Pavlovian eyeblink conditioning is severely impaired in tottering mice

2020 ◽  
Author(s):  
Nina L. de Oude ◽  
Freek E. Hoebeek ◽  
Michiel M. ten Brinke ◽  
Chris I. de Zeeuw ◽  
Henk-Jan Boele
Keyword(s):  
Neuronal Excitability ◽  
Eyeblink Conditioning ◽  
Learning Task ◽  
Loss Of Function ◽  
Oscillatory State ◽  
Voltage Dependent ◽  
Voltage Dependent Calcium Channels ◽  
Dependent Learning ◽  
The Brain ◽  
Normal Calcium

Cacna1a encodes the pore-forming α1A subunit of CaV2.1 voltage-dependent calcium channels, which regulate neuronal excitability and synaptic transmission. Purkinje cells in the cortex of cerebellum abundantly express these CaV2.1 channels. Here, we show that homozygous tottering (tg) mice, which carry a loss-of-function Cacna1a mutation, exhibit severely impaired learning in Pavlovian eyeblink conditioning, which is a cerebellar dependent learning task. Performance of reflexive eyeblinks is unaffected in tg mice. Transient seizure activity in tg mice further corrupted the amplitude of eyeblink CRs. Our results indicate that normal calcium homeostasis is imperative for cerebellar learning and that the oscillatory state of the brain can affect the expression thereof.

Halothane and Isoflurane Augment Depolarization-induced Cytosolic CA2+Transients and Attenuate Carbachol-stimulated CA2+Transients

2000 ◽  
Vol 92 (6) ◽  
pp. 1746-1756 ◽  
Author(s):  
Fang Xu ◽  
Jin Zhang ◽  
Esperanza Recio-Pinto ◽  
Thomas J. J. Blanck
Keyword(s):  
Neuronal Excitability ◽  
Neuroblastoma Cell ◽  
Volatile Anesthetic ◽  
Volatile Anesthetics ◽  
Neuroblastoma Cell Line ◽  
Inositol Triphosphate ◽  
Human Neuroblastoma Cell ◽  
Human Neuroblastoma ◽  
Voltage Dependent ◽  
Voltage Dependent Calcium Channels

Background Neuronal excitability is in part determined by Ca2+ availability that is controlled by regulatory mechanisms of cytosolic Ca2+ ([Ca2+]cyt). Alteration of any of those mechanisms by volatile anesthetics (VAs) may lead to a change in presynaptic transmission and postsynaptic excitability. Using a human neuroblastoma cell line, the effects of halothane and isoflurane on cytosolic Ca2+ concentration ([Ca2+]cyt) in response to K+ and carbachol stimulation were investigated. Methods Volatile anesthetic (0.05-1 mm) action on stimulated [Ca2+]cyt transients were monitored in suspensions of SH-SY5Y cells loaded with fura-2. Potassium chloride (KCl; 100 mm) was used to depolarize and activate Ca2+ entry through voltage-dependent calcium channels; 1 mm carbachol was used to activate muscarinic receptor-mediated inositol triphosphate (IP3)-dependent intracellular Ca2+ release. Sequential stimulations, KCl followed by carbachol and vice versa, were used to investigate interactions between intracellular Ca2+ stores. Results Halothane and isoflurane in clinically relevant concentrations enhanced the K+-evoked [Ca2+]cyt transient whether intracellular Ca2+ stores were full or partially depleted. In contrast, halothane and isoflurane reduced the carbachol-evoked [Ca2+]cyt transient when the intracellular Ca2+ stores were full but had no effect when the Ca2+ stores were partially depleted by KCl stimulation. Conclusions Volatile anesthetics acted on sites that differently affect the K+- and carbachol-evoked [Ca2+]cyt transients. These data suggest the involvement of an intracellular Ca2+ translocation from the caffeine-sensitive Ca2+ store to the inositol triphosphate-sensitive Ca2+ store that was altered by halothane and isoflurane.

scholarly journals Temporal Event Association and Output-Dependent Learning: A Proposed Scheme of Neural Molecular Connections

1999 ◽  
Vol 3 (4) ◽  
pp. 234-244 ◽  
Author(s):  
Yukifumi Shigematsu ◽  
◽  
Hiroshi Okamoto ◽  
Kazuhisa Ichikawa ◽  
Gen Matsumoto ◽  
...  
Keyword(s):  
Action Potentials ◽  
Single Neuron ◽  
Calcium Concentration ◽  
Molecular Mechanisms ◽  
Learning Algorithm ◽  
Learning Rule ◽  
Voltage Dependent ◽  
Temporal Events ◽  
Dependent Learning ◽  
The Brain

