Inhibitory neurotransmission drives endocannabinoid degradation to promote memory consolidation

Abstract

Endocannabinoids retrogradely regulate synaptic transmission and their abundance is controlled by the fine balance between endocannabinoid synthesis and degradation. While the common assumption is that “on-demand” release determines endocannabinoid signaling, their rapid degradation is expected to control the temporal profile of endocannabinoid action and may impact neuronal signaling. Here we show that memory formation through fear conditioning selectively accelerates the degradation of endocannabinoids in the cerebellum. Learning induced a lasting increase in GABA release and this was responsible for driving the change in endocannabinoid degradation. Conversely, Gq-DREADD activation of cerebellar Purkinje cells enhanced endocannabinoid signaling and impaired memory consolidation. Our findings identify a previously unappreciated reciprocal interaction between GABA and the endocannabinoid system in which GABA signaling accelerates endocannabinoid degradation, and triggers a form of learning-induced metaplasticity.

GluN2D NMDA Receptors Gate Fear Extinction Learning and Interneuron Plasticity

“…Fear conditioning has been shown to induce a lasting increase in spontaneous GABA release onto Purkinje and MLIs ( Scelfo et al, 2008 ; Dubois et al, 2020 ). We determined the effects of learning and extinction paradigms on GABA release from MLIs to synaptic connected MLIs.…”

“…No statistical method was used to predetermine sample sizes, but they are similar to previous studies (Liu and Cull-Candy, 2000;Lachamp et al, 2009;Dubois et al, 2016Dubois et al, , 2020. Each data set was obtained from mice from at least three different litters.…”

“…The cerebellum is not only critically involved in the consolidation and reconsolidation of associative fear memories ( Sacchetti et al, 2002 , 2007 ; Scelfo et al, 2008 ; Dubois et al, 2020 ), but also regulates extinction learning. A recent study shows that optogenetic activation of cerebellar neurons in the fastigial nucleus that projects to vlPAG accelerates extinction learning, whereas chemogenetic inhibition of this pathway attenuates extinction ( Frontera et al, 2020 ).…”

“…In addition to these extensively studied neuronal circuits, clinical studies implicate the cerebellum in emotional regulation and fear memory extinction ( Timmann et al, 2010 ; Linnman et al, 2011 ; Lange et al, 2015 ; Utz et al, 2015 ; Ernst et al, 2019 ). The cerebellum is required for associative fear memory formation, as reversible inhibition of neuronal activity or release endocannabinoids from Purkinje cells after learning disrupts memory consolidation ( Sacchetti et al, 2002 ; Dubois et al, 2020 ). Associative fear learning enhances both excitatory ( Sacchetti et al, 2004 ) and inhibitory ( Scelfo et al, 2008 ) transmission to Purkinje cells, and reduces endocannabinoid signaling, increasing GABA release ( Dubois et al, 2020 ).…”

“…The cerebellum is required for associative fear memory formation, as reversible inhibition of neuronal activity or release endocannabinoids from Purkinje cells after learning disrupts memory consolidation ( Sacchetti et al, 2002 ; Dubois et al, 2020 ). Associative fear learning enhances both excitatory ( Sacchetti et al, 2004 ) and inhibitory ( Scelfo et al, 2008 ) transmission to Purkinje cells, and reduces endocannabinoid signaling, increasing GABA release ( Dubois et al, 2020 ). Molecular layer interneurons (MLIs) in the cerebellar cortex control the activity of Purkinje cells and thus a learning-induced enhancement of GABA release from MLIs can alter the activity and output of cerebellar circuitry ( Scelfo et al, 2008 ).…”