Activity-dependent changes taking place at the hippocampal perforant pathway-dentate gyrus synapse during classical eyeblink conditioning were recorded in adult thyroidectomized (hypothyroid) and control (euthyroid) rats, and in animals treated with thyroid hormones 20 days after thyroidectomy (recovery rats). The aim was to determine the contribution of thyroid hormones and the consequences of adult-onset hypothyroidism to both associative learning and the physiological potentiation of hippocampal synapses during the actual learning process in alert behaving animals. Control and recovery rats presented similar learning curves, whereas hypothyroid animals presented lower values. A single pulse presented to the perforant pathway during the conditioned-unconditioned inter-stimulus interval evoked a monosynaptic field excitatory postsynaptic potential in dentate granule cells (whose slope was linearly related to the rate of acquisition in the control group), but not in hypothyroid and recovery animals. Input-output relationships and long-term potentiation evoked by train stimulation of the perforant pathway were significantly depressed in hypothyroid animals. Thyroid hormone treatment failed to normalize these two neurophysiological abnormalities observed in hypothyroid animals. In contrast, paired-pulse facilitation was not affected by thyroidectomy. The results indicate that thyroid hormone treatment after a short period of adult hypothyroidism helps to restore some hippocampally dependent functions, such as classical conditioning, but not other hippocampal properties, such as the synaptic plasticity evoked during associative learning and during experimentally induced long-term potentiation. The present results have important clinical implications for the handling of patients with adult-onset thyroid diseases.