A model of late long-term potentiation simulates aspects of memory maintenance.

Late long-term potentiation (L-LTP) denotes long-lasting strengthening of synapses between neurons. L-LTP appears essential for the formation of long-term memory, with memories at least partly encoded by patterns of strengthened synapses. How memories are preserved for months or years, despite molecular turnover, is not well understood. Ongoing recurrent neuronal activity, during memory recall or during sleep, has been hypothesized to preferentially potentiate strong synapses, preserving memories. This hypothesis has not been evaluated in the context of a mathematical model representing ongoing activity and biochemical pathways important for L-LTP. In this study, ongoing activity was incorporated into two such models - a reduced model that represents some of the essential biochemical processes, and a more detailed published model. The reduced model represents synaptic tagging and gene induction simply and intuitively, and the detailed model adds activation of essential kinases by Ca(2+). Ongoing activity was modeled as continual brief elevations of Ca(2+). In each model, two stable states of synaptic strength/weight resulted. Positive feedback between synaptic weight and the amplitude of ongoing Ca(2+) transients underlies this bistability. A tetanic or theta-burst stimulus switches a model synapse from a low basal weight to a high weight that is stabilized by ongoing activity. Bistability was robust to parameter variations in both models. Simulations illustrated that prolonged periods of decreased activity reset synaptic strengths to low values, suggesting a plausible forgetting mechanism. However, episodic activity with shorter inactive intervals maintained strong synapses. Both models support experimental predictions. Tests of these predictions are expected to further understanding of how neuronal activity is coupled to maintenance of synaptic strength. Further investigations that examine the dynamics of activity and synaptic maintenance can be expected to help in understanding how memories are preserved for up to a lifetime in animals including humans.

The effect of thyroxine and triiodothyronine on fatigue, depression, and memory in a hypothyroid population

Background. This study was planned at a time when important questions were being raised about the adequacy of using one hormone to treat hypothyroidism instead of two. Specifically, this trial aimed to replicate prior findings which suggested that substituting 12.5 μg of liothyronine for 50 μg of levothyroxine might improve mood, cognition, and physical symptoms. Additionally, this trial aimed to extend findings to fatigue. ^ Methods. A randomized, double-blind, two-period, crossover design was used. Hypothyroid patients stabilized on levothyroxine were invited to participate. Thirty subjects were recruited and randomized. Sequence one received their standard levothyroxine dose in one capsule and placebo in another during the first six weeks. Sequence two received their usual levothyroxine dose minus 50 μg in one capsule and 10 μg of liothyronine in another. At the end of the first six week period, subjects were crossed over. T tests were used to assess carry-over and treatment effects. ^ Results. Twenty-seven subjects completed the trial. The majority of completers had an autoimmune etiology. Mean baseline levothyroxine dose was 121 μg/d (±26.0). Subjects reported small increases in fatigue as measured by the Piper Fatigue Scale (0.9, p = 0.09) and in symptoms of depression measured by the Beck Depression Inventory-II (2.3, p = 0.16) as well as the General Health Questionnaire-30 (4.7, p = 0.14) while treated with substitution treatment. However, none of these differences was statistically significant. Measures of working memory were essentially unchanged between treatments. Thyroid stimulating hormone was about twice as high during substitution treatment (p = 0.16). Free thyroxine index was reduced by 0.7 (p < 0.001), and total serum thyroxine was reduced by 3.0 (p < 0.001) while serum triiodothyronine was increased by 20.5 (p < 0.001) on substitution treatment. ^ Conclusions. Substituting an equivalent amount of liothyronine for a portion of levothyroxine in patients with hypothyroidism does not decrease fatigue, symptoms of depression, or improve working memory. However, due to changes in serum hormone levels and small increments in fatigue and depression symptoms on substitution treatment, a question was raised about the role of T3 in the serum. ^