TONIC REGULATION OF HIPPOCAMPAL INHIBITION BY ENDOCANNABINOIDS
Barti Benjámin
János Szentágothai Neurosciences
Dr. Bereczki Dániel
ELKH KOKI Előadóterem
2024-09-30 16:00:00
Neuromorphology and cell biology
Dr. Alpár Alán
Dr. Katona István
Dr. Schlett Katalin
Dr. Varga Zoltán
Dr. Benyó Zoltán
Dr. Puskár Zita
Dr. Rácz Bence
Neurotransmission in the brain is achieved through delicate cooperation between distinct molecular machineries, which are segregated into functionally different, spatially aligned nanodomains at both excitatory and inhibitory synapses. Precise and specific arrangement of these molecular complexes allows the fine regulation of the neurotransmitter release probability, which defines the strength of the synapse. While our quantitative understanding of the molecular architecture that determines anterograde synaptic transmission is rapidly expanding, the nanoscale functional organization of retrograde synaptic communication remains elusive.
In this study, we show that a specific form of retrograde cannabinoid signaling is essential for setting target cell-dependent synaptic variability at hippocampal inhibitory synapses. Importantly, it does not require the activity of the two major endocannabinoid-producing enzymes diacylglycerol lipase-α (DAGLα) and N-acyl phosphatidylethanolamine phospholipase D (NAPE-PLD). By developing a workflow for the measurement of physiological, anatomical, and molecular parameters at the same unitary synapse, we demonstrate that the nanoscale stoichiometric ratio of CB1 receptors (CB1R) to the release machinery is sufficient to predict synapse-specific release probability. Accordingly, selective extrasynaptic CB1R reduction does not affect synaptic transmission, whereas in vivo treatment by the psychoactive phytocannabinoid Δ9-tetrahydrocannabinol (THC) disrupts the intrasynaptic nanoscale stoichiometry and reduces synaptic variability. Our results imply that synapses leverage the nanoscale stoichiometry of presynaptic receptor coupling to the release machinery to establish synaptic strength in a target cell-dependent manner. These findings provide insights into the molecular tolerance mechanisms underlying cannabis use disorder and highlight that nanodomain-specific molecular imaging is essential to understand the physiological consequences of drug effects.
