Neuronal mechanism of a BK channelopathy in absence epilepsy and dyskinesia

Dong, Ping; Zhang, Yang; Hunanyan, Arsen; Mikati, Mohamad A.; Cui, Jianmin; Yang, Huanghe

doi:10.1073/pnas.2200140119

Cited by 22 publications

(44 citation statements)

References 72 publications

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“…The Racine's scale evaluation was performed as described previously. 15 The parameters and corresponding scores are summarized in Table 1 . The highest score among the parameters for each rat was considered as the score of this rat.…”

Section: Methodsmentioning

confidence: 99%

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A neuron‐specific Isca1 knockout rat developments multiple mitochondrial dysfunction syndromes

Sheng

et al. 2023

Anim Models and Exp Med

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Background Multiple mitochondrial dysfunction syndromes (MMDS) are rare mitochondrial diseases caused by mutation of mitochondrial iron–sulfur cluster synthesis proteins. This study established a rat model simulating MMDS5 disease in the nervous system to investigate its pathological features and neuronal death. Methods We generated neuron‐specific Isca1 knockout rat (Isca1flox/flox ‐NeuN‐Cre) using CRISPR‐Cas9 technology. The brain structure changes of CKO rats were studied with MRI, and the behavior abnormalities were analyzed through gait analysis and open field tests, Y maze tests and food maze tests. The pathological changes of neurons were analyzed through H&E staining, Nissl staining, and Golgi staining. Mitochondrial damage was assessed by TEM, western blot and ATP assay, and the morphology of neurons was assessed by WGA immunofluorescence to detect the death of neurons. Results This study established the disease model of MMDS5 in the nervous system for the first time, and found that after Isca1 loss, the rats suffered from developmental retardation, epilepsy, memory impairment, massive neuronal death, reduced number of Nissl bodies and dendritic spines, mitochondrial fragmentation, cristae fracture, reduced content of respiratory chain complex protein, and reduced production of ATP. Isca1 knockout caused neuronal oncosis. Conclusions This rat model can be used to study the pathogenesis of MMDS. In addition, compared with human MMDS5, the rat model can survive up to 8 weeks of age, effectively extending the window of clinical treatment research, and can be used for the treatment of neurological symptoms in other mitochondrial diseases.

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Section: Methodsmentioning

confidence: 99%

“…The Racine's scale evaluation was performed as described previously 15 . The parameters and corresponding scores are summarized in Table 1.…”

Section: Methodsmentioning

confidence: 99%

A neuron‐specific Isca1 knockout rat developments multiple mitochondrial dysfunction syndromes

Sheng

et al. 2023

Anim Models and Exp Med

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“…In a GOF knock-in murine model carrying a human BK-D434G mutation, mice showed increased susceptibility to generalized seizures and motor deficits related to hyperexcitability in cortical pyramidal and cerebellar Purkinje neurons. Importantly, blocking BK channels with paxilline suppressed seizures, motor disturbances, and neuronal hyperexcitability [ 155 ]. Similarly, a D434G mutation that produces an increase in Ca 2+ sensitivity that potentiates BK channel activity [ 231 ] was described in individuals affected by epileptic seizures and/or PNKD [ 232 ].…”

Section: Bk Channel Dysfunction In Neurological Disordersmentioning

confidence: 99%

Ca2+- and Voltage-Activated K+ (BK) Channels in the Nervous System: One Gene, a Myriad of Physiological Functions

Ancatén-González

Segura

Alvarado-Sánchez

et al. 2023

IJMS

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BK channels are large conductance potassium channels characterized by four pore-forming α subunits, often co-assembled with auxiliary β and γ subunits to regulate Ca2+ sensitivity, voltage dependence and gating properties. BK channels are abundantly expressed throughout the brain and in different compartments within a single neuron, including axons, synaptic terminals, dendritic arbors, and spines. Their activation produces a massive efflux of K+ ions that hyperpolarizes the cellular membrane. Together with their ability to detect changes in intracellular Ca2+ concentration, BK channels control neuronal excitability and synaptic communication through diverse mechanisms. Moreover, increasing evidence indicates that dysfunction of BK channel-mediated effects on neuronal excitability and synaptic function has been implicated in several neurological disorders, including epilepsy, fragile X syndrome, mental retardation, and autism, as well as in motor and cognitive behavior. Here, we discuss current evidence highlighting the physiological importance of this ubiquitous channel in regulating brain function and its role in the pathophysiology of different neurological disorders.

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“…Interestingly, a comprehensive study by Dong et al, recently identified locomotor defects and dyskinesia-like movements in knock-in mice carrying the equivalent KCNMA1 D434G allele 19 . Notably, locomotor defects in KCNMA1 D434G mice were partially rescued by intraperitoneal injection of Paxilline, a BK channel blocker.…”

Section: Bk Channels and Neurodevelopmentmentioning

confidence: 99%

“…D434G enhances BK channel activity by increasing the Ca 2+ sensitivity of the channel [17, 18], and heterozygosity for D434G in humans results in a complex syndrome characterised by bouts of dystonic and dyskinetic movements in the limbs, mouth, and tongue [12]. Recent work in corresponding mouse models has also shown that D434G heterozygosity enhances the firing rate of murine cerebellar Purkinje neurons and dentate granule cells by accelerating the kinetics of the fAHP [19, 20].…”

Section: Introductionmentioning

confidence: 99%

BK channel gain-of-function disrupts limb control by suppressing neurotransmission during a critical developmental window

Lowe,

Wilson,

Aughey

et al. 2023

Preprint

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Gain-of-function mutations in BK potassium channels (BK GOF) cause debilitating involuntary limb movements. BK channels modulate action potential shape and neurotransmitter release in mature neurons, yet BK GOF mutations are also associated with neurodevelopmental phenotypes. Thus, whether BK GOF impairs limb control via acute changes in neuronal excitation/inhibition or by disrupting neurodevelopmental processes is unclear. We address this issue by developing a genetic method enabling spatiotemporal control of GOF BK channel expression in neurons of the fruit fly, Drosophila. Using high-resolution measurements of limb kinematics, we demonstrate that GOF BK channels act during a narrow neurodevelopmental window to perturb adult limb control. During this period, BK GOF alters synaptic localisation of the active zone protein Bruchpilot and suppresses excitatory neurotransmitter release, while enhancing neuronal excitability during development rescues motor defects in BK GOF flies. Collectively, our results suggest that BK GOF perturbs limb control largely by disrupting activity-dependent aspects of neuronal development.

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Neuronal mechanism of a BK channelopathy in absence epilepsy and dyskinesia

Cited by 22 publications

References 72 publications

A neuron‐specific Isca1 knockout rat developments multiple mitochondrial dysfunction syndromes

A neuron‐specific Isca1 knockout rat developments multiple mitochondrial dysfunction syndromes

Ca2+- and Voltage-Activated K+ (BK) Channels in the Nervous System: One Gene, a Myriad of Physiological Functions

BK channel gain-of-function disrupts limb control by suppressing neurotransmission during a critical developmental window

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