Cannabinoid type 2 receptors inhibit GABAA receptor-mediated currents in cerebellar Purkinje cells of juvenile mice

Abstract

Signaling through the endocannabinoid system is critical to proper functioning of the cerebellar circuit. However, most studies have focused on signaling through cannabinoid type 1 (CB1) receptors, while relatively little is known about signaling through type 2 (CB2) receptors. We show that functional CB2 receptors are expressed in Purkinje cells using a combination of immunohistochemistry and patch-clamp electrophysiology in juvenile mice. Pharmacological activation of CB2 receptors significantly reduces inhibitory synaptic responses and currents mediated by photolytic uncaging of RuBi-GABA in Purkinje cells. CB2 receptor activation does not change the paired-pulse ratio of inhibitory responses and its effects are blocked by inclusion of GDP-β-S in the internal solution, indicating a postsynaptic mechanism of action. However, CB2 receptors do not contribute to depolarization induced suppression of inhibition (DSI), indicating they are not activated by endocannabinoids synthesized and released from Purkinje cells using this protocol. This work demonstrates that CB2 receptors inhibit postsynaptic GABA A receptors by a postsynaptic mechanism in Purkinje cells. This represents a novel mechanism by which CB2 receptors may modulate neuronal and circuit function in the central nervous system.

Role of Cannabinoid CB2 Receptor in Alcohol Use Disorders: From Animal to Human Studies

“…Indeed, suppression of GABAergic inhibition could be induced by the CB 2 r agonist JWH133 and reversed by the CB 2 r antagonist AM630 [ 50 ]. Likewise, activation of CB 2 r inhibited GABA-A receptor-mediated currents [ 51 ]. Moreover, chronic treatment with a CB 2 r agonist increased excitatory transmission in glutamatergic as opposed to GABAergic synapses [ 41 ].…”

“…Despite some controversy, the progress in antibodies against CB 2 r have allowed identifying the expression of this cannabinoid receptor in neurons within the prefrontal cortex, dorsal striatum, NAcc, VTA, HIP, and cerebellum [ 28 , 29 , 38 , 39 , 40 , 41 , 42 , 43 , 44 ]. In more detail, CB 2 r is expressed in dopaminergic [ 38 , 42 , 45 , 46 , 47 , 48 ], glutamatergic [ 46 , 49 ], and GABAergic neurons [ 50 , 51 ]. In addition, CB 2 r has been identified in astrocytes [ 38 , 52 , 53 ] and microglia [ 44 , 54 , 55 , 56 ], in both basal and activated states, downregulating the gene expression of inflammatory mediators [ 57 , 58 , 59 ].…”

Portable Neuroimaging Guided Non-invasive Brain Stimulation of Cortico-cerebello-thalamo-cortical Loop in Substance Use Disorder

“…Here, CB1 receptor activity is required for long-term plasticity at parallel fiber-Purkinje cells synapses relevant for cerebellar learning. CB2 receptors in Purkinje cells may mainly participate in pathophysiological responses to exogenous cannabinoid compounds that can inhibit GABA receptor-mediated currents potentially causing cerebellar dysfunction (Sadanandan et al, 2020). This will reduce the inhibitory tone the cerebellum that can be investigated based on the primary This is a provisional file, not the final typeset article motor cortex, i.e., CBI, that can be impaired in CUD (Martin-Rodriguez et al, 2020) and schizophrenia (Walther and Strik, 2012).…”

Etomidate Depresses Spontaneous Complex Spikes Activity of Cerebellar Purkinje Cells via Cannabinoid 1 Receptor in vivo in Mice

“…Etomidate-induced sedation was increased and prolonged by activation of the CB1 receptor in vivo in mice [19]. Importantly, numerous evidences show that cerebellar Purkinje cell expresses abundant CB1 receptors, suggesting that etomidate may modulate Purkinje cell activity via activation of CB1 receptors [20–23]. Our previous results show that etomidate facilitates CB1 receptors in the absence of GABA A receptors activity, resulting in a depression of the sensory stimulation-evoked synaptic transmission via protein kinase A (PKA) signaling pathway in mouse cerebellar granular layer [24].…”