scholarly journals SAT-454 A Novel Role of Thyroid Hormone Receptor in Synaptic Plasticity in Cerebellar Purkinje Cells

2020 ◽  
Vol 4 (Supplement_1) ◽  
Author(s):  
Ayane Ninomiya ◽  
Nobutake Hosoi ◽  
Michifumi Kokubo ◽  
Izuki Amano ◽  
Asahi Haijima ◽  
...  
Keyword(s):  
Synaptic Plasticity ◽  
Thyroid Hormone ◽  
Intracellular Calcium ◽  
Target Genes ◽  
Motor Coordination ◽  
Motor Deficits ◽  
Calcium Dynamics ◽  
Intracellular Calcium Dynamics

Abstract Thyroid hormone (TH) is essential for the development and the maintenance of the brain function. TH action is mediated by TH receptor (TR). TR binds to a specific DNA sequence on TH-target genes and thus functions as a ligand-dependent transcription factor. In thyroid diseases such as congenital hypothyroidism or resistance to TH (RTH), TH-TR binding is dominantly disrupted, leading to the various symptoms such as motor deficits. However, in such cases, all the cells that express TR get affected by the disrupted TR signaling; thus, the specific mechanism has not been cleared. It has been well known that proper motor coordination is deeply related to long term depression (LTD) of synaptic transmission from parallel fiber (PF) to Purkinje cell (PC) in the cerebellum (Ito, 1989). Therefore, we examined the involvement of TR in synaptic plasticity at PF-PC synapses by using transgenic mice (Mf-1 mice) which express dominant-negative TR specifically in PCs. Since Mf-1 display the impairment of motor coordination and motor learning, a decrease in TR signaling in PCs may alter synaptic plasticity and contribute to motor incoordination. A whole-cell patch clamp recording of Mf-1 PCs revealed the inhibition of LTD but instead the induction of long term potentiation (LTP) of the synaptic transmission at PF-PC synapses. This indicates that the intracellular calcium dynamics may be disrupted in Mf-1 PCs since LTD requires a higher elevation of the intracellular calcium concentration in PCs than LTP does. Indeed, single-PC qPCR showed that the mRNA levels of some important molecules for the intracellular calcium dynamics in PCs (SERCA2, IP3R, and P/Q-type calcium channel) are downregulated in Mf-1 PCs. This result suggests those genes as possible TH-target genes. Taken together, the present study suggested a novel possible role of TR in synaptic plasticity at PF-PC synapses by regulating the expression of some important genes for LTD occurrence in the cerebellum. This finding could give a new insight into the mechanism of motor deficits in thyroid diseases.

An Active Role for Astrocytes in Synaptic Plasticity?

2010 ◽  
Vol 104 (3) ◽  
pp. 1216-1218 ◽  
Author(s):  
Ian Wenker
Keyword(s):  
Synaptic Plasticity ◽  
Transgenic Mice ◽  
Intracellular Calcium ◽  
Calcium Concentration ◽  
Active Role ◽  
Intracellular Calcium Concentration ◽  
Synaptic Potentiation ◽  
Calcium Dependent

Recently, Henneberger and colleagues blocked hippocampal long-term synaptic potentiation (LTP) induction by “clamping” intracellular calcium concentration of individual CA1 astrocytes, suggesting calcium-dependent gliotransmitter release from astocytes plays a role in hippocampal LTP induction. However, using transgenic mice to manipulate astrocytic calcium, Agulhon and colleagues demonstrated no effect on LTP induction. Until the question of how intracellular calcium causes gliotransmitter release is answered, the role of astrocytes in synaptic plasticity will be incompletely understood.

scholarly journals Action Potential–Induced Dendritic Calcium Dynamics Correlated With Synaptic Plasticity in Developing Hippocampal Pyramidal Cells

1999 ◽  
Vol 82 (4) ◽  
pp. 1993-1999 ◽  
Author(s):  
Yoshikazu Isomura ◽  
Nobuo Kato
Keyword(s):  
Synaptic Plasticity ◽  
Developmental Stage ◽  
Intracellular Calcium ◽  
Action Potentials ◽  
Pyramidal Cells ◽  
High Threshold ◽  
Calcium Dynamics ◽  
Ca1 Pyramidal Cells ◽  
Late Developmental Stage ◽  
Intracellular Calcium Dynamics

