Astrocytes in Neurotransmitter function in the recycling of Glutamate and GABA and prevent over excitability

Glutamatergic neurons (which produce glutamate) release glutamate across the synaptic gap. This glutamate binds to receptors on the next neuron, allowing positive ions to flow in, triggering that neuron to activate. After this, the glutamate needs to detach from the receptor to avoid overstimulating the neuron.

To prevent this excess activity, special transporter proteins recycle the glutamate back into the original neuron, where it's stored for future use. However, if these transporters become overloaded, glutamate can remain in the gap and continue to stimulate neighboring neurons.

Astrocytes, a type of support cell in the brain, can help manage this by absorbing extra glutamate. They convert it into glutamine, which is a more stable form, through an enzyme called glutamine synthetase. The astrocytes then release the glutamine back to the original neuron, which can convert it back into glutamate using another enzyme (glutaminase) and store it for reuse.

GABAergic neurons, which produce GABA (a calming neurotransmitter), can also regulate this process. GABA is actually made from glutamate. When there's too much GABA in the synaptic gap, it can be turned into glutamine, transported back into the original neuron, and then reconverted into glutamate. That glutamate can then be changed back into GABA, ensuring the neuron has a fresh supply of GABA ready to release.

 

Glial cells, Astrocytes – CNS only, part of the BBB

Glial cells are the supportive cells of the nervous system. Unlike neurons, which transmit signals, glial cells provide essential support functions such as maintaining homeostasis, protecting neurons, and helping with repair and waste removal. Types of glial cells include astrocytes, microglia, oligodendrocytes, and Schwann cells, each playing a role in insulating neurons, managing inflammation, and regulating the environment around nerve cells to ensure proper brain and spinal cord function.

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Astrocytes in respect to the blood brain barrier (BBB)

BBB is 3 layers

1. Inner: Endothelial cells bound together by tight junctions to control permeability

2. middle: Basal lamina – connective tissue (protein)

3. outside: Astrocytes with foot processes.  Astocytes secrete molecules/growth factors that stimulate the endothelial cells to make more tight junctions which increases permeability. As astrocytes malfunction, tight junction production decreases allowing unwanted increased permeability in the BBB.

 

Pericytes are also involved

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Astrocytes and the blood-brain barrier (BBB):

The BBB controls what moves between the blood and nervous tissue, but some areas in the brain don’t have a BBB to help monitor the blood:

1. Area postrema (near the medulla): This area lacks a BBB so the brain can detect toxins and trigger vomiting to remove them.

2. Osmoreceptors near the hypothalamus: These check blood for salt, sugar, or water imbalances and signal the body to drink more or less, or adjust urination via ADH from the pituitary.

3. Between the hypothalamus and pituitary: This open area allows hormones from the hypothalamus to reach the pituitary.

 

Astrocytes help control potassium levels around neurons. Too much potassium in a neuron makes it more excitable. Astrocytes "mop up" excess potassium to prevent overstimulation. When neurons send signals, sodium rushes in and potassium exits through channels. Astrocytes store excess potassium in the space around neurons, helping maintain balance. They also help redistribute potassium between themselves and neurons to prevent overexcitability, ensuring proper function.

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Sodium moving down the axon can also trigger Ca2+ influx

Astrocytes help control glucose levels to ensure neurons have enough energy (ATP). If a neuron lacks ATP because it doesn't have enough glucose, astrocytes step in. They can absorb glucose from the blood using a GLUT1 transporter and store it as glycogen. When energy is needed, they break down glycogen into glucose, then into pyruvate and lactate. Astrocytes can send lactate to neurons, which convert it into energy through the Krebs cycle. Neurons also have their own GLUT3 transporters that allow them to absorb glucose directly from the blood. In short, astrocytes and neurons use different GLUT transporters to make sure the brain gets enough glucose for energy.

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Astrocytes can increase synapses between neurons but that is a poorly understood concept.

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Satellite cells are like the astrocytes of the peripheral nervous system (PNS). They have similar functions; except they don't manage the blood-brain barrier (BBB). Satellite cells do the following:

1. Surround dorsal root ganglia, which help control nutrient supply (like glucose for energy), regulate potassium levels, and manage neurotransmitter diffusion.

2. Surround autonomic ganglia, which are involved in controlling the sympathetic and parasympathetic nervous systems. Parasympathetic ganglia are close to the target organs.

