The cannabinoid-1 receptor is abundantly expressed in striatal striosomes and striosome-dendron bouquets of the substantia nigra

Abstract

Presynaptic cannabinoid-1 receptors (CB1-R) bind endogenous and exogenous cannabinoids to modulate neurotransmitter release. CB1-Rs are expressed throughout the basal ganglia, including striatum and substantia nigra, where they play a role in learning and control of motivated actions. However, the pattern of CB1-R expression across different striatal compartments, microcircuits and efferent targets, and the contribution of different CB1-R-expressing neurons to this pattern, are unclear. We use a combination of conventional techniques and novel genetic models to evaluate CB1-R expression in striosome (patch) and matrix compartments of the striatum, and in nigral targets of striatal medium spiny projection neurons (MSNs). CB1-R protein and mRNA follow a descending dorsolateral-to-ventromedial intensity gradient in the caudal striatum, with elevated expression in striosomes relative to the surrounding matrix. The lateral predominance of striosome CB1-Rs contrasts with that of the classical striosomal marker, the mu opioid receptor (MOR), which is expressed most prominently in rostromedial striosomes. The dorsolateral-to-ventromedial CB1-R gradient is similar to Drd2 dopamine receptor immunoreactivity and opposite to Substance P. This topology of CB1-R expression is maintained downstream in the globus pallidus and substantia nigra. Dense CB1-R-expressing striatonigral fibers extend dorsally within the substantia nigra pars reticulata, and colocalize with bundles of ventrally extending, striosome-targeted, dendrites of dopamine-containing neurons in the substantia nigra pars compacta (striosome-dendron bouquets). Within striatum, CB1-Rs colocalize with fluorescently labeled MSN collaterals within the striosomes. Cre recombinase-mediated deletion of CB1-Rs from cortical projection neurons or MSNs, and MSN-selective reintroduction of CB1-Rs in knockout mice, demonstrate that the principal source of CB1-Rs in dorsolateral striosomes is local MSN collaterals. These data suggest a role for CB1-Rs in caudal dorsolateral striosome collaterals and striosome-dendron bouquet projections to lateral substantia nigra, where they are anatomically poised to mediate presynaptic disinhibition of both striosomal MSNs and midbrain dopamine neurons in response to endocannabinoids and cannabinomimetics.

Compartmental function and modulation of the striatum

“…Unlike KORs (the endogenous ligand of which is dynorphin), which are expressed homogenously throughout the striatum, MORs and DORs are enriched in striosomes and exo-patch neurons (Graybiel, 1990;Koizumi et al, 2013;Miura et al, 2007;Smith et al, 2016 (Miura et al, 2007). For example, cannabinoid-1 receptors (CB1Rs), which attenuate presynaptic glutamate and GABA release in much the same way as opioid receptors do (Adermark, Talani, & Lovinger, 2009;Atwood et al, 2014), are preferentially expressed in SPN axon collaterals within striosomes in the dorsolateral striatum (Davis et al, 2018). What was not clear from these studies was the local microcircuitry that was engaged.…”

“…It should be noted that the disinhibition of striosomal output may also be achieved in opioid receptor-independent ways. For example, cannabinoid-1 receptors (CB1Rs), which attenuate presynaptic glutamate and GABA release in much the same way as opioid receptors do (Adermark, Talani, & Lovinger, 2009;Atwood et al, 2014), are preferentially expressed in SPN axon collaterals within striosomes in the dorsolateral striatum (Davis et al, 2018). As presynaptic CB1Rs are key determinants of endocannabinoid-mediated, long-term depression (LTD) within the striatum (Lovinger, 2010), it is tempting to speculate that the propensity for LTD at inhibitory SPN-SPN collateral connections or extrastriatal SPN axonal targets is augmented in striosomes.…”

Functional dissection of basal ganglia inhibitory input onto SNc dopaminergic neurons

“…Axon tracing in monkeys shows that multiple neurons from a single striosome send axons into several distinct bouquet-like structures (Lévesque and Parent, 2005). Because there are several types of striosomes (Davis et al, 2018;Miyamoto et al, 2018), it will be important to determine whether striosomes act as isolated units (Banghart et al, 2015) or communicate cohesive signals.…”

Optogenetic interrogation of the role of striatal patches in habit formation and inhibition of striatal dopamine

“…As striatal patches are a unique striatal output population projecting to SNc (Crittenden et al, 2016; Davis et al, 2018; Evans et al, 2020), optogenetic stimulation of patches may alter responding by modulating dopamine release. We aimed to investigate this possibility by eliciting phasic increases in striatal dopamine with electrical stimulation of the pedunculopontine tegmental nucleus (PPTg; Forster and Blaha, 2003; Zweifel et al, 2009) with and without simultaneous optogenetic activation of patch projections.…”