Glutamate Signaling in Central Noradrenergic Neurons is Dispensable for Normal Breathing and Chemosensory Reflexes

Core Concepts

Vglut2-based glutamatergic signaling in central noradrenergic neurons is not required for normal baseline breathing, hypercapnic, or hypoxic ventilatory reflexes in unanesthetized and unrestrained mice.

Abstract

The study aimed to fully characterize the expression profiles of the three vesicular glutamate transporters (Vglut1, Vglut2, and Vglut3) in central noradrenergic (NA) neurons and to test the hypothesis that Vglut2-based glutamatergic release is required for respiratory control under physiological chemosensory challenges.

Key findings:

1. Fate mapping and in situ hybridization revealed a novel dynamic expression pattern for Vglut2 and an undescribed co-expression domain for Vglut3 in the central NA system.
2. Conditional deletion of Vglut2 in all NA neurons did not significantly impact breathing under room air, hypercapnic, or hypoxic conditions in unanesthetized and unrestrained mice.
3. The results challenge the prevalent perspective that NA-derived glutamate transmission is critical for respiratory homeostasis and suggest that glutamate may not be a key target to understand NA neuron dysfunction in respiratory diseases.

Stats

Vglut2 mRNA expression was 96.4 ± 0.226% decreased in Dbh-Cre; Vglut2 cKO mice compared to controls.
84.7 ± 5.82% of anterior C1/A1 NA neurons co-expressed Slc17a6 (Vglut2) mRNA.
90.1 ± 2.45% of posterior C2/A2 NA neurons co-expressed Slc17a6 (Vglut2) mRNA.
26.9 ± 3.16% of posterior C2/A2 NA neurons co-expressed Slc17a8 (Vglut3) mRNA.

Quotes

"Vglut2-based glutamatergic signaling in central NA neurons is not required for normal baseline breathing nor for the hypercapnic ventilatory reflex under distinct CO2 challenges."
"These data demonstrate that Vglut2-based glutamatergic signaling within the central NA system is not required for normal baseline breathing and hypercapnic, hypoxic chemosensory reflexes."

Key Insights Distilled From

Vglut2-based glutamatergic signaling in central noradrenergic neurons is dispensable for normal breathing and chemosensory reflexes

by Chang,Y., Lu... at www.biorxiv.org 04-16-2023

https://www.biorxiv.org/content/10.1101/2023.04.16.535729v4

Deeper Inquiries

What other neurotransmitters or neuromodulators in central noradrenergic neurons may compensate for the loss of Vglut2-based glutamatergic signaling to maintain normal breathing?

In central noradrenergic neurons, other neurotransmitters or neuromodulators that may compensate for the loss of Vglut2-based glutamatergic signaling include neuropeptide Y (NPY) and galanin. These neuropeptides have been shown to coexist in LC NA neurons and are involved in regulating energy metabolism, stress, or anxiety. NPY and galanin could potentially play a role in modulating breathing in the absence of glutamate signaling. Additionally, other neurotransmitters such as serotonin, dopamine, or acetylcholine may also contribute to maintaining normal breathing in the absence of Vglut2-based glutamatergic signaling. Further research is needed to fully understand the compensatory mechanisms at play in central noradrenergic neurons.

How might the role of Vglut2-based glutamatergic signaling in central noradrenergic neurons differ under pathological conditions compared to normal physiological challenges?

Under pathological conditions such as respiratory disorders like Rett Syndrome, Sudden Infant Death Syndrome (SIDS), or Congenital Central Hyperventilation Syndrome (CCHS), the role of Vglut2-based glutamatergic signaling in central noradrenergic neurons may be altered compared to normal physiological challenges. In these pathological conditions, there may be dysregulation or dysfunction in the central NA system, leading to abnormalities in breathing control. The loss of Vglut2-based glutamatergic signaling in central NA neurons may exacerbate respiratory symptoms or contribute to the pathophysiology of these disorders. Additionally, the compensatory mechanisms mentioned earlier may be insufficient or overwhelmed in pathological conditions, further impacting breathing regulation. Understanding the specific alterations in Vglut2-based glutamatergic signaling in the context of respiratory disorders is crucial for developing targeted therapeutic interventions.

Could the dynamic expression patterns of Vglut2 and Vglut3 in central noradrenergic neurons be regulated by developmental, behavioral, or environmental factors?

The dynamic expression patterns of Vglut2 and Vglut3 in central noradrenergic neurons could indeed be regulated by various factors including developmental, behavioral, and environmental influences. During development, the expression of Vglut2 and Vglut3 in central NA neurons may change as the neuronal circuitry matures and establishes connections with other brain regions involved in breathing control. Behavioral factors such as stress, anxiety, or exposure to different stimuli could also modulate the expression of these glutamate transporters in central NA neurons. Environmental factors like hypoxia, hypercapnia, or changes in oxygen levels may further impact the dynamic expression patterns of Vglut2 and Vglut3 in response to physiological challenges. Understanding the regulatory mechanisms that govern the expression of these glutamate transporters in central NA neurons is essential for elucidating their role in respiratory control and potential implications for respiratory disorders.