 

Oligodendrocytesare responsible for adding protective myelin sheaths to nerve fibers in the brain and optic nerve. They can myelinate many axons at once (30-60), but if they are damaged, the myelin they produce can’t regenerate. This is important in conditions like multiple sclerosis, where the body’s immune system can attack and damage oligodendrocytes.

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Schwann cells, on the other hand, myelinate nerves in the PNS, including spinal and cranial nerves (except the optic nerve). Unlike oligodendrocytes, Schwann cells can repair damaged myelin and help guide the regrowth of injured nerves.

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Microglia (immune cells of the brain) interact with blood vessels and may help repair the blood-brain barrier. Studies suggest certain probiotics, like Lactobacillus, can influence microglia behavior, boosting their response to injury.

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When nerves in the PNS are damaged, Schwann cells play a key role in guiding the regeneration of new nerve fibers, with help from macrophages, which clean up debris. In diseases like Guillain-Barré syndrome, Schwann cells are attacked by the immune system, leading to nerve damage starting from the extremities and moving inward.

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In the CNS, multiple sclerosiscan occur when the immune system mistakenly targets key proteins in oligodendrocytes, causing the breakdown of myelin, which disrupts nerve function.

 

Case Study Astrocyte involvement

 

In the Astrocyte to Motor Neuron Model of ALS, symptoms often start with speech changes and slow, stiff movements, like difficulty walking, though not everyone shows these signs. Astrocytes are essential for the survival of motor neurons, and if astrocytes are damaged, motor neurons can't function properly. One-way astrocytes get damaged is through exposure to chemicals like chlorine, fluorine, and bromine. After Maris' condition improved last year (he was the second person to reverse motor neuron disease, which was linked to chlorine exposure and Epstein-Barr Virus), I’ve been investigating this model. This led to the discovery of ALS cases in areas with high levels of chemicals like PFOAs, PFAS, and PCBs. Important note: test your water for these chemicals! If they're present, filter them out from your drinking and shower water immediately. This was one of the first steps we recommended to Greg and Maris.

 

1. Nutrient Support: Astrocytes provide essential nutrients like glucose and lactate to motor neurons, which need a lot of energy to function.

2. Ion and Calcium Balance: Astrocytes regulate ion and calcium levels around motor neurons, which helps control their activity and prevent overexcitability. This is also important because mitochondria need calcium to work properly.

3. Mitochondrial Support: Astrocytes supply mitochondria (the cell's energy producers) to motor neurons. This is crucial because motor neurons rely on astrocytes to provide healthy mitochondria and the calcium they need to function.

4. Neurotransmitter Recycling: Astrocytes help recycle neurotransmitters like glutamate. This is extremely important because too much glutamate can cause damage, which is a key issue in ALS. It's also the target of treatments like riluzole.

5. Protection Against Damage: Astrocytes produce antioxidants and remove harmful substances like reactive oxygen species (ROS), which can otherwise damage cells.

 

Astrocytes are especially vulnerable to environmental toxins, particularly chlorinated and fluorinated compounds. These chemicals have been shown to contribute to neuroinflammation and motor neuron damage in ALS. Here's how they affect the body:

 

1. Astrocyte Activation: In ALS, astrocytes can become overactive and release inflammatory chemicals, which can contribute to motor neuron damage.

2. Glutamate Imbalance: When astrocytes fail to manage glutamate properly, too much of it builds up, causing overexcitation and motor neuron death, a key feature of ALS.

3. Mitochondrial Problems: Astrocytes help keep motor neurons' mitochondria healthy. When this support fails, it leads to the mitochondrial issues often seen in ALS.

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We’ve been developing treatments focused on improving astrocyte function, and Greg and Maris are great examples of this. By looking at lab results and symptoms (such as which areas are affected first and how the disease progresses), we’ve grouped ALS into different “types” to find the best treatment for each. The main categories include:

 

1. Astrocytes

2. Infected microglia

3. Glutamate toxicity from pesticides

4. Exposure to hydrocarbons, petroleum, diesel, and military environments

5. Bulbar symptoms linked to astrocyte-acetylcholine damage

6. Oligodendrocyte-related frontal temporal dementia (FTD)

7. Neurodegeneration from herpes virus reactivation

8. Neurodegeneration from COVID-19 or Lyme disease

9. Familial/genetic ALS

 

If you're interested in the Astrocyte Protocol (Greg’s therapy), we recommend a two-week visit, followed by a one-week visit about four weeks later.