# Serotonin-Glutamate Co-transmission in the hippocampus

> **NIH NIH R21** · WAYNE STATE UNIVERSITY · 2020 · $192,500

## Abstract

Neuronal co-transmission, the phenomenon whereby a neuron releases more than one neurotransmitter, is a
generalized property of many synapses in the central and peripheral nervous system. Previous work has
shown that serotonergic neurons can release both serotonin and glutamate and recent studies have shown that
this co-transmission plays a significant role in the generation of behavioral output. However how the use of
two neurotransmitters, serotonin and glutamate, uniquely shapes the regulation of postsynaptic targets
remains poorly understood.
Serotonergic neurons of the Median and Dorsal Raphe nuclei project to the hippocampus where they innervate
pyramidal cells and interneurons. Surprisingly the synapses made by serotonergic neurons onto GABAergic
interneurons of the SR and SLM appear to rely primarily on glutamate acting on ionotropic receptors, while
those made onto pyramidal cells appear to rely primarily on serotonin acting on metabotropic 5-HT1A
receptors. This suggests that co-transmission in hippocampus facilitates the differential regulation of distinct
postsynaptic targets, a phenomenon that has previously been reported for co-transmission in invertebrates and
in autonomic ganglia. In this application we propose to elucidate the mechanisms underlying this remarkable
dichotomy.
The experiments proposed in this application will be conducted using whole cell electrophysiological
recordings in in vitro hippocampal brain slices. Slices will be prepared from SERT-Cre driver mice selectively
expressing channelrhodopsin in serotonergic neurons. We and others have previously shown that serotonergic
synapses onto GABAergic interneurons of the SR and SLM rely on GluA receptors to elicit robust EPSCs with
only sparse evidence for serotonin co-transmission. In the first specific Aim we will examine the potential
involvement of different mechanisms that can account for this phenomenon. Additionally we will also test the
idea that expression of serotonergic co-transmission is stimulation frequency dependent. In contrast to the
situation in interneurons, serotonergic synapses onto pyramidal cells rely primarily on serotonin to elicit 5-HT1A receptor mediated slow IPSCs. In the second Specific Aim we will use intersectional genetic strategies to
separate synapses made by neurons co-releasing serotonin and glutamate and test the hypothesis that
pyramidal cells are selectively innervated by neurons releasing only serotonin. We will also test the possibility
that serotonergic neurons may release glutamate that acts on higher affinity NMDA receptors. The results of
these experiments should clarify key mechanistic aspects of serotonin glutamate co-transmission in the
hippocampus and contribute to a better understanding of the pathophysiology and therapeutics of diseases
involving serotoninergic synapses.

## Key facts

- **NIH application ID:** 9817689
- **Project number:** 5R21MH116280-02
- **Recipient organization:** WAYNE STATE UNIVERSITY
- **Principal Investigator:** RODRIGO ANDRADE
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $192,500
- **Award type:** 5
- **Project period:** 2018-11-05 → 2021-10-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9817689

## Citation

> US National Institutes of Health, RePORTER application 9817689, Serotonin-Glutamate Co-transmission in the hippocampus (5R21MH116280-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9817689. Licensed CC0.

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