In hippocampal CA1 pyramidal cells, intracellular calcium increases are required for induction of long-term potentiation (LTP), an activity-dependent synaptic plasticity. LTP is known to develop in magnitude during the second and third postnatal weeks in the rats. Little is known, however, about development of intracellular calcium dynamics during the same postnatal weeks. We investigated postnatal development of intracellular calcium dynamics in the proximal apical dendrites of CA1 pyramidal cells by whole cell patch-clamp recordings and calcium imaging with the Ca2+ indicator fura-2. Dendritic calcium increases induced by intrasomatically evoked action potentials were slight during the first postnatal week but gradually became robust 3 to 6-fold during the second and third postnatal weeks. These calcium increases were blocked by application of 250 μM CdCl2, a nonspecific blocker for high-threshold voltage-dependent calcium channels (VDCCs). Under the voltage-clamp condition, both calcium currents and dendritic calcium accumulations induced by depolarization were larger at the late developmental stage (P15–18) than the early stage (P4–7), indicating developmental enhancement of calcium influx mediated by high-threshold VDCCs. Moreover, theta-burst stimulation (TBS), a protocol for LTP induction, induced large intracellular calcium increases at the late developmental stage, in synchrony with maturation of TBS-induced LTP. These results suggest that developmental enhancement of intracellular calcium increases induced by action potentials may underlie maturation of calcium-dependent functions such as synaptic plasticity in hippocampal neurons.

scholarly journals Role of pituitary adenylyl cyclase-activating polypeptide in intracellular calcium dynamics of neurons and satellite cells in rat superior cervical ganglia

2017 ◽  
Vol 38 (2) ◽  
pp. 99-109 ◽  
Author(s):  
Kanako ISOBE ◽  
Takuya YOKOYAMA ◽  
Kasumi MORIGUCHI-MORI ◽  
Miho KUMAGAI ◽  
Yoh-ichi SATOH ◽  
...  
Keyword(s):  
Intracellular Calcium ◽  
Adenylyl Cyclase ◽  
Satellite Cells ◽  
Calcium Dynamics ◽  
Intracellular Calcium Dynamics

scholarly journals Long-Term Oral Administration of Theaphenon-E Improves Cardiomyocyte Mechanics and Calcium Dynamics by Affecting Phospholamban Phosphorylation and ATP Production

2018 ◽  
Vol 47 (3) ◽  
pp. 1230-1243 ◽  
Author(s):  
Leonardo Bocchi ◽  
Monia Savi ◽  
Valeria Naponelli ◽  
Rocchina Vilella ◽  
Gianluca Sgarbi ◽  
...  
Keyword(s):  
Mechanical Properties ◽  
Intracellular Calcium ◽  
Green Tea ◽  
Mitochondrial Respiration ◽  
Calcium Dynamics ◽  
Dietary Polyphenols ◽  
Intracellular Calcium Dynamics ◽  
In Vivo Administration

Background/Aims: Dietary polyphenols from green tea have been shown to possess cardio-protective activities in different experimental models of heart diseases and age-related ventricular dysfunction. The present study was aimed at evaluating whether long term in vivo administration of green tea extracts (GTE), can exert positive effects on the normal heart, with focus on the underlying mechanisms. Methods: The study population consisted of 20 male adult Wistar rats. Ten animals were given 40 mL/day tap water solution of GTE (concentration 0.3%) for 4 weeks (GTE group). The same volume of water was administered to the 10 remaining control rats (CTRL). Then, in vivo and ex vivo measurements of cardiac function were performed in the same animal, at the organ (hemodynamics) and cellular (cardiomyocyte mechanical properties and intracellular calcium dynamics) levels. On cardiomyocytes and myocardial tissue samples collected from the same in vivo studied animals, we evaluated: (1) the intracellular content of ATP, (2) the endogenous mitochondrial respiration, (3) the expression levels of the Sarcoplasmic Reticulum Ca2+-dependent ATPase 2a (SERCA2), the Phospholamban (PLB) and the phosphorylated form of PLB, the L-type Ca2+ channel, the Na+-Ca2+ exchanger, and the ryanodine receptor 2. Results: GTE cardiomyocytes exhibited a hyperdynamic contractility compared with CTRL (the rate of shortening and re-lengthening, the fraction of shortening, the amplitude of calcium transient, and the rate of cytosolic calcium removal were significantly increased). A faster isovolumic relaxation was also observed at the organ level. Consistent with functional data, we measured a significant increase in the intracellular ATP content supported by enhanced endogenous mitochondrial respiration in GTE cardiomyocytes, as well as higher values of the ratios phosphorylated-PLB/PLB and SERCA2/PLB. Conclusions: Long-term in vivo administration of GTE improves cell mechanical properties and intracellular calcium dynamics in normal cardiomyocytes, by increasing energy availability and removing the inhibitory effect of PLB on SERCA2.

scholarly journals W246G Mutant ELOVL4 Impairs Synaptic Plasticity in Parallel and Climbing Fibers and Causes Motor Defects in a Rat Model of SCA34

2021 ◽  
Author(s):  
Raghavendra Y Nagaraja ◽  
David M Sherry ◽  
Jennifer L. Fessler ◽  
Megan A. Stiles ◽  
Feng Li ◽  
...  
Keyword(s):  
Synaptic Plasticity ◽  
Motor Function ◽  
Rat Model ◽  
Motor Coordination ◽  
Motor Deficits ◽  
Neuronal Function ◽  
Fatty Acid Elongase ◽  
Age Related ◽  
The Impact

