SSRIs target prefrontal to raphe circuits during development modulating synaptic connectivity and emotional behavior

Area of Science:

• Neuroscience
• Developmental Biology
• Pharmacology

Background:

• Selective serotonin reuptake inhibitors (SSRIs) are widely used antidepressants.
• SSRIs paradoxically increase anxiety and depression risk when used during perinatal periods.
• The underlying developmental mechanisms for these long-term effects remain unknown.

Purpose of the Study:

• To investigate the developmental role of the serotonin transporter (SERT) in prefrontal cortex (PFC) circuits.
• To elucidate the impact of early-life SSRI exposure on neural circuit development and adult behavior.
• To identify specific PFC descending circuits targeted by antidepressants during development.

Main Methods:

• Examined transient Slc6a4/SERT expression in mouse PFC layer 5-6 pyramidal neurons during early postnatal development (P0-P10).
• Investigated PFC-SERT+ neuron synaptic connections with dorsal raphe nucleus (DRN) serotonin and GABA neurons.
• Utilized complete and cortex-specific SERT ablation, early-life fluoxetine exposure, and pharmacogenetic manipulation of PFC-SERT+ neuron activity.

Main Results:

• Developmental SERT expression in PFC neurons influences the maturation of PFC-to-DRN glutamatergic synapses.
• SERT ablation or early fluoxetine exposure led to PFC-to-DRN hyperinnervation and anxiety/depressive-like behaviors.
• Pharmacogenetic modulation of PFC-SERT+ neuron activity bidirectionally altered stress-related behaviors.

Conclusions:

• Developmental SERT expression in specific PFC neurons is critical for regulating the maturation of PFC-to-DRN circuits.
• Early-life SSRI exposure can disrupt these circuits, leading to long-term behavioral alterations and increased stress vulnerability.
• These findings identify key developmental targets of SSRIs and offer insights into the basis of perinatal antidepressant side effects.