Nitric Oxide as the Maestro of the Endocannabinoid Symphony in the Cerebellum
Image generated from OpenArt Artificial Intelligence using prompt: “Colourful Cerebellar Symphony” https://openart.ai/discovery
What good is a packed restaurant if there is no chef to create a delicious meal? What good is an actor that plays their part to an empty theatre? What good is an orchestra without the guidance of a conductor or maestro? These questions highlight how important coordination and interactions are for achieving successful experiences whether in cooking, theatre, music, or even the molecular interactions within the brain.
The cerebellum, Latin for “little brain”, sits at the back of your head, behind where your spinal cord connects to your brain, and has the main function of maintaining both balance and posture, while coordinating and fine-tuning every muscle movement you perform. Think of the cerebellum as an orchestra, and within this orchestra, each specific neuron plays a different instrument to coordinate a symphony of finely tuned motor movements. To begin this symphony, the string instruments are played by the granule cells, which are neurons that release glutamate – a neurotransmitter or molecule that activates other neurons in its surrounding. The release of glutamate from granule cells is followed by the wind instruments joining in, which are played by Purkinje neurons and are the neurons that comprise the sole output of the cerebellum. But who – or what – oversees the timing and coordination of these interactions to ensure that the molecular symphony remains harmonious? In the case of the cerebellum, the job of the conductor falls upon the protein neuronal nitric oxide synthase (nNOS) – an enzyme that creates the gaseous molecule, nitric oxide, within the cerebellum.
The production of nitric oxide in the cerebellum regulates both the intensity and frequency of Purkinje neuron and granule cell firing, much like how a conductor of an orchestra regulates the timing and intensity of each note played by the orchestra. If the granule neurons and Purkinje neurons are the string and wind instruments, respectively, the components of the endocannabinoid system are the specific notes and melody that are played by each neuron. Much like the notes that make up a musical scale, the endocannabinoid system is comprised of different enzymes and molecules that sequentially work together to help regulate the symphony of fine motor movements performed by your cerebellum. But what would happen if the conductor of this orchestra were to vanish? What would happen if there was no nitric oxide within the cerebellum to guide and conduct this symphony?
Research from the University of Western Ontario conducted by Dr. Vasiliki Tellios, Ph.D., uncovered the changes that occur to the components of the endocannabinoid system in the cerebellum during postnatal development of a rodent model that does not express neuronal nitric oxide synthase and nitric oxide. This research study, published in the journal The Cerebellum, demonstrated that the gaseous molecule, nitric oxide, plays an important role in regulating the endocannabinoid pathway in the cerebellum during postnatal development. Much like a conductor overseeing the symphony of an orchestra to ensure the symphony remains harmonious and organized, nitric oxide was crucial for maintaining appropriate expression and activity of endocannabinoid proteins and enzymes in the cerebellum. Specifically, when the conductor was absent, and there was no nitric oxide during early postnatal development in the cerebellum, the research team found increased expression of both DAGLα, an enzyme that produces the endocannabinoid 2-Arachadonic Acid (2-AG) in Purkinje neurons, and CB1 Receptor, a receptor on granule neurons that binds 2AG. This mismatch in endocannabinoid proteins equates to both the string and wind instruments beginning the symphony with erroneously loud notes and a disorganized melody.
Importantly, the research team found that as the rodent model aged to the point where it could be considered an adult, DAGLα expression in Purkinje neurons returned to normal levels, 2-AG began to increase, and CB1 Receptor expression on granule neurons significantly decreased when compared to the normal rodent model that expressed both neuronal nitric oxide synthase and nitric oxide. Therefore, as the endocannabinoid symphony progressed without its conductor, the wind instruments played by the Purkinje neurons managed to eventually play a correct melody; however, this melody was louder than normal as it resulted in elevated levels of 2-AG, which was further accompanied by the granule cells playing their string instruments at a much lower volume, which further contributed to the disorganized performance. The research team further speculated that this dysregulation in endocannabinoid signalling contributes to an excitotoxic phenotype whereby the neurons, specifically the Purkinje neurons, become sick and unable to function properly, which could negatively impact fine motor movements, balance, and coordination.
In conclusion, the work conducted by this research team to uncover the intricacies of the endocannabinoid symphony in the cerebellum during postnatal development is crucial to further understand how these molecular disruptions lead to problems with balance and motor coordination, which may contribute to the development of therapeutic targets to treat these deficiencies.
Tellios, Maksoud, M. J. E., Nagra, R., Jassal, G., & Lu, W.-Y. (2022). Neuronal Nitric Oxide Synthase Critically Regulates the Endocannabinoid Pathway in the Murine Cerebellum During Development. Cerebellum (London, England). https://doi.org/10.1007/s12311-022-01493-2