Nearly a decade ago, researchers determined that the brain contains a molecule that mimics the active ingredient in marijuana, but its location and role in the brain were unclear. Now, UCSF researchers have discovered that the molecule acts, at least in part, in a region of the brain that plays a key role in learning and memory.
The study, reported in the March 29 issue of Nature, suggests, the researchers say, that the molecule, known as a cannabinoid, plays a role in particular cognitive functions within a structure known as the hippocampus. Paradoxically, marijuana disrupts cognitive function and the likely explanation, the researchers say, is that marijuana disrupts the very cognitive system the cannabinoid normally supports.
The circumstances under which cannabinoid might act are unknown, but one possibility is that it contributes to the formation of new memories, says the lead author of the study, Rachel I. Wilson, a graduate student in the laboratory of Roger A. Nicoll, PhD, UCSF professor of cellular and molecular pharmacology and physiology and a member of the Keck Center for Integrative Neuroscience at UCSF.
Another possibility is that cannabinoid enables neurons to shift from one behavioral state to another. “We know that when the brain is carrying out different behaviors - whether directing the body to a desired destination or sleeping - it has different patterns of synchronous rhythms. Cannabinoid might enable neurons to shift from one behavioral state to another,” she says.
In either case, she says, the cannabinoid system would be supporting cognitive processes. While merely speculative at this point, the hypothesis is reasonable, says Wilson, as the cell receptor through which cannabinoid acts has been conserved through evolution, suggesting the cannabinoid molecule is beneficial to many species.
“It seems to me than anything expressed so heavily and conserved throughout evolution must be good for you. Why would we express the receptor at high levels if it just made us stupid?”
Marijuana, meanwhile, could be disrupting the system by acting in a nondiscriminatory manner, says Wilson.
The researchers, conducting their study in rats, discovered that cannabinoid is the signaling molecule within a unique system of communication that is activated intermittently between two of the brain’s most ubiquitous nerve cells —neurons containing the inhibitory neurotransmitter GABA, and neurons containing the excitatory neurotransmitter glutamate. The modulation of inhibitory and excitatory signals leads to the regulation of excitation and inhibition within clusters of neurons that is the basis for all action and thought.
Normally, brain cells containing the inhibitory neurotransmitter GABA release their signal and it diffuses across a synapse and on to receptors on cells containing the excitatory neurotransmitter glutamate, thereby dampening excitatory behavior. This orderly flow of information from pre-synaptic to post-synaptic cell is the classical form of communication in the nervous system.
But, of interest to the researchers, when excitatory glutamate neurons are highly charged electrically, they release a molecular signal that moves backwards, across the synapse, to a subset of inhibitory GABAergic neurons that have a receptor known as CB1. The event briefly inhibits the release of inhibitory GABA neurotransmitters, thus allowing the excitatory neurons to fire messages of excitation repeatedly and intensely, thereby “strengthening” their synaptic connections with other nerve cells. The strengthening of synapses, otherwise known as long term potentiation, or LTP, is thought to be the basis of learning and establishing memories. The signal inciting this event, the researchers determined, is a cannabinoid molecule.
“Signaling by the cannabinoid system represents a mechanism by which neurons can communicate backwards across synapses to modulate their inputs,” says senior author Nicoll.
Notably, this rare, so-called retrograde system is only activated when excitatory neurons are in a particularly heightened electrical state, which probably explains a unique characteristic: While neurons package and store classical neurotransmitters in compartments known as vesicles, and then release them on demand, neurons must make cannabinoid when they need it.
“Prepackaging is for speed, which this system doesn’t need,” says Nicoll. “There’s no need to waste energy storing the molecule if it’s only going to be used occasionally.”
The conditions under which the retrograde system might be ignited are unknown, but one possibility is that the cannabinoid system might be recruited in situations where the hippocampus is particularly active—meaning situations where the brain has to form new memories, says Wilson.
Another possibility is that cannabinoid helps orchestrate a shift in behavioral states. Cannabinoid acts only on GABA cells containing the CB1 receptor. These cells, a subtype of a class of cells known as interneurons, are interspersed among the glutamate-releasing cells. Researchers are just beginning to understand the role of interneurons. In the hippocampus, just one inhibitory interneuron orchestrates the actions of hundreds of glutamatergic cells, prompting them to fire their neurotransmitters in synchrony. It may be, the researchers say, that the cannabinoid system breaks down synchrony, enabling glutamatergic neurons to move out of one synchronous rhythm and into another.
“There may be times when the synchrony should be powerful, and at times when it should be weak,” says Wilson.
Marijuana, meanwhile, could be inciting changes in synaptic strength left and right, causing a chaotic pattern of changes in synaptic strength. Alternatively, the drug could be disrupting synchrony at the wrong time.
The researchers drew their conclusion that cannabinoid was the signaling molecule by determining that the receptor on the pre-synaptic cells was CB1. Other scientists had previously determined that this receptor for marijuana existed, though it had not been clear where or how it acted in the brain. Still others had determined the existence of two naturally occurring cannabinoids, though, again, their location and role in the brain was unknown. A third is expected to be reported shortly. Most likely, the scientists say, the molecule they are studying is one of these three.
The fact that the CB1 cannabinoid receptor is found throughout the brain suggests, says senior author Nicoll, that cannabinoid may have functions in other parts of the brain, as well.
“Cannabinoid joins a small group of molecules identified as fast retrograde signals in the nervous system. As such, it provides a tool for sorting out the roles of various classes of inhibitory interneurons, whose roles we’re just beginning to understand,” he says.
The study was funded by grants from the National Institutes of Health, the Bristol-Myers Squibb Corporation, the National Science Foundation Fellowship and a UC Regents Fellowship.