Nicotinic Acetylcholine Receptors Expressed by Striatal Interneurons Inhibit Striatal Activity and Control Striatal-Dependent Behaviors

Bas, Irina Ribeiro; Modrák, Martin; Čapek, Martin; Minich, Jessica; Tyshkevich, Alexandra; Naser, Shahed; Rangotis, Revan; Houdek, Pia; Sumová, Alena; Dumas, Sylvie; Bernard, Véronique; Janickova, Helena

doi:10.1523/jneurosci.1627-21.2022

Cited by 11 publications

(7 citation statements)

References 71 publications

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“…Nonetheless, other mechanisms may also play a role. The nAChRs are expressed by CINs themselves ( Azam et al, 2003 ; Abbondanza et al, 2022 ), and given their absence in SPNs, a network of CINs recruited through nAChRs may bring strong support to the highly recurrent pathological state found during DA depletion ( Jáidar et al, 2010 ; Pérez-Ortega et al, 2016 ). This hypothetical CINs network also needs to be demonstrated.…”

Section: Discussionmentioning

confidence: 99%

“…Finally, striatal GABAergic interneurons also express nAChRs ( Koós and Tepper, 2002 ; Luo et al, 2013 ; Plata et al, 2013b ; Ibáñez-Sandoval et al, 2015 ; Faust et al, 2016 ; Assous, 2021 ; Abbondanza et al, 2022 ) and produce SPNs inhibition via CINs. Thus, inhibition of any known interneuron class may be responsible for Parkinsonian hyperactivity in the striatal circuitry.…”

Section: Discussionmentioning

confidence: 99%

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Synaptic determinants of cholinergic interneurons hyperactivity during parkinsonism

Padilla‐Orozco

Duhne

Fuentes-Serrano

et al. 2022

Front. Synaptic Neurosci.

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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.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Synaptic determinants of cholinergic interneurons hyperactivity during parkinsonism

Padilla‐Orozco

Duhne

Fuentes-Serrano

et al. 2022

Front. Synaptic Neurosci.

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“…Acetylcholinesterase, the enzyme that breaks down acetylcholine was also highly expressed (50% increase) in Chrna5+ neurons, which may benefit their nicotinic responses by protecting receptors from overactivation and desensitization. Of note, Chrnb2 expression does seem to be in fewer cells than expected (Fig 3E), which can be attributed to sparse detection of Chrnb2 levels by scRNAseq approaches 54,56 S3. Notably, the top three genes with highest fold change in Chrna5+ neurons were the GPI-anchored lynx prototoxins: Lynx2 encoded by Lypd1 (Fold change: 2.55), Ly6g6e (2.03), and Lypd6b (1.51).…”

Section: Single-cell Transcriptomics Identifies Chrna5+ Subplate Neur...mentioning

confidence: 62%

Chrna5 and lynx prototoxins identify acetylcholine super-responder subplate neurons

Venkatesan

Chen

Liu

et al. 2022

Preprint

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Attention depends on cholinergic excitation of prefrontal neurons. Knockout/knockdown studies indicate nicotinic alpha5 subunits encoded by Chrna5 are required for this response, but their native cellular roles and molecular interactions are unknown. Here, we probe endogenous cholinergic regulation of prefrontal Chrna5-expressing neurons (Chrna5+) using compound transgenic mice. Chrna5+ neurons show high sensitivity to acetylcholine, with a subpopulation clearly different from nearby, well-examined Syt6+ cells. Transcriptomic analysis reveals this distinct Chrna5+ population as subplate neurons, a diverse group of firstborn cells that have eluded previous transgenic characterization. Intriguingly, Chrna5+ subplate neurons express a distinct profile of GPI-anchored lynx prototoxins, suggesting specialized regulation of their cholinergic responses. In brain slices, endogenous nicotinic responses can be bidirectionally altered by perturbing GPI-anchored lynxes with phospholipase C activation or exogenous application of recombinant Ly6g6e prototoxin. Our work reveals cell-type specific Chrna5 and Lynx modulation leading to exquisite cholinergic sensitivity of prefrontal subplate neurons in adulthood.TeaserChrna5-expression identifies subplate neurons in the adult prefrontal cortex with enhanced cholinergic sensitivity.

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“…Because SPNs themselves do not express nAChRs, the action of mecamylamine must be indirect. Functional nAChR are expressed at multiple loci of the striatal circuit, including afferent axonal terminals and intrastriatal interneurons (Nelson, Hammack et al 2014, Faust, Assous et al 2016, Abudukeyoumu, Hernandez-Flores et al 2019, Assous 2021, Abbondanza, Ribeiro Bas et al 2022, Morgenstern, Isidro et al 2022). While the broad antagonistic actions of mecamylamine and DHβE should block nicotinic receptors at most of these loci, α7 nAChRs, which are predominantly expressed at corticostriatal axon terminals, may be spared (Solinas, Scherma et al 2007, Licheri, Lagström et al 2018, Assous 2021).…”

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

A tonic nicotinic brake controls spike timing in striatal spiny projection neurons

Matityahu

Malgady

Schirelman

et al. 2021

Preprint

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Striatal spiny projection neurons (SPNs) transform convergent excitatory corticostriatal inputs into an inhibitory signal that shapes basal ganglia output. This process is fine-tuned by striatal GABAergic interneurons (GINs), which receive overlapping cortical inputs and mediate rapid corticostriatal feedforward inhibition of SPNs. Adding another level of control, cholinergic interneurons (CINs), which are also vigorously activated by corticostriatal excitation, can 1) disynaptically inhibit SPNs by activating alpha4beta2 nicotinic acetylcholine receptors (nAChRs) on various GINs and 2) directly modulate corticostriatal synaptic strength via pre-synaptic alpha7 nAChR receptors. Measurements of the disynaptic inhibitory pathway, however, indicate that it is too slow to compete with direct GIN-mediated feed-forward inhibition. Moreover, functional nAChRs are also present on populations of GINs that do not respond to phasic activation of CINs, such as parvalbumin-positive fast-spiking interneurons (PV-FSIs), making the overall role of nAChRs in shaping striatal synaptic integration unclear. Using acute striatal slices we show that upon synchronous optogenetic activation of corticostriatal projections, blockade of alpha7 nAChRs delayed SPN spikes, whereas blockade of alpha4beta2 nAChRs advanced SPN spikes and increased postsynaptic depolarizations. The nAChR-dependent inhibition was mediated by downstream GABA release, and data suggest that the GABA source was not limited to GINs that respond to phasic CIN activation. In particular, the observed spike-advancement caused by nAChR blockade was associated with a diminished frequency of spontaneous inhibitory postsynaptic currents in SPNs, and a parallel hyperpolarization of PV-FSIs. Taken together, we describe opposing roles for tonic (as opposed to phasic) engagement of nAChRs in striatal function. We conclude that tonic activation of nAChRs by CINs both sharpens the temporal fidelity of corticostriatal signaling via pre-synaptic alpha7 nAChRs and maintains a GABAergic brake on cortically-driven striatal output, processes that may shape SPN spike timing, striatal processing and synaptic plasticity.

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Nicotinic Acetylcholine Receptors Expressed by Striatal Interneurons Inhibit Striatal Activity and Control Striatal-Dependent Behaviors

Cited by 11 publications

References 71 publications

Synaptic determinants of cholinergic interneurons hyperactivity during parkinsonism

Synaptic determinants of cholinergic interneurons hyperactivity during parkinsonism

Chrna5 and lynx prototoxins identify acetylcholine super-responder subplate neurons

A tonic nicotinic brake controls spike timing in striatal spiny projection neurons

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