The potassium channel auxiliary subunit Kvβ2 (<i>Kcnab2</i>) regulates Kv1 channels and dopamine neuron firing

Yee, Joshua X.; Rastani, Ariana; Soden, Marta E.

doi:10.1152/jn.00194.2022

Cited by 14 publications

(9 citation statements)

References 43 publications

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“…At baseline firing rates, Kv4 inactivation may be the major slow variable that can respond to V m perturbations. In addition, Kv1 channels can also affect pacemaking in DA neurons in SNc ( Guzman et al, 2009 ) and the VTA ( Yee et al, 2022 ). But how can brief perturbations alter Kv channel inactivation to change the phase of a neuron?…”

Section: Discussionmentioning

confidence: 99%

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SK and Kv4 Channels Limit Spike Timing Perturbations in Pacemaking Dopamine Neurons

Higgs

Jones²,

Wilson³

et al. 2023

eNeuro

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Midbrain dopamine (DA) neurons are among the best characterized pacemaker neurons, having intrinsic, rhythmic firing activity even in the absence of synaptic input. However, the mechanisms of DA neuron pacemaking have not been systematically related to how these cells respond to synaptic input. The input-output properties of pacemaking neurons can be characterized by the phase resetting curve (PRC), which describes the sensitivity of inter-spike interval (ISI) length to inputs arriving at different phases of the firing cycle. Here we determined PRCs of putative DA neurons in the substantia nigra pars compacta (SNc) in brain slices from male and female mice using gramicidin-perforated current-clamp recordings with electrical noise stimuli applied through the patch pipette. On average, and compared to nearby putative GABA neurons, DA neurons showed a low, nearly constant level of sensitivity across most of the ISI, but individual cells had PRCs showing relatively greater sensitivity at early or late phases. Pharmacological experiments showed that DA neuron PRCs are shaped by small-conductance calcium-activated potassium (SK) and Kv4 channels, which limit input-sensitivity across early and late phases of the ISI. Our results establish the PRC as a tractable experimental measurement of individual DA neuron input-output relationships and identify two of the major ionic conductances that limit perturbations to rhythmic firing. These findings have applications in modeling and for identifying biophysical changes in response to disease or environmental manipulations.SIGNIFICANCE STATEMENTIn substantia nigra pars compacta dopamine neurons, pacemaking mechanisms determine the response to an instantaneous synaptic input according to the phase resetting curve (PRC). Here we measured PRCs of dopamine neurons and determined how they are shaped by small-conductance calcium-activated potassium (SK) and Kv4 channels, which regulate pacemaking rate and regularity. We found that both types of channel limit sensitivity to perturbations in firing. Thus, the currents responsible for slow pacemaking also control spike time responses to synaptic input.

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Section: Discussionmentioning

confidence: 99%

“…This mechanism could potentially explain why some DA neurons have left-weighted PRCs. In contrast, Kv1 channels in DA neurons appear to have somewhat higher inactivation voltages ( Yee et al, 2022 ), so their inactivation may be perturbed more effectively at later phases.…”

Section: Discussionmentioning

confidence: 99%

SK and Kv4 Channels Limit Spike Timing Perturbations in Pacemaking Dopamine Neurons

Higgs

Jones²,

Wilson³

et al. 2023

eNeuro

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“…In conclusion, prolonged α-syn burden impairs different K + channel subtypes (BK and A-type K v ) that shape repolarization/afterhyperpolarization phases of action potentials, thus controlling spontaneous firing activity and excitability of nigral DA neurons. 31,35,[38][39][40]…”

Section: α-Syn Overexpression Affects Intrinsic Conductance Of Snpc D...mentioning

confidence: 99%

Morpho‐Functional Changes of Nigral Dopamine Neurons in an α‐Synuclein Model of Parkinson's Disease

