Targeting parvalbumin-expressing neurons in the substantia nigra pars reticulata restores motor function in parkinsonian mice

Cell Reports, Journal Year: 2023, Volume and Issue: 42(10), P. 113287 - 113287

Published: Oct. 1, 2023

The activity of substantia nigra pars reticulata (SNr) neurons, the main output structure basal ganglia, is altered in Parkinson's disease (PD). However, neither underlying mechanisms nor type neurons responsible for PD-related motor dysfunctions have been elucidated yet. Here, we show that parvalbumin-expressing SNr (SNr-PV+) occupy dorsolateral parts and possess specific electrophysiological properties compared with other cells. We also report only SNr-PV+ neurons' intrinsic excitability reduced by downregulation sodium leak channels a PD mouse model. Interestingly, anesthetized parkinsonian mice vivo, display bursty pattern dependent on glutamatergic tone. Finally, demonstrate chemogenetic inhibition sufficient to alleviate impairments mice. Overall, our findings establish cell-type-specific dysfunction experimental parkinsonism provide potential cellular therapeutic target symptoms PD.

Language: Английский

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TRPC3 and NALCN channels drive pacemaking in substantia nigra dopaminergic neurons

eLife, Journal Year: 2021, Volume and Issue: 10

Published: Aug. 19, 2021

Midbrain dopamine (DA) neurons are slow pacemakers that maintain extracellular DA levels. During the interspike intervals, subthreshold depolarization underlies autonomous pacemaking and determines its rate. However, ion channels determine unknown. Here we show TRPC3 NALCN together form sustained inward currents responsible for of nigral neurons. Specific channel blockade completely blocked neuron pacemaking, but activity in knock-out (KO) mice was perfectly normal, suggesting presence compensating channels. Blocking abolished both KO wild-type mice. The current mRNA protein expression increased mice, indicating compensates currents. In normal conditions, contribute equally to depolarization. Therefore, conclude two major leak drive robust

Language: Английский

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Structural architecture of the human NALCN channelosome

Nature, Journal Year: 2021, Volume and Issue: 603(7899), P. 180 - 186

Published: Dec. 20, 2021

Language: Английский

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Circadian regulation of dentate gyrus excitability mediated by G-protein signaling

Cell Reports, Journal Year: 2023, Volume and Issue: 42(2), P. 112039 - 112039

Published: Feb. 1, 2023

The central circadian regulator within the suprachiasmatic nucleus transmits time of day information by a diurnal spiking rhythm driven molecular clock genes controlling membrane excitability. Most brain regions, including hippocampus, harbor similar intrinsic transcriptional machinery, but whether these programs generate oscillations properties is unclear. Here, we show that excitability mouse dentate granule neurons exhibits 24-h oscillation controls probability. Diurnal changes in are mediated antiphase G-protein regulation potassium and sodium currents reduce during Light phase. Disruption machinery conditional deletion Bmal1 enhances selectively phase removing regulation. These results reveal regulates coordinated ion channels signaling, highlighting potential novel mechanism cell-autonomous oscillations.

Language: Английский

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RGS6 negatively regulates inhibitory G protein signaling in dopamine neurons and positively regulates binge‐like alcohol consumption in mice

British Journal of Pharmacology, Journal Year: 2023, Volume and Issue: 180(16), P. 2140 - 2155

Published: March 17, 2023

Drugs of abuse, including alcohol, increase dopamine in the mesocorticolimbic system via actions on neurons ventral tegmental area (VTA). Increased transmission can activate inhibitory G protein signalling pathways VTA neurons, those controlled by GABA

Language: Английский

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The sodium leak channel NALCN is regulated by neuronal SNARE complex proteins

Science Advances, Journal Year: 2025, Volume and Issue: 11(11)

Published: March 14, 2025

NALCN (sodium leak channel, nonselective) is vital for regulating electrical activity in neurons and other excitable cells, mutations the channel or its auxiliary proteins lead to severe neurodevelopmental disorders. Here, we show that neuronal SNARE (soluble N -ethylmaleimide–sensitive factor attachment protein receptors) complex syntaxin SNAP25 (synaptosome-associated 25), which enable synaptic transmission nervous system, inhibit of both heterologous systems primary neurons. The existence this interaction suggests neurotransmitter release machinery can regulate signaling directly therefore modulate threshold own activity. We further find reduction currents sufficient promote cell survival syntaxin-depleted cells. This disinhibited may cause puzzling phenomenon rapid death absence syntaxin. could offer opportunities future drug development against genetic diseases linked NALCN- protein–containing complexes.

