Sunday, May 11, 2025
5/11/2025
Activity-dependent degradation of a neuromodulator - Neuromodulators control both synaptic transmission and the intrinsic excitability of neurons and are essential for CNS function. Most studies of neuroplasticity have focused on the regulation of neuromodulator synthesis or the receptors through which they signal. In contrast, the enzymatic degradation of these compounds has received less attention even though this controls the temporal profile of their modulatory action. This is surprising given the therapeutic potential of regulating the rate of degradation. For example inhibition of endocannabinoid degradation can reduce anxiety-like behaviors in rodents. In theory, an activity-dependent change in degradation would be expected to alter local neuromodulator levels and provide a powerful mechanism to regulate the activity of an entire neuronal circuit. Surprisingly studies of physiological regulation of degradation have lagged compared to its use clinically. We propose that neuronal activity can regulate the degradation of a neuromodulator, endocannabinoids. Endocannabinoids such as 2-AG, are released when neurons are activated (“on-demand”) and suppress neurotransmitter release and intrinsic excitability. MAGL (Monoacylglycerol lipase), a 2-AG degrading enzyme, terminates their activity and this process can be altered by experience because the level of MAGL changes following stress and alcohol abuse. In this application, we propose to investigate whether neuronal activity can regulate the degradation of 2-AG in the cerebellum, a brain region critical for motor control and associative fear memory formation. While searching for a physiological stimulus that could activate this pathway we found that fear conditioning can elevate both MAGL levels and 2-AG degradation, and furthermore these effects were blocked by administration of a PPARα inhibitor. We therefore propose that PPARα acts as a master regulator of MAGL/2-AG signaling, in that it couples a change in neuronal activity to a change in 2-AG degradation. Our central hypothesis is that neuronal activity upregulates 2-AG degradation via a PPARα-dependent pathway and thereby increases the activity of this cerebellar circuit. In aim 1 we will test whether neuronal activity induces a lasting increase in MAGL and 2-AG degradation via a PPARα-dependent pathway. In aim 2 we will determine whether fear learning elevates 2-AG degradation via a PPARα-MAGL dependent pathway and alters the activity of a cerebellar circuit. Investigation of how neuronal activity regulates endocannabinoid degradation is fundamental to our understanding of neuronal plasticity at the circuit level. If we can confirm a role for PPARα in an activity-dependent increase in MAGL expression this may allow us to selectively prevent, or facilitate, MAGL-dependent plasticity without affecting the basal level of this enzyme. This could provide a distinct therapeutic advantage over inhibitors of MAGL which elevate 2-AG levels and can lead to functional desensitization of the endocannabinoid system. Such regulation of MAGL expression in the cerebellum is likely to contribute to fear memory formation and motor function.
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