Endocannabinoid System Science

Retrograde Signaling, Learning, and the Endocannabinoid System

Our brains work sort of like computers, and where computer chips have transistors, we have synapses. A synapse is the tiny gap where two neurons meet and exchange information in the form of chemical neurotransmitters (chemicals like dopamine or serotonin).

The neuron which sends the signal is called presynaptic, and the receiving neuron is called postsynaptic. This is the essential way that our brain works, and neurologists have understood the basic process for decades; it’s called anterograde signaling.

Anterograde simply means in a forward direction. But there have been missing links as to how we learn and how certain neural pathways get reinforced, and even how negative feedback works. For years, researchers speculated that there had to be a retrograde signaling system that allowed neurons to communicate in the “reverse direction” of traditional signaling. With the discovery of the endocannabinoid system in the early ‘90s, they had found their lost sheep.

What is retrograde signaling?

The discovery of actual retrograde signaling finally allowed the study of complex processes like learning and higher thought. It allows our nervous system and the rest of our body to utilize circuits in the same way as computers: in order to provide feedback in the opposite direction of the first instructions, almost like how teachers give students information, but if the students can’t ask questions then they’ll never have a full understanding of the subject. Retrograde signaling allows our cells to ask each other questions and thus perfect whatever process they’re undertaking.

How it works

Anterograde signaling is what the structure of our brain allows it to do best. Neurons have two basic parts, an axon and a dendrite. The axon is the presynaptic part of the neuron which produces and releases neurotransmitters into the synapse. The dendrite is the postsynaptic part of the neuron which has receptors that bind with neurotransmitters and produce an effect in the cell. Every neuron has both of these parts. This however only allows for one-way communication between two neurons: from the axon of one to the dendrite of another.

Retrograde signaling occurs when the postsynaptic dendrite of a neuron (which usually receives a signal) produces neurotransmitters and releases them, as opposed to the presynaptic axon performing this function like usual. When these retrograde neurotransmitters (the best-known examples are the endocannabinoids (eCBs) anandamide and 2-AG) are released into the synapse, they travel in the reverse direction of typical neurotransmitters (hence retrograde) and bind with receptors on the presynaptic axon of their neighboring neuron.

Why it matters

Retrograde signaling ultimately allows our cells and organ systems to establish and maintain homeostasis, which is the internal stability of conditions amidst unstable external conditions. 2-way communication between cells is the way that positive and negative feedback systems work, which are what facilitate homeostasis and physically keep it within a healthy range.

In a positive feedback loop, Cell 1 does something (anterograde) that has some effects on Cell 2. One of the effects is that Cell 2 is induced by that message to have a retrograde response that travels back to Cell 1 and tells it to increase its activity. Negative feedback is identical except the result is a decrease in the activity of Cell 1 rather than an increase. As long as our cells are healthy, then the balance between positive and negative feedback will be stable and everything will remain in balance

How is the endocannabinoid system involved?

The endocannabinoid system was the first retrograde system discovered. Almost all of the CB1 receptors in our brains are located in the presynaptic axons of neurons. This was the first sign that the endocannabinoids could facilitate retrograde transmission. The subsequent discovery of how anandamide and 2-AG, our endocannabinoids, are produced solved the mystery completely.

Dendritic synthesis of endocannabinoids

Remember that the dendrite is the postsynaptic part of the neuron, which usually is on the receiving end of communication. With the endocannabinoid system, however, the dendrite makes the call and the axon receives the instructions, the reverse of normal transmission. In excitatory neurons, anterograde signaling causes calcium channels to open in the postsynaptic neuron, which alters the charge of the cell and produces an action potential, which is a fancy terminology for “the neuron fires.”

The calcium that pours into the neuron also has the effect of activating an enzyme that produces endocannabinoids. If the calcium influx is healthy, then it produces 2-AG, if it’s unhealthy, then AEA is produced. When one of these is produced, it automatically gets released back into the synapse travelling the opposite direction, backward to the axon of the presynaptic neuron. There, it binds with the CB1 receptors and causes the cell to produce more or less of the first signal it sent: AEA (which mimics THC) produces an inhibitory response and 2-AG, an excitatory one.

Is this how we remember things?

Long-term memory (any memory at all if we’re being honest) is a near complete mystery to the field of neuroscience. They understand the basic chemical processes that take place in our brains, but understanding how that translates to our minds and our consciousness, and how something as transcendent as consciousness is produced is still widely uncharted territory. There are theories that use retrograde signaling to explain how neurons form stronger and stronger bonds with one another, which is a classic feature of neuroscience called plasticity; neurons’ tendency to either increase or decrease the strength of their synapses with other neurons; why and how they do this is the unknown part.

Essentially, the theory says that retrograde signaling produces a positive feedback message that increases the rate of firing of neurotransmitters from the presynaptic neuron. The postsynaptic neuron will then increase the amount of receptors so that it can bind with all of the neurotransmitters being released. This in turn causes another increase of neurotransmission until a much stronger communication and higher-resolution synapse is formed, with moreof the neurotransmitter released, and more receptors for it to bind to.

The hippocampus, which is where much of memorization and memory encoding takes place, is notable for its massive expression of CB1 cannabinoid receptors. In the hippocampus, the release of 2-AG suppresses the activity of the inhibitory GABA neurons that usually cause us to treat information as unnecessary “brain clutter”, deleting it. When this endocannabinoid is released, it suppresses that reaction, allowing the neurons to form stronger and stronger connections with one another, due to increased firing rates. We’ll go into more detail about the exact mechanism of long-term memory encoding and “long term potentiation” by endocannabinoids in a future post, but retrograde signaling is the mechanism of how it works, and it solved a decades-old mystery in the field of neurology.