scholarly journals Of mice and intrinsic excitability: genetic background affects the size of the postburst afterhyperpolarization in CA1 pyramidal neurons

2011 ◽  
Vol 106 (3) ◽  
pp. 1570-1580 ◽  
Author(s):  
Shannon J. Moore ◽  
Benjamin T. Throesch ◽  
Geoffrey G. Murphy
Keyword(s):  
Genetic Background ◽  
Neuronal Excitability ◽  
Pyramidal Neurons ◽  
Critical Role ◽  
Genetically Engineered ◽  
Gradual Transition ◽  
Cellular Mechanisms ◽  
Ca1 Pyramidal Neurons ◽  
Genetically Engineered Mice ◽  
Cell Current

As the use of genetically engineered mice has become increasingly prevalent in neurobiological research, evidence has steadily accumulated that substantial differences exist between strains. Although a number of studies have reported effects of genetic background on behavior, few have focused on differences in neurophysiology. The postburst afterhyperpolarization (AHP) is an important determinant of intrinsic neuronal excitability and has been suggested to play a critical role in the cellular mechanisms underlying learning and memory. Using whole cell current-clamp recordings of CA1 pyramidal neurons, we examined the magnitude of different phases of the AHP (peak, medium, and slow) in two commonly used genetic backgrounds, C57BL/6 (B6) and 129SvEv (129), as well as in an F2 hybrid B6:129 background (F2). We found that neurons from B6 and F2 animals exhibited a significantly larger AHP compared with 129 animals and that this difference was consistent across all phases. Furthermore, our recordings revealed a marked dichotomy in the shape of the AHP waveform, which was independent of genetic background. Approximately 60% of cells exhibited an AHP with a sharp transition between the peak AHP and medium AHP, whereas the remaining 40% exhibited a more gradual transition. Our data add to the growing body of work suggesting that genetic background can affect neuronal function as well as behavior. In addition, these results highlight the innate heterogeneity of CA1 pyramidal neurons, even within a single genetic background. These differences should be taken into consideration during the analysis and comparison of experimental results.

scholarly journals Anatomical and Electrophysiological Comparison of CA1 Pyramidal Neurons of the Rat and Mouse

2009 ◽  
Vol 102 (4) ◽  
pp. 2288-2302 ◽  
Author(s):  
Brandy N. Routh ◽  
Daniel Johnston ◽  
Kristen Harris ◽  
Raymond A. Chitwood
Keyword(s):  
Pyramidal Neurons ◽  
Three Dimensional ◽  
Input Resistance ◽  
Genetically Engineered ◽  
Morphological Properties ◽  
Mouse Strains ◽  
Sprague Dawley ◽  
Maximal Conductance ◽  
Ca1 Pyramidal Neurons ◽  
Genetically Engineered Mice

The study of learning and memory at the single-neuron level has relied on the use of many animal models, most notably rodents. Although many physiological and anatomical studies have been carried out in rats, the advent of genetically engineered mice has necessitated the comparison of new results in mice to established results from rats. Here we compare fundamental physiological and morphological properties and create three-dimensional compartmental models of identified hippocampal CA1 pyramidal neurons of one strain of rat, Sprague–Dawley, and two strains of mice, C57BL/6 and 129/SvEv. We report several differences in neuronal physiology and anatomy among the three animal groups, the most notable being that neurons of the 129/SvEv mice, but not the C57BL/6 mice, have higher input resistance, lower dendritic surface area, and smaller spines than those of rats. A surprising species-specific difference in membrane resonance indicates that both mouse strains have lower levels of the hyperpolarization-activated nonspecific cation current Ih. Simulations suggest that differences in Ih kinetics rather than maximal conductance account for the lower resonance. Our findings indicate that comparisons of data obtained across strains or species will need to account for these and potentially other physiological and anatomical differences.

scholarly journals Impact of inhibitory constraint of interneurons on neuronal excitability

2013 ◽  
Vol 110 (11) ◽  
pp. 2520-2535 ◽  
Author(s):  
Vallent Lee ◽  
Jamie Maguire
Keyword(s):  
Neuronal Excitability ◽  
Pyramidal Neurons ◽  
Molecular Layer ◽  
Critical Role ◽  
Tonic Inhibition ◽  
Stratum Radiatum ◽  
Gabaergic Inhibition ◽  
Seizure Susceptibility ◽  
Ca1 Pyramidal Neurons ◽  
The Impact

Tonic inhibition is thought to dampen the excitability of principal neurons; however, little is known about the role of tonic GABAergic inhibition in interneurons and the impact on principal neuron excitability. In many brain regions, tonic GABAergic inhibition is mediated by extrasynaptic, δ-subunit-containing GABAA receptors (GABAARs). In the present study we demonstrate the importance of GABAAR δ-subunit-mediated tonic inhibition in interneurons. Selective elimination of the GABAAR δ-subunit from interneurons was achieved by crossing a novel floxed Gabrd mouse model with GAD65-Cre mice ( Gabrd/Gad mice). Deficits in GABAAR δ-subunit expression in GAD65-positive neurons result in a decrease in tonic GABAergic inhibition and increased excitability of both molecular layer (ML) and stratum radiatum (SR) interneurons. Disinhibition of interneurons results in robust alterations in the neuronal excitability of principal neurons and decreased seizure susceptibility. Gabrd/Gad mice have enhanced tonic and phasic GABAergic inhibition in both CA1 pyramidal neurons and dentate gyrus granule cells (DGGCs). Consistent with alterations in hippocampal excitability, CA1 pyramidal neurons and DGGCs from Gabrd/Gad mice exhibit a shift in the input-output relationship toward decreased excitability compared with those from Cre−/− littermates. Furthermore, seizure susceptibility, in response to 20 mg/kg kainic acid, is significantly decreased in Gabrd/Gad mice compared with Cre−/− controls. These data demonstrate a critical role for GABAAR δ-subunit-mediated tonic GABAergic inhibition of interneurons on principal neuronal excitability and seizure susceptibility.

