Regional and genotypic differences in intrinsic electrophysiological properties of cerebellar Purkinje neurons from wild-type and dystrophin-deficient mdx mice

Increased “persistent” current, caused by delayed inactivation, through voltage-gated Na+ (NaV) channels leads to cardiac arrhythmias or epilepsy. The underlying molecular contributors to these inactivation defects are poorly understood. Here, we show that calmodulin (CaM) binding to multiple sites within NaV channel intracellular C-terminal domains (CTDs) limits persistent Na+ current and accelerates inactivation across the NaV family. Arrhythmia or epilepsy mutations located in NaV1.5 or NaV1.2 channel CTDs, respectively, reduce CaM binding either directly or by interfering with CTD–CTD interchannel interactions. Boosting the availability of CaM, thus shifting its binding equilibrium, restores wild-type (WT)–like inactivation in mutant NaV1.5 and NaV1.2 channels and likewise diminishes the comparatively large persistent Na+ current through WT NaV1.6, whose CTD displays relatively low CaM affinity. In cerebellar Purkinje neurons, in which NaV1.6 promotes a large physiological persistent Na+ current, increased CaM diminishes the persistent Na+ current, suggesting that the endogenous, comparatively weak affinity of NaV1.6 for apoCaM is important for physiological persistent current.

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Gjd2b-mediated gap junctions promote glutamatergic synapse formation and dendritic elaboration in Purkinje neurons

10.1101/2020.01.31.928242 ◽

2020 ◽

Author(s):

Sahana Sitaraman ◽

Gnaneshwar Yadav ◽

Shaista Jabeen ◽

Vandana Agarwal ◽

Vatsala Thirumalai

Keyword(s):

Gap Junctions ◽

Dendritic Growth ◽

Synapse Formation ◽

Purkinje Neurons ◽

Dendritic Arbor ◽

Glutamatergic Synapse ◽

Wild Type ◽

Synapse Density ◽

Chemical Synapses ◽

Cerebellar Purkinje Neurons

AbstractGap junctions between neurons serve as electrical synapses, in addition to conducting metabolites and signaling molecules. These functions of gap junctions have led to the idea that during development, gap junctions could prefigure chemical synapses. We present evidence for this idea at a central, glutamatergic synapse and provide some mechanistic insights. Here, we show that reduction or loss of Gjd2b-containing gap junctions led to a decrease in glutamatergic synapse density in cerebellar Purkinje neurons (PNs) in larval zebrafish. Gjd2b-/- larvae exhibited faster mEPSCs and a consistent decrease in dendritic arbor size. These PNs also showed decreased branch elongations but normal rate of branch retractions. Further, the dendritic growth deficits in gjd2b-/- mutants were rescued by expressing full length Gjd2b in single PNs. This suggests that Gjd2b may form heterotypic channels with other connexins in gjd2b-/- larvae, though it is not clear if PNs in wild type animals make homotypic or heterotypic gap junction channels. Dendritic growth deficits were not rescued by expressing a deletion mutant of Gjd2b unable to form functional channels. Finally, the expression levels of five isoforms of camkii were increased in gjd2b-/- larvae and inhibition of CaMKII restored dendritic arbor lengths of mutant larvae to wild type levels. These results suggest a link between signaling via Gjd2b-containing gap junctions, CaMKII function and dendritic growth. In sum, our results demonstrate that Gjd2b-mediated gap junctions are key regulators of glutamatergic synapse formation and dendritic elaboration in PNs.

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Maternal exposure to the CB1 cannabinoid agonist WIN 55212–2 produces robust changes in motor function and intrinsic electrophysiological properties of cerebellar Purkinje neurons in rat offspring

Neuroscience ◽

10.1016/j.neuroscience.2010.10.031 ◽

2011 ◽

Vol 172 ◽

pp. 139-152 ◽

Cited By ~ 27

Author(s):

M. Shabani ◽

N. Hosseinmardi ◽

M. Haghani ◽

V. Shaibani ◽

M. Janahmadi

Keyword(s):

Motor Function ◽

Maternal Exposure ◽

Purkinje Neurons ◽

Electrophysiological Properties ◽

Rat Offspring ◽

Cerebellar Purkinje Neurons ◽

Cannabinoid Agonist

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Chronic Interleukin-6 Exposure Alters Electrophysiological Properties and Calcium Signaling in Developing Cerebellar Purkinje Neurons in Culture