We introduce a model of temporal-event-associated and output-dependent learning rule, genetically acquired and expressed in a single neuron. This is essentially indispensable for the brain to acquire algorithms, how to process its self-selected information, by itself. This proposed learning rule is revised-Hebbian with a synaptic history trace to correlate one temporal event to others. Temporal events are memorized to be expressed at the synaptic site of inputs and in the form of the asymmetric neural strength corrections associated with temporal events. This learning algorithm has an advantage to associate one temporal event with others, resulting in the neuron with predictability but also makes recalling flexible. Re ’ calling is, according to this learning, independent of timing, supposed to be crucial in learning. Underlying molecular mechanisms for our proposed learning rule are discussed and we identify three important factors: 1) the back-propagating action potentials experimentally observed a single neuron play a crucial role for outputdependent learning, 2) temporally associated, nonlinear couplings are modeled at molecular levels with glutamate receptors, voltage-dependent channels, intracellular calcium concentration, protein kinases and phosphatase, and 3) intracellular concentration of inositol-tri-phosphate [IP3] is the memory substrate of synaptic history.

scholarly journals Intrinsic Excitability Increase in Cerebellar Purkinje Cells Following Delay Eyeblink Conditioning in Mice

2018 ◽  
Author(s):  
Heather K. Titley ◽  
Gabrielle V. Watkins ◽  
Carmen Lin ◽  
Craig Weiss ◽  
Michael McCarthy ◽  
...  
Keyword(s):  
Purkinje Cells ◽  
Neuronal Excitability ◽  
Eyeblink Conditioning ◽  
Underlying Mechanism ◽  
Learning Task ◽  
Sk Channels ◽  
Calcium Dependent ◽  
Cerebellar Learning ◽  
Intrinsic Plasticity ◽  
Cerebellar Purkinje Cells

AbstractCerebellar learning is canonically thought to rely on synaptic plasticity, particularly at synaptic inputs to Purkinje cells. Recently, however, other complementary mechanisms have been identified. Intrinsic plasticity is one such mechanism, and depends in part on the down-regulation of calcium-dependent SK-type K channels, which is associated with an increase in neuronal excitability. In the hippocampus, SK-mediated intrinsic plasticity has been shown to play a role in trace eyeblink conditioning; however, it is not yet known how intrinsic plasticity contributes to a cerebellar learning task such as delay eyeblink conditioning. Whole cell recordings were obtained from acute cerebellar slices from mice ~48 hours after learning a delay eyeblink conditioning task. Over a period of repeated training sessions mice received either distinctly paired trials of a tone co-terminating with a periorbital shock (conditioned mice) or trials in which these stimuli were presented in an unpaired manner (pseudoconditioned mice). Conditioned mice show a significantly reduced afterhyperpolarization (AHP) following trains of parallel fiber stimuli. Moreover, we find that SK-dependent intrinsic plasticity is occluded in conditioned, but not pseudoconditioned mice. These findings show that excitability is enhanced in Purkinje cells after delay eyeblink conditioning and point toward a downregulation of SK channels as a potential underlying mechanism.

scholarly journals Purinergic Receptors Regulate Myogenic Tone in Cerebral Parenchymal Arterioles

2012 ◽  
Vol 33 (2) ◽  
pp. 293-299 ◽  
Author(s):  
Joseph E Brayden ◽  
Yao Li ◽  
Matthew J Tavares
Keyword(s):  
Tissue Perfusion ◽  
P2y Receptors ◽  
Fundamental Aspect ◽  
Myogenic Tone ◽  
Resistance Arteries ◽  
Receptor Isoforms ◽  
Voltage Dependent ◽  
Voltage Dependent Calcium Channels ◽  
The Brain ◽  
Intravascular Pressure

Myogenic tone is a fundamental aspect of vascular behavior in resistance arteries. This contractile response to changes in intravascular pressure is critically involved in blood flow autoregulation in tissues such as the brain, kidneys, and heart. Myogenic tone also helps regulate precapillary pressure and provides a level of background tone upon which vasodilator stimuli act to increase tissue perfusion when appropriate. Despite the importance of these processes in the brain, little is known about the mechanisms involved in control of myogenic tone in the cerebral microcirculation. Here, we report that pharmacological inhibition of P2Y4 and P2Y6 pyrimidine receptors nearly abolished myogenic tone in cerebral parenchymal arterioles (PAs). Molecular suppression of either P2Y4 or P2Y6 receptors using antisense oligodeoxynucleotides reduced myogenic tone by 44% ± 8% and 45% ± 7%, respectively. These results indicate that both receptor isoforms are activated by increased intravascular pressure, which enhances the activity of voltage-dependent calcium channels and increases myogenic tone in PAs. Enhancement or inhibition of ectonucleotidase activity had no effect on parenchymal arteriolar myogenic tone, indicating that this response is not mediated by local release of nucleotides, but rather may involve direct mechanical activation of P2Y receptors in the smooth muscle cells.

