Parkinson's Disease Alters Serotonergic and Dopaminergic Neurons in the Dorsal Raphe Nucleus

Core Concepts

Parkinson's disease induces distinct changes in the electrophysiological and morphological properties of serotonergic and dopaminergic neurons in the dorsal raphe nucleus, with the serotonergic neurons being particularly sensitive to the loss of noradrenaline.

Abstract

The study investigated the electrophysiological and morphological properties of serotonergic (DRN5-HT) and dopaminergic (DRNDA) neurons in the dorsal raphe nucleus (DRN) under control conditions and in a mouse model of Parkinson's disease (PD) induced by striatal injection of 6-hydroxydopamine (6-OHDA).
Key highlights:

DRN5-HT and DRNDA neurons have distinct electrophysiological and morphological profiles, which can be used to reliably identify them.
In the 6-OHDA PD model, the excitability of DRN5-HT neurons was increased when the noradrenergic system was protected, suggesting that the loss of dopamine alone can induce homeostatic changes.
However, the combined loss of dopamine and noradrenaline led to more profound changes in the firing properties and morphology of DRN5-HT neurons, including shorter action potentials, afterhyperpolarizations, and membrane time constants, as well as a reduction in soma size and dendritic branching.
In contrast, the changes in DRNDA neurons were primarily driven by the loss of dopamine and were less affected by the concomitant loss of noradrenaline.
Selective lesioning of the locus coeruleus noradrenergic system induced only minor changes in the DRN subpopulations, suggesting that the combined depletion of dopamine and noradrenaline is required to induce the more pronounced alterations observed.
These findings highlight the complex interplay between dopaminergic, serotonergic, and noradrenergic systems in the DRN and provide insights into how the pathology in Parkinson's disease may contribute to non-motor symptoms.

Stats

The striatal injection of 6-OHDA led to a 60-70% reduction of tyrosine hydroxylase levels in the striatum.
The 6-OHDA injection induced approximately 60% loss of noradrenaline in the striatum.

Quotes

"Striatal injection of 6-OHDA has also been found to produce a partial loss of NA neurons in the LC and ELISA analysis showed that this approach induces approximately 60% loss of NA in the striatum."
"Our results show that DRN neurons are affected by depletion of both DA and NA, thus raising the possibility that non-motor symptoms in PD are a result of the intricate organization of DA and NA neuromodulation as well as the interactions between the different DRN neuronal populations."

Key Insights Distilled From

Serotonergic and dopaminergic neurons in the dorsal raphe are differentially altered in a mouse model for parkinsonism

by Boi,L., Joha... at www.biorxiv.org 07-22-2023

https://www.biorxiv.org/content/10.1101/2023.07.21.550014v3

Deeper Inquiries

How do the changes in DRN5-HT and DRNDA neurons observed in this study relate to the specific non-motor symptoms experienced by Parkinson's disease patients

The changes observed in DRN5-HT and DRNDA neurons in this study have significant implications for the specific non-motor symptoms experienced by Parkinson's disease (PD) patients. DRN5-HT neurons, which are primarily serotonergic, displayed increased excitability and firing rates in response to the loss of dopamine, particularly when the noradrenergic system was also affected. These changes could be linked to the sleep disturbances, affective dysfunctions, and cognitive impairments commonly seen in PD patients. Serotonergic dysfunction in the DRN has been associated with mood disorders and sleep disturbances, which are prevalent non-motor symptoms in PD. Therefore, the alterations in DRN5-HT neurons observed in this study may contribute to the manifestation of these non-motor symptoms in PD patients.
On the other hand, DRNDA neurons showed changes in their electrophysiological properties and morphology in response to the loss of dopamine, independent of noradrenaline depletion. These alterations in DRNDA neurons could be related to the regulation of pain, motivational processes, and wakefulness, which are functions associated with this neuronal population. The changes in DRNDA neurons may contribute to the motor impairments and other non-motor symptoms such as cognitive dysfunction experienced by PD patients. Therefore, the differential responses of DRN5-HT and DRNDA neurons to dopamine and noradrenaline loss provide insights into the neural mechanisms underlying the diverse non-motor symptoms in PD.

What are the potential mechanisms underlying the differential sensitivity of DRN5-HT and DRNDA neurons to the loss of dopamine versus noradrenaline

The differential sensitivity of DRN5-HT and DRNDA neurons to the loss of dopamine versus noradrenaline could be attributed to the distinct roles of these neurotransmitters in modulating neuronal activity and function in the dorsal raphe nucleus (DRN). Dopamine depletion primarily affects DRNDA neurons, leading to changes in their electrophysiological properties, such as altered firing rates and action potential characteristics. DRNDA neurons are known to be involved in pain regulation, motivational processes, and wakefulness, and the loss of dopamine may disrupt these functions, contributing to motor impairments and other symptoms in PD.
On the other hand, noradrenaline depletion affects DRN5-HT neurons, resulting in increased excitability and firing rates. Serotonergic neurons in the DRN play a crucial role in mood regulation, sleep-wake cycles, and cognitive functions. The alterations in DRN5-HT neurons due to noradrenaline loss may impact the serotonergic transmission throughout the brain, leading to disturbances in mood, sleep, and cognition observed in PD patients.
The differential sensitivity of these neuronal populations to dopamine and noradrenaline loss could be attributed to the specific receptors and signaling pathways involved in dopaminergic and noradrenergic modulation of DRN neurons. Dopamine and noradrenaline may have distinct effects on ion channels, neurotransmitter release, and synaptic plasticity in DRN5-HT and DRNDA neurons, resulting in the observed changes in their activity and morphology.

Could targeting the interactions between dopaminergic, serotonergic, and noradrenergic systems in the DRN represent a novel therapeutic approach for addressing non-motor symptoms in Parkinson's disease

Targeting the interactions between dopaminergic, serotonergic, and noradrenergic systems in the DRN could represent a novel therapeutic approach for addressing non-motor symptoms in Parkinson's disease. The complex interplay between these neurotransmitter systems in the DRN plays a crucial role in regulating mood, sleep, cognition, and other non-motor functions affected in PD. By modulating the activity of DRN neurons through targeted interventions, it may be possible to alleviate non-motor symptoms and improve the overall quality of life for PD patients.
One potential therapeutic strategy could involve the development of drugs that selectively target specific receptors or signaling pathways in DRN5-HT and DRNDA neurons. For example, modulating serotonin receptors in DRN5-HT neurons or dopamine receptors in DRNDA neurons could help restore the balance of neurotransmission disrupted in PD. Additionally, interventions that enhance noradrenergic signaling in the DRN may counteract the effects of dopamine depletion on DRN5-HT neurons, potentially mitigating mood disorders and sleep disturbances in PD.
Furthermore, deep brain stimulation (DBS) targeted at the DRN or its afferent and efferent pathways could be explored as a therapeutic option for PD patients. By modulating the activity of DRN neurons through DBS, it may be possible to restore the balance of neurotransmission and alleviate non-motor symptoms associated with PD. Overall, targeting the interactions between dopaminergic, serotonergic, and noradrenergic systems in the DRN holds promise as a novel therapeutic approach for addressing non-motor symptoms in Parkinson's disease.