Striatonigral direct pathway 2-arachidonoylglycerol contributes to ethanol effects on synaptic transmission and behavior

Abstract

Endocannabinoids (eCB) and cannabinoid receptor 1 (CB1) play important roles in mediating short- and long-term synaptic plasticity in many brain regions involved in learning and memory, as well as the reinforcing effects of misused substances. Ethanol-induced plasticity and neuroadaptations predominantly occur in striatal direct pathway projecting medium spiny neurons (dMSNs). It is hypothesized that alterations in eCB neuromodulation may be involved. Recent work has implicated a role of eCB 2-arachidonoylglycerol (2-AG) in the rewarding effects of ethanol. However, there is insufficient research to answer which cellular subtype is responsible for mediating the 2-AG eCB signal that might be involved in the rewarding properties of ethanol and the mechanisms by which that occurs. To examine the role of dMSN mediated 2-AG signaling in ethanol related synaptic transmission and behaviors, we used conditional knockout mice in which the 2-AG-synthesizing enzyme diacylglycerol lipase α (DGLα) was deleted in dMSNs, DGLαD1-Cre+. Using acute brain slice photometry and a genetically encoded fluorescent eCB sensor, GRABeCB2.0, to assess real-time eCB mediated activity of sensorimotor inputs from primary motor cortices (M1/M2) to the dorsolateral striatum, we showed that DGLαD1-Cre+ mice had blunted evoked eCB-mediated presynaptic eCB signaling compared to littermate controls. Furthermore, ethanol induced eCB inhibition was significantly reduced in DGLαD1-Cre+ deficient mice. Additionally, there was a reduction in the duration of loss of righting reflex (LORR) to a high dose of ethanol in the DGLαD1-Cre+ mice compared to controls. These mice also showed a male-specific decrease in ethanol preference accompanied by an increase in ethanol-induced water consumption in a voluntary drinking paradigm. There were no significant differences observed in sucrose and quinine consumption between the genotypes. These findings reveal a novel role for dMSN mediated 2-AG signaling in modulating ethanol effects on presynaptic function and behavior.

Astrocytic Regulation of Endocannabinoid-Dependent Synaptic Plasticity in the Dorsolateral Striatum

“…In conclusion, while the tools available to disentangle astrocytes from neurons are limited, and the methods used in this study cannot be considered fully specific, the data retrieved collectively support an active role for astrocytes in modulating neurotransmission and synaptic plasticity in the form of eCB-LTD. The effects appear to be especially linked to changes in glutamatergic neurotransmission, which, in combination with alterations in striatal eCB signaling, could have a major impact on striatal-based learning and behavior (Augustin et al, 2023;Hilario et al, 2007;Rueda-Orozco et al, 2008) [95][96][97].…”

Cerebellar output neurons impair non-motor behaviors by altering development of extracerebellar connectivity

“…In line with these conclusions, removal of the cerebellum or vermis neonatally in genetically dystonic rats 74,75 or weaver mutants 76,77 significantly rescues the adult motor coordination deficits seen in both mutants. Circuits that comprise the ILM-cortico-striatal circuitry have been implicated in motor learning 36,37,78 , cognitive flexibility 37,79,80 , and spatial working memory 81 . The excessive connectivity seen in Atoh1-En1/2 CKOs using dMRI might thus be caused by the remaining En1/2-lacking eCN and contribute to their behavioral deficits.…”