AGING DOES NOT ALTER THE BINDING CHARACTERISTICS TO VOLTAGE DEPENDENT CALCIUM CHANNELS IN THE BRAIN OF CW1 MICE

1992 ◽  
Vol 3 (2) ◽  
Author(s):  
Ahuva Golik ◽  
Tamar Kadar ◽  
Lily Raveh ◽  
David Modai ◽  
Ben Avi Weissman
Keyword(s):  
Calcium Channels ◽  
Binding Characteristics ◽  
Voltage Dependent ◽  
Voltage Dependent Calcium Channels ◽  
The Brain

scholarly journals A Novel KCNA2 Variant in a Patient with Non-Progressive Congenital Ataxia and Epilepsy: Functional Characterization and Sensitivity to 4-Aminopyridine

2021 ◽  
Vol 22 (18) ◽  
pp. 9913
Author(s):  
Paola Imbrici ◽  
Elena Conte ◽  
Rikard Blunck ◽  
Fabrizia Stregapede ◽  
Antonella Liantonio ◽  
...  
Keyword(s):  
Neuronal Excitability ◽  
Functional Characterization ◽  
In Silico Analysis ◽  
Epileptic Encephalopathy ◽  
Loss Of Function ◽  
Hek 293 ◽  
Functional Studies ◽  
Whole Cell Patch Clamp ◽  
Voltage Dependent ◽  
Novel Variant

Kv1.2 channels, encoded by the KCNA2 gene, are localized in the central and peripheral nervous system, where they regulate neuronal excitability. Recently, heterozygous mutations in KCNA2 have been associated with a spectrum of symptoms extending from epileptic encephalopathy, intellectual disability, and cerebellar ataxia. Patients are treated with a combination of antiepileptic drugs and 4-aminopyridine (4-AP) has been recently trialed in specific cases. We identified a novel variant in KCNA2, E236K, in a Serbian proband with non-progressive congenital ataxia and early onset epilepsy, treated with sodium valproate. To ascertain the pathogenicity of E236K mutation and to verify its sensitivity to 4-AP, we transfected HEK 293 cells with Kv1.2 WT or E236K cDNAs and recorded potassium currents through the whole-cell patch-clamp. In silico analysis supported the electrophysiological data. E236K channels showed voltage-dependent activation shifted towards negative potentials and slower kinetics of deactivation and activation compared with Kv1.2 WT. Heteromeric Kv1.2 WT+E236K channels, resembling the condition of the heterozygous patient, confirmed a mixed gain- and loss-of-function (GoF/LoF) biophysical phenotype. 4-AP inhibited both Kv1.2 and E236K channels with similar potency. Homology modeling studies of mutant channels suggested a reduced interaction between the residue K236 in the S2 segment and the gating charges at S4. Overall, the biophysical phenotype of E236K channels correlates with the mild end of the clinical spectrum reported in patients with GoF/LoF defects. The response to 4-AP corroborates existing evidence that KCNA2-disorders could benefit from variant-tailored therapeutic approaches, based on functional studies.

Differential effect of desipramine and 2-hydroxydesipramine on depolarization-induced calcium uptake in synaptosomes from rat limbic sites

1995 ◽  
Vol 73 (5) ◽  
pp. 619-623 ◽  
Author(s):  
G. Beauchamp ◽  
P.-A. Lavoie ◽  
R. Elie
Keyword(s):  
Calcium Channel ◽  
Plasma Concentrations ◽  
Cingulate Cortex ◽  
Clinical Activity ◽  
Ca Uptake ◽  
Voltage Dependent ◽  
Dependent Inhibition ◽  
Voltage Dependent Calcium Channels ◽  
A Minor ◽  
The Brain

