Serotonin Deficits Modulate Hippocampal Plasticity

Abstract

Serotonin (5-HT) modulates a wide variety of functions across the central nervous systems. It is a key regulator of neuroplasticity, particularly in the hippocampus, where increased serotonergic signaling generally enhances the plasticity processes. However, the consequences of 5-HT deficiency on brain plasticity remain poorly understood, which is essential for clarifying the role of 5-HT in the etiology and treatment of psychiatric disorders. Here, we survey findings from pharmacological and genetic models of 5-HT depletion, focusing on molecular, cellular, and neural circuit changes in the hippocampus, alongside related phenotypes. Evidence indicates that lowering 5-HT levels differentially impacts the distinct forms of plasticity. While chronic depletion frequently increases molecular plasticity markers, dendritic spines, and neurogenesis, it simultaneously impairs neural circuit plasticity and hippocampus-dependent memory. In contrast, both acute and developmental 5-HT depletion consistently reduce both the structural and functional neuronal plasticity of the hippocampus. These findings highlight that the effects of 5-HT deficiency are highly dependent on the timing, duration, and developmental stages of the manipulation. Deconstructing this complexity is critical to interpreting how reduced 5-HT levels alter hippocampal plasticity and contribute to psychiatric pathophysiology.