Sleep is a natural process that preserves energy, facilitates development, and restores the nervous system in higher animals. Sleep loss resulting from physiological and pathological conditions exerts tremendous pressure on neuronal circuitry responsible for sleep-wake regulation. It is not yet clear how acute and chronic sleep loss modify neuronal activities and lead to adaptive changes in animals. Here, we show that acute and chronic prolonged wakefulness in mice induced by modafinil treatment produced long-term potentiation (LTP) of glutamatergic synapses on hypocretin/orexin neurons in the lateral hypothalamus, a well-established arousal/ wake-promoting center. A similar potentiation of synaptic strength at glutamatergic synapses on hypocretin/orexin neurons was also seen when mice were sleep deprived for 4 hours by gentle handling. Blockade of dopamine D1 receptors attenuated prolonged wakefulness and synaptic plasticity in these neurons, suggesting that modafinil functions through activation of the dopamine system. Also, activation of the cAMP pathway was not able to further induce LTP at glutamatergic synapses in brain slices from mice treated with modafinil. These results indicate that synaptic plasticity due to prolonged wakefulness occurs in circuits responsible for arousal and may contribute to changes in the brain and body of animals experiencing sleep loss.

Decreased activity of central nAChRs has antidepressant-like effects in both the TST and FST and these effects are dependent on both beta2 and alpha7 subunits. Therefore, compounds that decrease nAChR activity may be attractive new candidates for development as antidepressants in humans.

The adducin family of proteins interacts with the actin cytoskeleton and the plasma membrane in a calcium-and cAMP-dependent manner. Thus, adducins may be involved in changes in cytoskeletal organization resulting from synaptic stimulation. ␤-Adducin knockout mice were examined in physiological and behavioral paradigms related to synaptic plasticity to elucidate the role the adducin family plays in processes underlying learning and memory. In situ hybridization for ␣-and ␤-adducin demonstrates that these mRNAs are found throughout the brain, with high levels of expression in the hippocampus. Schaffer collateral-CA1 tetanic long-term potentiation decayed rapidly in acute hippocampal slices from ␤-adducin knock-out mice, although baseline spine morphology and postsynaptic density were normal. Interestingly, the input-output relationship was significantly increased in hippocampal slices from ␤-adducin knock-out mice. Furthermore, ␤-adducin knock-out mice were impaired in performance of fear conditioning and the water maze paradigm. The current results indicate that ␤-adducin may play an important role in the cellular mechanisms underlying activitydependent synaptic plasticity associated with learning and memory.

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