plasticity is a possible mechanism for this savings effect. During training procedures many neurons experience an increase in intrinsic excitability. This increase in excitability persists even after the memory fades. Substance dependence Drugs of abuse typically affect the mesolimbic system, or more specifically, the reward pathway of the nervous system. Amongst the common drugs of abuse, nicotine is one of the strongest agonists at the nicotinic cholinergic synapse. Nicotine, competing with acetylcholine (ACh), acts through the nonsynaptic, preterminal, nicotinic acetylcholine receptor (nAChRs) to initiate a membrane potential change and propagate an intracellular Ca2+ signal, thus encouraging the release of neurotransmitters. The specific and characteristic role of calcium current mediated nAChR activity has a different voltage-dependence than other Ca2+ permeable ion channels, as well as different temporal and spatial distribution and as a result, the nonsynaptic nAChR activity enhances the induction of synaptic potentiation, promoting the learning of substance dependence. Applications to disease After damage Nonsynaptic plasticity can function to alleviate the effects of brain damage. When one of the vestibular nerves is damaged, disparity in the firing rates of neurons in the vestibular nuclei causes unnecessary vestibular reflexes. The symptoms of this damage fade over time. This is likely due to modifications of intrinsic excitability in the neurons of the vestibular nucleus. Seizure activity Nonsynaptic plasticity also plays a key role in seizure activity. Febrile seizures, seizures due to fever early in life, can lead to increased excitability of hippocampal neurons. These neurons become highly sensitized to convulsant agents. It has been shown that seizures early in life can predispose one to more seizures through nonsynaptic mechanisms. Trauma, including stroke that results in cortical injury, often results in epilepsy. Increased excitability and NMDA conductances result in epileptic activity, suggesting that nonsynaptic plasticity may be the mechanism through which epilepsy is induced after trauma. Autism Valproic acid (VPA) is a treatment for epilepsy, migraines, and bipolar disorder that has been linked to many conditions including autism. An animal model of autism exists in which pregnant rats are given VPA. The offspring have traits similar to those of humans with autism. Shortly after birth, these animals exhibit decreased excitability and increased NMDA currents. These effects are corrected at later stages in life. The changes in intrinsic excitability in these animals helped to offset the effects of increased NMDA currents on network activity, a form of homeostatic plasticity. It is believed that this