Synaptic determinants of cholinergic interneurons hyperactivity during parkinsonism

Abstract

Parkinson’s disease is a neurodegenerative ailment generated by the loss of dopamine in the basal ganglia, mainly in the striatum. The disease courses with increased striatal levels of acetylcholine, disrupting the balance among these modulatory transmitters. These modifications disturb the excitatory and inhibitory balance in the striatal circuitry, as reflected in the activity of projection striatal neurons. In addition, changes in the firing pattern of striatal tonically active interneurons during the disease, including cholinergic interneurons (CINs), are being searched. Dopamine-depleted striatal circuits exhibit pathological hyperactivity as compared to controls. One aim of this study was to show how striatal CINs contribute to this hyperactivity. A second aim was to show the contribution of extrinsic synaptic inputs to striatal CINs hyperactivity. Electrophysiological and calcium imaging recordings in Cre-mice allowed us to evaluate the activity of dozens of identified CINs with single-cell resolution in ex vivo brain slices. CINs show hyperactivity with bursts and silences in the dopamine-depleted striatum. We confirmed that the intrinsic differences between the activity of control and dopamine-depleted CINs are one source of their hyperactivity. We also show that a great part of this hyperactivity and firing pattern change is a product of extrinsic synaptic inputs, targeting CINs. Both glutamatergic and GABAergic inputs are essential to sustain hyperactivity. In addition, cholinergic transmission through nicotinic receptors also participates, suggesting that the joint activity of CINs drives the phenomenon; since striatal CINs express nicotinic receptors, not expressed in striatal projection neurons. Therefore, CINs hyperactivity is the result of changes in intrinsic properties and excitatory and inhibitory inputs, in addition to the modification of local circuitry due to cholinergic nicotinic transmission. We conclude that CINs are the main drivers of the pathological hyperactivity present in the striatum that is depleted of dopamine, and this is, in part, a result of extrinsic synaptic inputs. These results show that CINs may be a main therapeutic target to treat Parkinson’s disease by intervening in their synaptic inputs.

Transient dystonia correlates with parkinsonism after 1-methyl-4-phenyl-1,2,3,6- tetrahydropyridine in non- human primates

“…As the relative ratio of striatal acetylcholine/dopamine relates to acute dystonia in mice treated with acute reserpine, one might anticipate that this ratio would normalize with downregulation of mGluR1, potentially translating to the end of the dystonic phase. This speculation supports growing data that ChIs play a role in dystonia and may serve as the main drivers of pathological hyperactivity in the striatum secondary to dopamine depletion and altered extrinsic synaptic inputs ( 51 ). Post-mortem histopathological measures of choline acetyltransferase (ChAT) or in vivo PET measures of [18F]fluoroethoxybenzovesamicol, (−)-[18F] FEOBV,(−)-(2R,3R)-trans-2-hydroxy-3-(4- phenylpiperidino)-5-(2-[18F]fluoroethoxy)-1,2,3,4-tetralin ( 52 ) or (−)-(1-(8-(2-[(18)F)fluoroethoxy)-3-hydroxy-1,2,3,4-tetrahydronaphtalen-2-yl)-pi peridi n -4 -yl) (4-fluorophenyl)methanone([18F]VAT) ( 53 ) may provide clues with respect to altered ChI activity during the transient dystonia phase in this NHP MPTP model.…”

Role of M4‐receptor cholinergic signaling in direct pathway striatal projection neurons during dopamine depletion

“…This result suggests that if M 4 Rs are upregulated, they may explain the increase in Cdk5 during DA‐depletion. In addition to this finding, notice that parkinsonian tissue courses with a hypercholinergic state due to an increase in the activity of striatal cholinergic interneurons (Galarraga et al., 1999; Padilla‐Orozco et al., 2022). Together, these conditions may enhance M 4 R‐Cdk5 signaling.…”

“…Indeed, M 2 Rs and M 4 Rs are main auto receptors of striatal cholinergic interneurons (Bernard et al., 1998; Ding et al., 2006) and are inhibitory heteroceptors in somatostatin expressing interneurons (Melendez‐Zaidi et al., 2019). However, it can be argued that in a hypercholinergic state (Galarraga et al., 1999; Padilla‐Orozco et al., 2022) a down regulation of M 4 Rs would take place in these neurons, not an increase in their expression. This is not the case of dSPNs in which M 4 Rs actions are facilitatory in control conditions (Hernández‐Flores et al., 2015).…”

“…For this study, 85 D 1 Cre or BACD 1 mice were intraperitoneal administrated using a mixture of ketamine–xylazine (85–15 mg/kg) to anesthetized and prepared for stereotaxic surgery, in which .6 μL of 6 hydroxydopamine (6‐OHDA) were injected at a rate of .2 μL/min. The coordinates used were −2.6 mm AP, −1.2 mm LM, and −4.5 mm DV from Bregma, with the SNpc as the target, as previously reported (Lara‐González et al., 2019; Padilla‐Orozco et al., 2022). A total of 25 animals of the same breed were injected with saline in the same place (sham controls).…”

Rethinking the network determinants of motor disability in Parkinson’s disease

“…It is also possible that the iSPN synaptic pruning is driven by aberrant plasticity mechanisms and is not homeostatic. In most models, with the loss of DA signaling, ChIs become more responsive to thalamic glutamatergic input and ACh release is disinhibited ( MacKenzie et al, 1989 ; DeBoer et al, 1996 ; Ding et al, 2006 ; Sanchez et al, 2011 ; Chuhma et al, 2014 ; Straub et al, 2014 ; Tanimura et al, 2019 ; Padilla-Orozco et al, 2022 ; c.f., McKinley et al, 2019 ; Choi et al, 2020 ). These adaptations are consistent with a disruptive, set-shifting role for ChIs as striatal DA levels fall (described above).…”