Salt, Glia, and Pressure: Microglia Turn on Neurons by 'Pruning' Astrocytes - and Raises Pressure

The McGill team showed how microglia (the brain's immune cells) can rewire neuronal activity by physically rewiring neighboring astrocytes. In a rat model fed a high-salt diet, reactive microglia accumulate around vasopressin-secreting neurons in the hypothalamus. They phagocytose ("pruning") astrocytic processes, which impairs the uptake of glutamate from synapses. This causes glutamate to "spill" to extrasynaptic NMDA receptors, causing neurons to become overexcited. As a result, the vasopressin system is activated, and the animals develop salt-dependent hypertension. Blocking microglial "pruning" of astrocytes reduces neuronal overexcitation and reduces the hypertensive effect of salt.

Background of the study

Neurons do not work alone: their activity is finely tuned by glial cells. Astrocytes are especially important, with their thin peri-synaptic processes tightly “hugging” synapses, removing excess glutamate and ions (via EAAT carriers), buffering K⁺ and thus preventing overexcitation. These processes are mobile: in different physiological states - from osmotic shifts to lactation - astrocytes can open up or, conversely, pull in processes, changing the degree of synapse coverage and the rate of “cleaning up” of mediators. A classic example of such plasticity has long been described in the hypothalamus: with chronic salt consumption, the astrocytic coating of magnocellular neurons (vasopressin/oxytocin) decreases, but the mechanism of this restructuring remained unclear.

The second key figure is microglia, the brain's resident immune cells. In addition to being "on duty" during inflammation, they are capable of sculpting neural networks: in development and disease, microglia "trim" synapses by phagocytizing excess elements. It was logical to assume that it could also influence the structure of astrocytes, but there was almost no direct evidence or cause-and-effect relationships. The question was: if microglia are activated locally, can they physically remove astrocytic processes and thereby indirectly increase the excitability of neurons?

The context for this problem is salt-sensitive hypertension. Excess salt raises blood pressure not only through the kidneys and blood vessels, but also through the brain: osmosensory nodes and neurons secreting vasopressin are activated, increasing water retention and vascular tone. If astrocytes lose their synaptic “cuffs” during a high-salt diet, glutamate is less well cleared and can spill over to extrasynaptic NMDA receptors, increasing excitatory drive to vasopressin neurons. But it remained unclear who triggers this structural reorganization of astrocytes and whether it is possible to intervene in such a way as to break the “salt → brain → blood pressure” chain.

Against this background, the current work tests a specific hypothesis: high salt locally makes microglia reactive around vasopressin neurons; they, in turn, phagocytize peri-synaptic astrocytic processes, reducing glutamate clearance, which leads to activation of extrasynaptic NMDA receptors, increased activity of these neurons and, as a consequence, to a vasopressin-dependent increase in blood pressure. The applied link is also critically important: if microglial “pruning” is blocked, will it be possible to reduce neuronal overexcitation and salt-dependent hypertension? The answer to this question closes the long-standing gap between the observed astrocytic plasticity and real physiological outcomes.

Why is this important?

Glial cells are often thought of as the “service personnel” of neurons. This work goes one step further: microglia are active orchestrators of the neural network, changing the structure of astrocytes and thereby fine-tuning synaptic transmission. This links lifestyle (excess salt) to neuron-glia-neuron mechanics and, ultimately, to blood pressure. It provides a plausible explanation for how salt raises blood pressure via the brain, not just via the kidneys and blood vessels.

How it works (mechanism - step by step)

• Salt → reactive microglia. On a high-salt diet, a “cap” of activated microglia grows around vasopressin neurons (locally, not throughout the brain).
• Microglia → astrocyte "pruning". Microglia phagocytose peri-synaptic processes of astrocytes, reducing their coverage of neurons.
• Fewer astrocytes → more glutamate. Glutamate clearance is weakened - spillover to extrasynaptic NMDA receptors occurs.
• NMDA drive → hyperactivation of neurons. Vasopressin-secreting cells are “turned on” and increase the hormonal response.
• Vasopressin → hypertension. Blood pressure increases through water retention and vascular effects.
• Inhibition of "pruning" → protection. Pharmacological/genetic blockade of microglial "pruning" normalizes neuronal activity and attenuates salt-dependent hypertension.

What exactly did they do?

The researchers took a "classic" example of structural plasticity of astrocytes - their loss of peri-synaptic processes in the magnocellular system of the hypothalamus during chronic salt consumption. They focused on vasopressin neurons and showed:

• microglia accumulate locally precisely here against the background of salt;
• absorbs astrocytic processes, reducing astrocytic coverage of neurons;
• this leads to a disruption of glutamate clearance and activation of extrasynaptic NMDA receptors;
• Inhibition of microglial pruning reduces neuronal activity and attenuates salt-induced hypertension.

What does this mean for pressure physiology?

Traditionally, salt has been linked to blood pressure via renal sodium/water reabsorption and vascular stiffness. Here, a central link is added: salt → microglia → astrocytes → glutamate → vasopressin → BP. This explains why neural interventions (e.g. targeting osmoregulatory nodes) affect hypertension and why diet can act quickly and powerfully - via brain networks.

Who is this especially relevant for?

• For people with salt-sensitive hypertension and those whose blood pressure rises when they eat salty foods.
• Patients with water-salt balance disorders (heart failure, decreased GFR), where the vasopressin axis is already tense.
• For researchers developing anti-inflammatory/microglial targets for cardiometabolic diseases.

What's new compared to previous ideas

• Glia as a causal factor, not a background: microglia structurally reconfigure astrocytes, changing neuronal excitability.
• Extrasynaptic NMDA receptors come to the fore as "amplifiers" of glutamate influx.
• Locality of the effect: not the entire brain, but a node of vasopressin neurons - a point of application for future interventions.

Limitations and accuracy of interpretation

This is work on rats; human transferability needs to be tested. Astrocyte pruning is a dynamic process: it is important to find out whether the restructuring is reversible and how quickly. Mechanisms need to be clarified: what microglial signals trigger phagocytosis of astrocytic processes? What role do complement, cytokines, and recognition receptors play? And where is the boundary between adaptation and pathology with moderate vs. high salt intake.

What's Next (Ideas for the Next Wave of Research)

• Therapeutic targets:
  • molecules that control microglial phagocytosis (complement, TREM2, etc.);
  • astrocyte glutamate transporters (EAAT1/2) to restore clearance;
  • extrasynaptic NMDA receptors as "volume controls".
• Marker studies in humans: neuroimaging of glial inflammation, plasma/CSF signatures, renin-angiotensin-vasopressin axis.
• Nutrition and behavior: how quickly does a high-salt diet reverse glial remodeling? Does physical activity/sleep act as moderators?

Conclusion

A high-salt diet can "bypass" the classic peripheral pathways and raise blood pressure through the brain: microglia eat up protective astrocytic "cuffs", glutamate spills out, NMDA receptors drive neurons, vasopressin - blood pressure. This is a non-trivial connection between the structural plasticity of glia and cardiometabolics. In a practical sense, it reinforces the main advice: less salt - fewer reasons for glia to "rebuild" the neural networks of pressure, and in the future - targeted interventions that will return astrocytes to their "shock-absorbing" role.

Source: Gu N., Makashova O., Laporte C., Chen CQ, Li B., Chevillard P.-M., … Khoutorsky A., Bourque CW, Prager-Khoutorsky M. Microglia regulate neuronal activity via structural remodeling of astrocytes. Neuron (in press, 2025). Pre-print version: bioRxiv, 19 Feb 2025, doi:10.1101/2025.02.18.638874.