et al. 2022

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Background: The accumulation of α-synuclein (α-syn) fibrils in intraneuronal inclusions called Lewy bodies and Lewy neurites is a pathological signature of Parkinson's disease (PD). Although several aspects linked to α-syn-dependent pathology (concerning its spreading, aggregation, and activation of inflammatory and neurodegenerative processes) have been under intense investigation, less attention has been devoted to the real impact of α-syn overexpression on structural and functional properties of substantia nigra pars compacta (SNpc) dopamine (DA) neurons, particularly at tardive stages of α-syn buildup, despite this has obvious relevance to comprehending mechanisms beyond PD progression. Objectives: We aimed to determine the consequences of a prolonged α-syn overexpression on somatodendritic morphology and functions of SNpc DA neurons. Methods: We performed immunohistochemistry, stereological DA cell counts, analyses of dendritic arborization, ex vivo patch-clamp recordings, and in vivo DA microdialysis measurements in a 12-to 13-month-old transgenic rat model overexpressing the full-length human α-syn (Snca +/+ ) and age-matched wild-type rats.Results: Aged Snca +/+ rats have mild loss of SNpc DA neurons and decreased basal DA levels in the SN. Residual nigral DA neurons display smaller soma and compromised dendritic arborization and, in parallel, increased firing activity, switch in firing mode, and hyperexcitability associated with hypofunction of fast activating/ inactivating voltage-gated K + channels and Ca 2+ -and voltage-activated large conductance K + channels. These intrinsic currents underlie the repolarization/ afterhyperpolarization phase of action potentials, thus affecting neuronal excitability. Conclusions: Besides clarifying α-syn-induced pathological landmarks, such evidence reveals compensatory functional mechanisms that nigral DA neurons could adopt during PD progression to counteract neurodegeneration.

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“…One possible explanation for the increased rheobase is an adapted function and/ or expression of factors supporting intrinsic excitability. DA cell firing properties and responsivity have been shown to rely on several ion channel functions and other postsynaptic mechanisms sensitive to drugs, including opioids [90][91][92][93][94][95] . Potassium current alterations may be the most parsimonious candidate, being an opioid-sensitive direct modulator of intrinsic excitability 96 .…”

Section: Discussionmentioning

confidence: 99%

Protracted morphine withdrawal corresponds with sex-specific alterations to motivated behavior and mesoaccumbal subcircuit dopamine cell plasticity

Gomez¹,

Kahl²,

Brettingen³

et al. 2023

Preprint

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Background: Opioid use disorder is associated with enduring psychological withdrawal symptoms believed to contribute to drug abuse. Amongst these are shifts in motivational states, wherein pursuit of drug consumption exceeds that of non-drug rewards, reinforcing escalated opioid use and relapse vulnerability. A critical regulator of behavioral reinforcement, the mesoaccumbal dopamine (DA) system is thought to be both necessary and sufficient for opioid motivation. However, previous research into its involvement in opioid withdrawal has been limited to acute vs protracted timepoints, global neuroadaptations vs those in subcircuits, and overwhelmingly focused on males vs females. Methods: Evaluations of effort-based motivated behavior for both sucrose and morphine reward were combined with patch clamp electrophysiological assessments of synaptic plasticity within lateral vs medial DA neurons projecting to the lateral vs medial nucleus accumbens shell during protracted morphine withdrawal in male and female mice. Further effects of mesoaccumbal subcircuit inhibition on motivated behavior for sucrose were also measured. Results: Protracted morphine withdrawal was found to be associated with elevations in morphine seeking, intake, and motivation compared to saline controls in both sexes. Escalation of intake was paralleled by a male-exclusive reduction in motivation for the non-drug reward, sucrose. Male-exclusive neuroadaptations during protracted withdrawal were also found, with reductions in neuronal excitability and increased inhibitory (GABAAR-dependent) synaptic transmission found in lateral ventral tegmental area (VTA) DA neurons projecting to the lateral nucleus accumbens shell, though not in medial DA projections to the medial shell. Finally, chemogenetic inhibition of the lateral but not medial subcircuit was found to significantly reduce motivated responding for sucrose in male morphine-naive mice. Conclusions: These data suggest that protracted opioid withdrawal is associated with a sex-independent increase in opioid consumption and motivation. They also suggest that male-specific reductions in motivation for non-drug reward during protracted withdrawal may be driven by a hypoactive state in a lateral mesoaccumbal DA subcircuit driven in part by increased inhibition of DA cells. These insights may be useful in development of therapies that temper withdrawal-associated psychological states predisposed towards prolonged and escalated opioid intake, a major treatment goal for OUD patients.

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The potassium channel auxiliary subunit Kvβ2 (Kcnab2) regulates Kv1 channels and dopamine neuron firing

Cited by 14 publications

References 43 publications

SK and Kv4 Channels Limit Spike Timing Perturbations in Pacemaking Dopamine Neurons

SK and Kv4 Channels Limit Spike Timing Perturbations in Pacemaking Dopamine Neurons

Morpho‐Functional Changes of Nigral Dopamine Neurons in an α‐Synuclein Model of Parkinson's Disease

Protracted morphine withdrawal corresponds with sex-specific alterations to motivated behavior and mesoaccumbal subcircuit dopamine cell plasticity

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