The Effect of Serotonin-Targeting Antidepressants on Neurogenesis and Neuronal Maturation of the Hippocampus Mediated via 5-HT1A and 5-HT4 Receptors

Abstract

Antidepressant drugs such as selective serotonin reuptake inhibitors (SSRIs) specifically increase serotonin (5-HT) levels in the synaptic cleft and are widely used to treat mood and anxiety disorders. There are 14 established subtypes of 5-HT receptors in rodents, each of which has regionally different expression patterns. Many preclinical studies have suggested that the hippocampus, which contains abundant 5-HT1A and 5-HT4 receptor subtypes in the dentate gyrus (DG), is critically involved in the mechanisms of action of antidepressants. This review article will analyze studies demonstrating regulation of hippocampal functions and hippocampus-dependent behaviors by SSRIs and similar serotonergic agents. Multiple studies indicate that 5-HT1A and 5-HT4 receptor signaling in the DG contributes to SSRI-mediated promotion of neurogenesis and increased neurotrophic factors expression. Chronic SSRI treatment causes functions and phenotypes of mature granule cells (GCs) to revert to immature-like phenotypes defined as a “dematured” state in the DG, and to increase monoamine reactivity at the dentate-to-CA3 synapses, via 5-HT4 receptor signaling. Behavioral studies demonstrate that the 5-HT1A receptors on mature GCs are critical for expression of antidepressant effects in the forced swim test and in novelty suppressed feeding; such studies also note that 5-HT4 receptors mediate neurogenesis-dependent antidepressant activity in, for example, novelty-suppressed feeding. Despite their limitations, the collective results of these studies describe a potential new mechanism of action, in which 5-HT1A and 5-HT4 receptor signaling, either independently or cooperatively, modulates the function of the hippocampal DG at multiple levels, any of which could play a critical role in the antidepressant actions of 5-HT-enhancing drugs.

Ultra-high field imaging of hippocampal neuroanatomy in first episode psychosis demonstrates receptor-specific morphometric patterning

“…Both 5HT1A and 5HT4 are preferentially expressed during early embryonic development (48), prompting a developmental interpretation of the hippocampal volume deficits in schizophrenia. Further, both 5-HT1A(49) and 5-HT4 (50,51) expression is enriched in the ventral pole (anterior hippocampus) (51), and the dentate gyrus (52). In line with this, higher NMDA and AMPA expression has been reported in the anterior CA1 than CA3 (26,53).…”

“…5HT4 receptors play a crucial role in the potentiation of pyramidal CA3-CA1 synapses of the trisynaptic pathway (58), and promote dendritic spine formation (52), explaining the observed coexpression with NMDA receptors. Taken together, our results are in line with the strong evidence for serotonin and glutamate receptor co-localization within the hippocampus, explaining the increased susceptibility to glutamate-mediated changes in CA1 and dentate gyrus, and the ventral hippocampal surface.…”

iPlasticity: Induced juvenile‐like plasticity in the adult brain as a mechanism of antidepressants

“…Chronic SSRI treatment has been shown to stimulate all stages of adult neurogenesis, including the proliferation, differentiation, and survival of adult‐born granule cells (abGC) (Fig. ). Fluoxetine does not affect the division of stem‐like cells but increases symmetric divisions of early progenitor/precursor cells .…”

“…Model of dematuration and adult neurogenesis in the dentate gyrus (DG) by chronic selective serotonin reuptake inhibitors (SSRI) treatment. The upper section indicates expression markers of each neuron state . In the middle section, a mature neuron change to an immature state by dematuration after chronic SSRI treatment or electroconvulsive stimulation (ECS).…”

“…Finally, the matured adult‐born cell is functionally similar to other mature cells. The picture is combined and modified from Zhang and Jiao and Segi‐Nishida . DCX, doublecortin; ML, molecular layer; GL, granule layer; PSA‐NCAM, polysialic acid neural cell adhesion molecule; SGZ, subgranular zone.…”