Journal of Neurophysiology ◽

10.1152/jn.2002.88.1.475 ◽

2002 ◽

Vol 88 (1) ◽

pp. 475-486 ◽

Cited By ~ 36

Author(s):

Thomas E. Nelson ◽

Christina L. Ur ◽

Donna L. Gruol

Keyword(s):

Intracellular Calcium ◽

Interleukin 6 ◽

Intracellular Signaling ◽

Neurological Diseases ◽

Electrical Response ◽

Purkinje Neurons ◽

Calcium Signal ◽

Electrophysiological Properties ◽

Physiological Properties ◽

Cerebellar Purkinje Neurons

The cytokine interleukin-6 (IL-6) is chronically expressed at elevated levels within the CNS in many neurological disorders and may contribute to the histopathological, pathophysiological, and cognitive deficits associated with such disorders. However, the effects of chronic IL-6 exposure on neuronal function in the CNS are largely unknown. Therefore using intracellular recording and calcium imaging techniques, we investigated the effects of chronic IL-6 exposure on the physiological properties of cerebellar Purkinje neurons in primary culture. Two weeks of exposure to 1,000 units/ml (U/ml) IL-6 resulted in altered electrophysiological properties of Purkinje neurons, including a significant reduction in action potential generation, an increase in input resistance, and an enhanced electrical response to the ionotropic glutamate receptor agonist, α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) compared with untreated neurons. Lower concentrations of IL-6 (100 and 500 U/ml) had no effects on these electrophysiological parameters. However, neurons exposed to 500 U/ml chronic IL-6 resulted in significantly elevated resting levels of intracellular calcium as well as an increase in the intracellular calcium signal of Purkinje neurons in response to AMPA, effects not observed in neurons exposed to 1,000 U/ml chronic IL-6. Morphometric analysis revealed a lack of gross structural changes following chronic IL-6 treatment, such as in the number, size, and extent of dendritic arborization of Purkinje neurons in culture. Using immunohistochemistry, we found that cultured Purkinje neurons express both the IL-6 receptor and its intracellular signaling subunit, gp130, indicating that IL-6 may act directly on Purkinje neurons to alter their physiological properties. The present data show that chronic exposure to elevated levels of IL-6, such as occurs in various neurological diseases, produces alterations in several important physiological properties of Purkinje neurons and that these changes occur in the absence of neuronal toxicity, damage, or death. The results support the hypothesis that chronic IL-6 exposure can disrupt normal CNS function and thereby contribute to the pathophysiology associated with many neurological diseases.

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Twenty-one days of low-intensity eccentric training improve morphological characteristics and function of soleus muscles of mdx mice

Scientific Reports ◽

10.1038/s41598-020-79168-3 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Paulo S. Pedrazzani ◽

Tatiana O. P. Araújo ◽

Emilly Sigoli ◽

Isabella R. da Silva ◽

Daiane Leite da Roza ◽

...

Keyword(s):

Soleus Muscle ◽

Morphological Characteristics ◽

Training Group ◽

Mdx Mice ◽

Eccentric Training ◽

Active Force ◽

Wild Type ◽

Low Intensity ◽

Sedentary Group ◽

Group 3

AbstractDuchene muscular dystrophy (DMD) is caused by the absence of the protein dystrophin, which leads to muscle weakness, progressive degeneration, and eventually death due to respiratory failure. Low-intensity eccentric training (LIET) has been used as a rehabilitation method in skeletal muscles after disuse. Recently, LIET has also been used for rehabilitating dystrophic muscles, but its effects are still unclear. The purpose of this study was to investigate the effects of 21 days of LIET in dystrophic soleus muscle. Thirty-six male mdx mice were randomized into six groups (n = 6/each): mdx sedentary group; mdx training group-3 days; mdx training group-21 days; wild-type sedentary group; wild-type training group-3 days and wild-type training group-21 days. After the training sessions, animals were euthanized, and fragments of soleus muscles were removed for immunofluorescence and histological analyses, and measurements of active force and Ca2+ sensitivity of the contractile apparatus. Muscles of the mdx training group-21 days showed an improvement in morphological characteristics and an increase of active force when compared to the sedentary mdx group. The results show that LIET can improve the functionality of dystrophic soleus muscle in mice.

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