.

Long-term potentiation and long-term depression (LTD) are cellular mechanisms of learning and memory in the mammalian brain. We have previously shown that adult hyperthyroid rats showed a delay in the acquisition of a place learning task and attenuated long-term potentiation. However, changes in LTD in hyperthyroidism remain unclear. Rats were administered 0.2 mg/kg/day of L-thyroxine for 21 days starting at postnatal day 40 to induce hyperthyroidism. LTD was induced in the dentate gyrus using low-frequency stimulation (LFS) of the perforant pathway. The mRNA expressions of p38 mitogen-activated protein kinase (p38-MAPK) and protein phosphatase 1 (PP1) were evaluated using a quantitative reverse transcriptase PCR. In control rats, a standard LFS protocol induced a slight depression of the population spike (PS) amplitude during the induction phase of LTD (76±13% vs. baseline), but a small potentiation of the PS amplitude was observed in the early (107±18%) and late (111±20%) phases of LTD. Interestingly, in the hyperthyroid rats, the same LFS protocol induced a reliable LTD in the dentate gyrus of the hippocampus as evidenced by a marked depression in the PS amplitude during the induction (54±6% vs. baseline) and the early phases (56±8%) of LTD. Elevated mRNA levels of p38-MAPK and PP1 were observed in the hippocampus of the LFS-treated hyperthyroid rats compared with the hippocampus of the vehicle-treated hyperthyroid rats. No significant change in p38-MAPK or PP1 mRNA expression was observed in the euthyroid rats. The present study shows that a standard LFS protocol can induce a durable depression of synaptic strength and an upregulation of PP1 and p38-MAPK mRNA in hyperthyroid rats. We conclude that hyperthyroidism can induce molecular changes associated with degeneration of the hippocampus. The relationship between the levels of thyroid hormone and dementia requires further investigation.

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