Abstract Background: Spinocerebellar ataxias (SCA) are a group of neurodegenerative disorders characterized by neuronal degeneration leading to loss of motor coordination. A number of different mutations gives rise to different types of SCA with characteristic ages of onset, symptomatology, and rates of progression. SCA type 34 (SCA34) is an age-related cerebellar neurodegenerative disorder caused by mutations in the fatty acid elongase-4 (ELOVL4). The ELOVL4 is an essential enzyme that mediates biosynthesis of Very Long Chain Saturated and Polyunsaturated Fatty Acids (VLC-SFA and VLC-PUFA, resp., ≥28 carbons) that are critical for the normal function of brain, skin, retina, Meibomian glands, and testes in which ELOVL4 is expressed. Global deletion or homozygous expression of truncated mutant ELOVL4 that lack VLC-SFA and VLC-PUFA biosynthesis cause severe skin disorders, seizures and neonatal mortality in rodents and humans. Methods: To understand role of ELOVL4 and its products in neuronal function and to evaluate the consequences of ELOVL4 mutations in pathogenesis of age-related SCA34, we generated a rat model of SCA34 by knock-in of the SCA34-causing 736T>G (p.W246G) ELOVL4 mutation. We performed biochemical, neuroanatomical and behavioral analyses by rotorod to measure motor function. We used electrophysiological recordings from cerebellar slices to determine the impact of the W246G mutation on neuronal function. Results were analyzed using GraphPad Prism Statistical software. Results: Heterozygous and homozygous rats carrying the W246G mutation developed impaired motor deficits by two months of age. To understand the mechanism of these motor deficits, we performed electrophysiological studies using cerebellar slices from rats homozygous for W246G mutant ELOVL4 and found marked reduction of long-term potentiation at parallel fiber synapses and long-term depression at climbing fiber synapses onto Purkinje cells. Neuroanatomical analysis of the cerebellum up 6 months of age showed normal cytoarchitectural organization despite the early-onset motor deficits and defects in synaptic plasticity. Conclusions: Our results point to ELOVL4 and its products being essential for motor function and cerebellar synaptic plasticity. The results further suggest that in SCA34 patients, ataxia arises from primary impairment of synaptic plasticity and cerebellar network desynchronization that precedes cerebellar degeneration and loss of motor coordination with aging.

scholarly journals W246G Mutant ELOVL4 Impairs Synaptic Plasticity in Parallel and Climbing Fibers and Causes Motor Defects in a Rat Model of SCA34

2021 ◽  
Author(s):  
Raghavendra Nagaraja ◽  
David Sherry ◽  
Jennifer Fessler ◽  
Megan Stiles ◽  
Feng Li ◽  
...  
Keyword(s):  
Synaptic Plasticity ◽  
Rat Model ◽  
Motor Coordination ◽  
Neurodegenerative Disorder ◽  
Long Term Potentiation ◽  
Motor Deficits ◽  
Spinocerebellar Ataxias ◽  
Fatty Acid Elongase ◽  
Age Related

Abstract Spinocerebellar ataxias (SCA) are a group of neurodegenerative disorders caused by a number of different mutations the leads to loss of motor coordination with characteristic ages of onset, symptomatology, and rates of progression. SCA type 34 (SCA34) is an age-related cerebellar neurodegenerative disorder caused by mutations in the Fatty Acid Elongase-4 (ELOVL4). The ELOVL4 is an essential enzyme that mediates biosynthesis of Very Long Chain Saturated and Polyunsaturated Fatty Acids (VLC-SFA and VLC-PUFA, resp., ≥28 carbons) that are critical for the normal function of brain, skin, retina, Meibomian glands, and testes in which ELOVL4 is expressed. Global deletion or homozygous expression of truncated mutant ELOVL4 that lack VLC-SFA and VLC-PUFA biosynthesis cause severe skin disorders, seizures and neonatal mortality in rodents and humans. To understand the consequences of ELOVL4 mutations in pathogenesis of SCA34, we generated a rat model of SCA34 by knock-in of the SCA34-causing 736T>G (p.W246G) ELOVL4 mutation. We show that heterozygous and homozygous rats carrying the W246G mutation developed impaired motor deficits by two months of age. Our electrophysiological studies using cerebellar slices found marked reduction of long-term potentiation at parallel fiber synapses and long-term depression at climbing fiber synapses onto Purkinje cells in the homozygous W246G mutant rats. Our results further point to ELOVL4 products as being essential for motor function and cerebellar synaptic plasticity. These results suggest that in SCA34 patients, ataxia likely arises from primary impairment of synaptic plasticity and cerebellar network desynchronization that precedes cerebellar degeneration and loss of motor coordination with aging.

Sign in / Sign up

Export Citation Format

Share Document