Dual action of serotonin on local excitatory and inhibitory neural circuits regulating the corticotropin-releasing factor neurons in the paraventricular nucleus of the hypothalamus

by Selleckchem | Dec 16 2023

Serotonergic neurons originating from the raphe nuclei have been proposed to regulate corticotropin-releasing factor (CRF) neurons in the paraventricular nucleus of the hypothalamus (PVH). Since glutamate- and γ-aminobutyric acid (GABA)-containing neurons, constituting the hypothalamic local circuits, innervate PVH CRF neurons, we examined whether they mediate the actions of serotonin (5-hydroxytryptamine [5-HT]) on CRF neurons. Spontaneous excitatory postsynaptic currents (sEPSCs) or spontaneous inhibitory postsynaptic currents (sIPSCs) were recorded in PVH CRF neurons, under whole cell patch-clamp, using the CRF-modified yellow fluorescent protein (Venus) ΔNeo mouse. Serotonin elicited an increase in the frequency of sEPSCs in 77% of the cells and a decrease in the frequency of sIPSCs in 71% of the cells, tested in normal medium. Neither the amplitude nor decay time of sEPSC and sIPSC was affected, thus the site(s) of action of serotonin may be presynaptic. In the presence of tetrodotoxin (TTX), serotonin had no significant effects on either parameter of sEPSC or sIPSC, indicating that the effects of serotonin are action potential-dependent, and that the presynaptic interneurons are largely intact within the slice; distant neurons may exist, though, since some 20%-30% of neurons did not respond to serotonin without TTX. We next examined through what receptor subtype(s) serotonin exerts its effects on presynaptic interneurons. DOI (5-HT2A/2C agonist) mimicked the action of serotonin on the sIPSCs, and the serotonin-induced decrease in sIPSC frequency was inhibited by a selective 5-HT2C antagonist RS102221. 8-OH-DPAT (5-HT1A/7 agonist) mimicked the action of serotonin on the sEPSCs, and the serotonin-induced increase in sEPSC frequency was inhibited by a selective 5-HT7 antagonist SB269970. Thus, serotonin showed a dual action on PVH CRF neurons, by upregulating glutamatergic- and downregulating GABAergic interneurons; the former may partly be mediated by 5-HT7 receptors, whereas the latter by 5-HT2C receptors. The CRF-Venus ΔNeo mouse was useful for the electrophysiological examination.

Comments:

It seems like you have provided a detailed summary of a research study investigating the effects of serotonin on corticotropin-releasing factor (CRF) neurons in the paraventricular nucleus of the hypothalamus (PVH). The study used electrophysiological techniques to explore how serotonin influences the activity of glutamatergic and GABAergic neurons that innervate PVH CRF neurons.

Here's a breakdown of the key findings from the study:

1. **Serotonin Effects on PVH CRF Neurons:**
   - Serotonin increased the frequency of spontaneous excitatory postsynaptic currents (sEPSCs) in 77% of the PVH CRF neurons.
   - Serotonin decreased the frequency of spontaneous inhibitory postsynaptic currents (sIPSCs) in 71% of the PVH CRF neurons.
   - These effects were observed in normal medium, indicating that serotonin modulates the activity of presynaptic interneurons regulating PVH CRF neurons.

2. **Action Potential Dependency:**
- Serotonin's effects were found to be action potential-dependent, as they were abolished in the presence of tetrodotoxin (TTX), a sodium channel blocker. This suggests that the effects of serotonin on PVH CRF neurons require the firing of action potentials.

3. **Receptor Subtypes Mediating Serotonin Effects:**
   - The study identified specific serotonin receptor subtypes involved in the modulation of glutamatergic and GABAergic interneurons.
   - DOI, a 5-HT2A/2C agonist, mimicked serotonin's action on sIPSCs, and the serotonin-induced decrease in sIPSC frequency was blocked by a selective 5-HT2C antagonist (RS102221).
   - 8-OH-DPAT, a 5-HT1A/7 agonist, mimicked serotonin's action on sEPSCs, and the serotonin-induced increase in sEPSC frequency was blocked by a selective 5-HT7 antagonist (SB269970).

4. **Dual Action of Serotonin:**
- Serotonin exhibited a dual action on PVH CRF neurons: it upregulated glutamatergic interneurons (possibly mediated by 5-HT7 receptors) and downregulated GABAergic interneurons (possibly mediated by 5-HT2C receptors).

5. **Use of CRF-Modified Mouse Model:**
- The study utilized the CRF-modified yellow fluorescent protein (Venus) ΔNeo mouse for electrophysiological examinations, indicating the usefulness of this mouse model in understanding serotonin's effects on PVH CRF neurons.

In summary, the study demonstrates that serotonin modulates the activity of PVH CRF neurons by influencing the presynaptic glutamatergic and GABAergic interneurons. This modulation is mediated through specific serotonin receptor subtypes (5-HT7 for glutamatergic neurons and 5-HT2C for GABAergic neurons) and is dependent on action potentials. The findings provide valuable insights into the complex neural circuits regulating stress-related responses in the hypothalamus.