ADAM17 Supports Disinhibition of Pre-sympathetic Glutamatergic Neurons Through Microglial Chemotaxis
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Updated: May 3, 2026
Methodology for Biomimetic Chemical Neuromodulation of Rat Retinas with the Neurotransmitter Glutamate In Vitro
Published on: December 19, 2017
Jiawei Wang1, Zihan Qiu1, Yue Han1
1Department of Physiology and Pathophysiology, Xi'an Jiaotong University Health Science Center, Xi'an, 710061, China.
Abstract:
A disintegrin and metalloprotease 17 (ADAM17) is a membrane-bound enzyme that cleaves cell-surface proteins. Here, we discovered that neuronal ADAM17-mediated signaling supports the reduction of inhibitory presynaptic inputs to the pre-sympathetic glutamatergic neural hub, located in the paraventricular nucleus of the hypothalamus (PVN), upon stimulation by angiotensin II (Ang-II). For Ang-II-induced disinhibition, targeting microglial migration had an effect similar to ADAM17 knockout in glutamatergic neurons. Ang-II promoted neuron-mediated chemotaxis of microglia via neuronal CX3CL1 and ADAM17. Inhibiting microglial chemotaxis by targeting CX3CR1 abolished the Ang-II-induced microglial displacement of GABAergic presynaptic terminals and significantly blunted Ang-II's pressor response. Using conditional and targeted knockout models of ADAM17, an increase in the contact between pre-sympathetic neurons and reactive microglia in the PVN was demonstrated to be neuronal ADAM17-dependent during the developmental stage of salt-sensitive hypertension. Collectively, this study provides evidence that neuronal ADAM17-mediated microglial chemotaxis facilitates the disinhibition of pre-sympathetic glutamatergic tone upon hormonal stimulation.
Insights
Neuronal ADAM17 signaling reduces inhibitory inputs to the hypothalamus's pre-sympathetic neurons. This process involves angiotensin II, promoting microglial migration and disinhibition, crucial for blood pressure regulation.
Area of Science:
- Neuroscience
- Molecular Biology
- Cardiovascular Physiology
Background:
- ADAM17 is a membrane-bound metalloprotease involved in cleaving cell-surface proteins.
- The paraventricular nucleus (PVN) of the hypothalamus is a key neural hub regulating sympathetic outflow and blood pressure.
- Angiotensin II (Ang-II) is a hormone that plays a critical role in cardiovascular regulation.
Purpose of the Study:
- To investigate the role of neuronal ADAM17 in regulating inhibitory presynaptic inputs to the PVN.
- To elucidate the mechanism by which Ang-II-induced disinhibition occurs in the PVN.
- To determine the involvement of microglia in ADAM17-mediated signaling in the PVN.
Main Methods:
- Utilized conditional and targeted knockout models of ADAM17 in glutamatergic neurons.
- Investigated the effects of Ang-II stimulation on neuronal signaling and microglial migration in the PVN.
- Examined the role of CX3CL1/CX3CR1 signaling in mediating microglial chemotaxis.
- Assessed the impact of microglial displacement on GABAergic presynaptic terminals and blood pressure.
Main Results:
- Neuronal ADAM17 signaling reduces inhibitory presynaptic inputs to PVN glutamatergic neurons upon Ang-II stimulation.
- Ang-II promotes neuron-mediated microglial chemotaxis via neuronal CX3CL1 and ADAM17.
- Inhibiting microglial chemotaxis abolished Ang-II-induced microglial displacement of GABAergic terminals and blunted the pressor response.
- Neuronal ADAM17 is crucial for increased neuron-microglia contact in the PVN during salt-sensitive hypertension.
Conclusions:
- Neuronal ADAM17-mediated microglial chemotaxis facilitates the disinhibition of pre-sympathetic glutamatergic tone.
- This pathway is critical for hormonal regulation of sympathetic outflow and blood pressure.
- ADAM17 in neurons plays a significant role in neuroinflammation and cardiovascular control.
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