Endocannabinoids and Dopamine Balance Basal Ganglia Output.

Lilach Gorodetski,Izhar Bar-Gad,Yocheved Loewenstern,Kim T Blackwell,Alon Korngreen,Anna Faynveitz

doi:10.3389/fncel.2021.639082

Lilach Gorodetski, Izhar Bar-Gad + Show 4 more

Open Access

https://doi.org/10.3389/fncel.2021.639082

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Abstract

The entopeduncular nucleus is one of the basal ganglia's output nuclei, thereby controlling basal ganglia information processing. Entopeduncular nucleus neurons integrate GABAergic inputs from the Striatum and the globus pallidus, together with glutamatergic inputs from the subthalamic nucleus. We show that endocannabinoids and dopamine interact to modulate the long-term plasticity of all these primary afferents to the entopeduncular nucleus. Our results suggest that the interplay between dopamine and endocannabinoids determines the balance between direct pathway (striatum) and indirect pathway (globus pallidus) in entopeduncular nucleus output. Furthermore, we demonstrate that, despite the lack of axon collaterals, information is transferred between neighboring neurons in the entopeduncular nucleus via endocannabinoid diffusion. These results transform the prevailing view of the entopeduncular nucleus as a feedforward “relay” nucleus to an intricate control unit, which may play a vital role in the process of action selection.

Highlights

We recently showed that post-synaptic depolarization of neurons in the entopeduncular nucleus (EP) induces the release of endocannabinoids, which leads to long-term depression of glutamatergic input to these neurons (Gorodetski et al, 2018)
We tested the effect of eCB release on GABAergic inputs to the EP from the direct) electric stimulation to the striatum) and indirect pathways of the basal ganglia (BG)
Repeating the experiment with post-HFS induction of 50 Hz resulted in a smaller long-term depression (LTD), whereas post-HFS using an induction frequency of 10 Hz did not affect synaptic strength

Summary

Introduction

The basal ganglia (BG) are a set of nuclei implicated in addiction (Hiroi et al, 1999), motor control (Yin, 2010), reinforcement learning (Cromwell et al, 2005; Yin et al, 2005; Lex and Hauber, 2010), and many brain disorders such as Parkinson’s disease, Huntington’s disease (Alexander et al, 1990; Wichmann and DeLong, 1996; Feigin et al, 2007; Kloppel et al, 2009), and Tourette syndrome (Leckman et al, 2010). The passage of information through the BG is analogous to a funnel having the striatum (Str) for a mouth, the globus pallidus (GP) as a smaller intermediate structure, and the substantia nigra pars reticulata (SNr) together with the entopeduncular nucleus (EP in rodents, homologs to the GPi in primates) as the nozzle This funneling is characterized by a reduction in the neuronal population, which goes from (in the rodent) millions in the Str to only thousands in the EP, where the direct, indirect, and hyperdirect pathways of the BG converge (Nagy et al, 1978; Van Der Kooy and Carter, 1981; Bolam and Smith, 1992; Bevan et al, 1997; Nambu et al, 2002; Nambu, 2004; Bosch et al, 2012). In addition to this structural polarization, striatal projections to the EP display short-term facilitation (Sims et al, 2008; Kim and Kita, 2013), while pallidal projections to the EP display short-term depression (Kita, 2001; Sims et al, 2008; Connelly et al, 2010; Bugaysen et al, 2013)

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