Language: Английский

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Functional expression of CLIFAHDD and IHPRF pathogenic variants of the NALCN channel in neuronal cells reveals both gain- and loss-of-function properties

Scientific Reports, Journal Year: 2019, Volume and Issue: 9(1)

Published: Aug. 13, 2019

Abstract The excitability of neurons is tightly dependent on their ion channel repertoire. Among these channels, the leak sodium NALCN plays a crucial role in maintenance resting membrane potential. Importantly, mutations lead to complex neurodevelopmental syndromes, including infantile hypotonia with psychomotor retardation and characteristic facies (IHPRF) congenital contractures limbs face, developmental delay (CLIFAHDD), which are recessively dominantly inherited, respectively. Unfortunately, biophysical properties still largely unknown date, as well functional consequences both IHPRF CLIFAHDD current. Here we have set-up heterologous expression neuronal cell line NG108-15 investigate electrophysiological carrying representative mutations. Several original wild-type (wt) current were retrieved: mainly carried by external Na + , blocked Gd 3+ insensitive TTX potentiated low Ca 2+ concentration. However, found that this displays time-dependent inactivation −80/−40 mV range potential, non linear current-voltage relationship indicative voltage sensitivity. no detectable was recorded missense mutation p.Trp1287Leu (W1287L), while mutants, p.Leu509Ser (L509S) p.Tyr578Ser (Y578S), showed higher densities slower inactivation, compared wt This study reveals can be achieved mutants. From our results, conclude loss- gain-of-function variants,

Language: Английский

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Congenital Ataxia with Progressive Cerebellar Atrophy, Camptodactyly, and Hypertrichosis: A Novel Recognizable Phenotype for NALCN Heterozygous Variants

Neuropediatrics, Journal Year: 2025, Volume and Issue: unknown

Published: Feb. 6, 2025

Abstract Background Non-selective sodium leak channel (NALCN) protein encoded by the NALCN gene is of key importance for neuronal cell excitability. Previous reports showed that biallelic pathogenic variants cause infantile hypotonia with psychomotor retardation and characteristic facies 1 (IHPRF1) while monoallelic lead to congenital contractures limbs face, hypotonia, developmental delay (CLIFAHDD). In our work, we aimed expand heterozygous NALCN-related clinical spectrum, presenting two affected individuals a literature review. Methods We describe new unrelated subjects harboring identified through exome sequencing review current other patients. Results The c.3542G > A (p.Arg1181Gln) novel c.3423C (p.Phe1141Leu) missense were disclosed in manifesting similar phenotype characterized ataxia progressive cerebellar atrophy, camptodactyly, hypertrichosis arms (CAPCACH). Other overlapping features have already been reported. combination these neuroimaging findings suggests definition CAPCACH phenotype. Conclusion spectrum from more severe CLIFFAHDD milder These conditions should be considered differential diagnosis syndromic ataxias, presence camptodactyly and/or may represent peculiar diagnostic clues.

Language: Английский

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Enhanced excitability of cortical neurons in low-divalent solutions is primarily mediated by altered voltage-dependence of voltage-gated sodium channels

eLife, Journal Year: 2021, Volume and Issue: 10

Published: May 11, 2021

Increasing extracellular [Ca2+] ([Ca2+]o) strongly decreases intrinsic excitability in neurons but the mechanism is unclear. By one hypothesis, [Ca2+]o screens surface charge, reducing voltage-gated sodium channel (VGSC) activation and by another activates Calcium-sensing receptor (CaSR) closing sodium-leak (NALCN). Here we report that neocortical from CaSR-deficient (Casr-/-) mice had more negative resting potentials did not fire spontaneously reduced divalent-containing solution (T0.2) contrast with wild-type (WT). However, after setting membrane potential to -70 mV, T0.2 application similarly depolarized increased action firing Casr-/- WT neurons. Enhanced of VGSCs was dominant contributor depolarization increase occurred due hyperpolarizing shifts VGSC window currents. CaSR deletion currents affect NALCN activation. Regulation gating external divalents key mediating divalent-dependent changes neuron excitability.

Language: Английский

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Contributions of the Sodium Leak Channel NALCN to Pacemaking of Medial Ventral Tegmental Area and Substantia Nigra Dopaminergic Neurons

Journal of Neuroscience, Journal Year: 2023, Volume and Issue: 43(41), P. 6841 - 6853

Published: Aug. 28, 2023

We tested the role of sodium leak channel, NALCN, in pacemaking dopaminergic neuron (DAN) subpopulations from adult male and female mice. In situ hybridization revealed NALCN RNA all DANs, with lower abundance medial ventral tegmental area (VTA) relative to substantia nigra pars compacta (SNc). Despite we found that acute pharmacological blockade VTA DANs slowed by 49.08%. also examined electrophysiological properties projection-defined DAN identified retrograde labeling. Inhibition reduced projecting nucleus accumbens (NAc) others lateral NAc 70.74% 31.98%, respectively, suggesting is a primary driver DANs. SNc potentiating lowering extracellular calcium concentration speeded wildtype but not conditional knockout mice, demonstrating functional presence NALCN. contrast however, was unaffected inhibition Instead, increased gain frequency-current plots at firing frequencies slower than spontaneous firing. Similarly, hyperpolarization-activated cyclic nucleotide-gated (HCN) conductance had little effect on pacemaking. Interestingly, simultaneous HCN resulted significant reduction pacemaker rate. Thus, makes substantial contributions driving subpopulations. critical for cells more sensitive hyperpolarizing stimuli.SIGNIFICANCE STATEMENT Pacemaking midbrain neurons relies multiple subthreshold conductances, including leak. Whether contributes located has yet been determined. Using electrophysiology pharmacology, show plays prominent By contrast, does rely regulates excitability reducing neuron's response inhibitory stimuli. Together, these findings will inform future efforts obtain subpopulation-specific treatments use neuropsychiatric disorders.

Language: Английский

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