Invertebrate animal models show simple behaviors supported by neural circuits easily accessible for experimentation and yet complex enough to provide necessary information on the cellular and molecular mechanisms that govern the vertebrate nervous system’s function. The mechanisms underlying simple forms of learning have been extensively studied in the marine gastropod Aplysia californica, in which elementary non-associative learning of the behavioral habituation and sensitization type has been studied using the gill withdrawal reflex. A strong stimulus applied to the neck or tail improves the reflex response through heterosynaptic facilitation. The neurotransmitter serotonin is involved in both behavioral sensitization and dishabituation by acting through the second messenger cyclic adenosine monophosphate, protein kinase A, the phosphorylation of a K {}^{+} channel, causing its closure. This broadens the action potential profile, increases the influx of Ca {}^{2+} through voltage-gated Ca {}^{2+} channels, and enhances the neurotransmitter glutamate’s release. Short-term memory is based on covalent modifications of pre-existing proteins, while long-term memory requires gene transcription, protein translation and growth of new synapses. Another simple invertebrate model is the leech Hirudo medicinalis. In nearly-intact preparations, the repetitive application of light electrical stimuli at the level of the caudal portion of the body wall can induce the habituation of swimming induction. At the same time, the stroke on the dorsal skin generates behavioral sensitization or dishabituation. Knowledge of the molecular mechanisms of activity-dependent forms of synaptic plasticity provides a basis for understanding the mechanisms underlying learning, memory, other forms of brain plasticity, and pathological conditions and suggests potential therapeutic interventions.