The chapter discusses the concept of metaplasticity, which refers to the ability of neurons to modify their structure and function in response to activity, crucial for learning and memory. Metaplasticity involves changes in the physiological or biochemical state of neurons or synapses that alter their ability to generate synaptic plasticity, such as long-term potentiation (LTP) and long-term depression (LTD). These changes persist beyond the initial triggering activity and can affect subsequent plasticity events. The chapter reviews various intercellular signaling molecules, including catecholamines, GABA, acetylcholine, cytokines, and hormones, which directly regulate LTP and LTD. Additionally, it explores the role of NMDA receptors in mediating metaplasticity, where priming stimulation can inhibit subsequent LTP or enhance LTD. The chapter also discusses heterosynaptic metaplasticity, where activity at one set of synapses can affect neighboring synapses, and the involvement of protein synthesis in maintaining the persistence of LTP and LTD. Finally, it examines the behavioral and clinical implications of metaplasticity, including the effects of environmental stimuli and developmental processes on synaptic plasticity.The chapter discusses the concept of metaplasticity, which refers to the ability of neurons to modify their structure and function in response to activity, crucial for learning and memory. Metaplasticity involves changes in the physiological or biochemical state of neurons or synapses that alter their ability to generate synaptic plasticity, such as long-term potentiation (LTP) and long-term depression (LTD). These changes persist beyond the initial triggering activity and can affect subsequent plasticity events. The chapter reviews various intercellular signaling molecules, including catecholamines, GABA, acetylcholine, cytokines, and hormones, which directly regulate LTP and LTD. Additionally, it explores the role of NMDA receptors in mediating metaplasticity, where priming stimulation can inhibit subsequent LTP or enhance LTD. The chapter also discusses heterosynaptic metaplasticity, where activity at one set of synapses can affect neighboring synapses, and the involvement of protein synthesis in maintaining the persistence of LTP and LTD. Finally, it examines the behavioral and clinical implications of metaplasticity, including the effects of environmental stimuli and developmental processes on synaptic plasticity.