This study was conducted to investigate the inhibition of synaptosomal 45Ca uptake by desipramine and its major metabolite 2-hydroxydesipramine in the rat hippocampus and cingulate cortex, areas associated with emotional control. A concentration-dependent inhibition of net depolarization-induced 45Ca uptake was observed for desipramine (20–200 μM) in synaptosomes from both sites. However, 20 μM 2-hydroxydesipramine failed to inhibit calcium channel function in either of the two limbic sites; higher concentrations (60 or 200 μM) did produce a minor degree of inhibition in hippocampus synaptosomes. Others have shown that the clinically encountered plasma concentrations of 2-hydroxydesipramine are lower than those of desipramine, and the brain concentration of 2-hydroxydesipramine is therefore not expected to surpass or even reach 20 μM. In view of the previously observed clinical activity of 2-hydroxydesipramine, the present results indicate that calcium channel antagonism may not be the basis for the therapeutic effect of tricyclic antidepressants.Key words: voltage-dependent calcium channels, 45Ca uptake, hippocampus, cingulate cortex, tricyclic antidepressants.

Metallic prions

2004 ◽  
Vol 71 ◽  
pp. 193-202 ◽  
Author(s):  
David R Brown
Keyword(s):  
Prion Protein ◽  
Binding Capacity ◽  
Normal Function ◽  
Transmissible Spongiform Encephalopathies ◽  
Published Data ◽  
Normal Brain ◽  
Copper Binding ◽  
Loss Of Function ◽  
Spongiform Encephalopathies ◽  
The Brain

Prion diseases, also referred to as transmissible spongiform encephalopathies, are characterized by the deposition of an abnormal isoform of the prion protein in the brain. However, this aggregated, fibrillar, amyloid protein, termed PrPSc, is an altered conformer of a normal brain glycoprotein, PrPc. Understanding the nature of the normal cellular isoform of the prion protein is considered essential to understanding the conversion process that generates PrPSc. To this end much work has focused on elucidation of the normal function and activity of PrPc. Substantial evidence supports the notion that PrPc is a copper-binding protein. In conversion to the abnormal isoform, this Cu-binding activity is lost. Instead, there are some suggestions that the protein might bind other metals such as Mn or Zn. PrPc functions currently under investigation include the possibility that the protein is involved in signal transduction, cell adhesion, Cu transport and resistance to oxidative stress. Of these possibilities, only a role in Cu transport and its action as an antioxidant take into consideration PrPc's Cu-binding capacity. There are also more published data supporting these two functions. There is strong evidence that during the course of prion disease, there is a loss of function of the prion protein. This manifests as a change in metal balance in the brain and other organs and substantial oxidative damage throughout the brain. Thus prions and metals have become tightly linked in the quest to understand the nature of transmissible spongiform encephalopathies.

scholarly journals The NALCN Channel Regulator UNC-80 Functions in a Subset of Interneurons To Regulate Caenorhabditis elegans Reversal Behavior

2019 ◽  
Vol 10 (1) ◽  
pp. 199-210 ◽  
Author(s):  
Chuanman Zhou ◽  
Jintao Luo ◽  
Xiaohui He ◽  
Qian Zhou ◽  
Yunxia He ◽  
...  
Keyword(s):  
Plant Hormone ◽  
Neuronal Excitability ◽  
Resting Membrane Potential ◽  
Loss Of Function ◽  
Wild Type ◽  
C Elegans ◽  
Link Type ◽  
Complex Functions ◽  
And Function ◽  
Multiple Loss

NALCN (Na+leak channel, non-selective) is a conserved, voltage-insensitive cation channel that regulates resting membrane potential and neuronal excitability. UNC79 and UNC80 are key regulators of the channel function. However, the behavioral effects of the channel complex are not entirely clear and the neurons in which the channel functions remain to be identified. In a forward genetic screen for C. elegans mutants with defective avoidance response to the plant hormone methyl salicylate (MeSa), we isolated multiple loss-of-function mutations in unc-80 and unc-79. C. elegans NALCN mutants exhibited similarly defective MeSa avoidance. Interestingly, NALCN, unc-80 and unc-79 mutants all showed wild type-like responses to other attractive or repelling odorants, suggesting that NALCN does not broadly affect odor detection or related forward and reversal behaviors. To understand in which neurons the channel functions, we determined the identities of a subset of unc-80-expressing neurons. We found that unc-79 and unc-80 are expressed and function in overlapping neurons, which verified previous assumptions. Neuron-specific transgene rescue and knockdown experiments suggest that the command interneurons AVA and AVE and the anterior guidepost neuron AVG can play a sufficient role in mediating unc-80 regulation of the MeSa avoidance. Though primarily based on genetic analyses, our results further imply that MeSa might activate NALCN by direct or indirect actions. Altogether, we provide an initial look into the key neurons in which the NALCN channel complex functions and identify a novel function of the channel in regulating C. elegans reversal behavior through command interneurons.

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