scholarly journals Metrifonate Increases Neuronal Excitability in CA1 Pyramidal Neurons from Both Young and Aging Rabbit Hippocampus

1999 ◽  
Vol 19 (5) ◽  
pp. 1814-1823 ◽  
Author(s):  
M. Matthew Oh ◽  
John M. Power ◽  
Lucien T. Thompson ◽  
Pamela L. Moriearty ◽  
John F. Disterhoft
Keyword(s):  
Neuronal Excitability ◽  
Pyramidal Neurons ◽  
Ca1 Pyramidal Neurons ◽  
Rabbit Hippocampus

Differential Maintenance and Frequency-Dependent Tuning of LTP at Hippocampal Synapses of Specific Strains of Inbred Mice

2000 ◽  
Vol 84 (5) ◽  
pp. 2484-2493 ◽  
Author(s):  
Peter V. Nguyen ◽  
Steven N. Duffy ◽  
Jennie Z. Young
Keyword(s):  
Genetic Background ◽  
Pyramidal Neurons ◽  
Inbred Mice ◽  
Inbred Mouse ◽  
Mouse Strains ◽  
Synaptic Facilitation ◽  
Ca1 Pyramidal Neurons ◽  
Hippocampal Synapses ◽  
Strain Dependent

Transgenic and knockout mice are used extensively to elucidate the molecular mechanisms of hippocampal synaptic plasticity. However, genetic and phenotypic variations between inbred mouse strains that are used to construct genetic models may confound the interpretation of cellular neurophysiological data derived from these models. Using in vitro slice stimulation and recording methods, we compared the membrane biophysical, cellular electrophysiological, and synaptoplastic properties of hippocampal CA1 neurons in four specific strains of inbred mice: C57BL/6J, CBA/J, DBA/2J, and 129/SvEms/J. Hippocampal long-term potentiation (LTP) induced by theta-pattern stimulation, and by repeated multi-burst 100-Hz stimulation at various interburst intervals, was better maintained in area CA1 of slices from BL/6J mice than in slices from CBA and DBA mice. At an interburst interval of 20 s, maintenance of LTP was impaired in CBA and DBA slices, as compared with BL/6J slices. When the interburst interval was reduced to 3 s, induction of LTP was significantly enhanced in129/SvEms slices, but not in DBA and CBA slices. Long-term depression (LTD) was not significantly different between slices from these four strains. For the four strains examined, CA1 pyramidal neurons showed no significant differences in spike-frequency accommodation, membrane input resistance, and number of spikes elicited by current injection. Synaptically-evoked glutamatergic postsynaptic currents did not significantly differ among CA1 pyramidal neurons in these four strains. Since the observed LTP deficits resembled those previously seen in transgenic mice with reduced hippocampal cAMP-dependent protein kinase (PKA) activity, we searched for possible strain-dependent differences in cAMP-dependent synaptic facilitation induced by forskolin (an activator of adenylate cyclase) and IBMX (a phosphodiesterase inhibitor). We found that forskolin/IBMX-induced synaptic facilitation was deficient in area CA1 of DBA/2J and CBA/J slices, but not in BL/6J and 129/SvEms/J slices. These defects in cAMP-induced synaptic facilitation may underlie the deficits in memory, observed in CBA/J and DBA/2J mice, that have been previously reported. We conclude that hippocampal LTP is influenced by genetic background and by the temporal characteristics of the stimulation protocol. The plasticity of hippocampal synapses in some inbred mouse strains may be “tuned” to particular temporal patterns of synaptic activity. From a broader perspective, our data support the notion that strain-dependent variation in genetic background is an important factor that can influence the synaptoplastic phenotypes observed in studies that use genetically modified mice to explore the molecular bases of synaptic plasticity.

Abstract 378: Physiologic Role of Rpl13a SnoRNAs in Cell Size Regulation

2020 ◽  
Vol 127 (Suppl_1) ◽  
Author(s):  
Hsiang Ting T Ho ◽  
Christopher L Holley
Keyword(s):  
Protein Expression ◽  
Cell Size ◽  
Antisense Oligonucleotides ◽  
Critical Role ◽  
Mrna Translation ◽  
Genetically Engineered ◽  
H9c2 Cell ◽  
Candidate Gene Approach ◽  
Genetically Engineered Mice ◽  
Gene And Protein Expression

Objectives: Box C/D small nucleolar RNAs (snoRNA) are a multifunctional family of ncRNAs that play a critical role in guiding 2'- O -methylation (Nm) of ribosomal RNA (rRNA). My work has recently revealed that box C/D snoRNAs can also direct methylation of messenger RNA (mRNA), and that this methylation can regulate mRNA translation in the heart. In studies of genetically-engineered mice lacking four box C/D snoRNAs, I have observed that the knockout animals have relatively small hearts compared to wild-type. The objective of my current study is to define the specific mechanisms by which box C/D snoRNAs regulate heart size. Methods: I investigated the hearts of genetically-engineered mice lacking four box C/D snoRNAs from the Rpl13a locus (snoRNAs U32a, U33, U34 and U35a ). I also used antisense oligonucleotides to knock down these snoRNAs in H9c2 rat cardiomyoblasts. Changes in gene and protein expression were assessed by qPCR and immunoblot. Relative Nm modification of mRNA was determined by reverse transcription at low dNTP concentrations, followed by real-time PCR (RTL-P). Results: Germline knockout of the four box C/D Rpl13a snoRNAs ( U32a, U33, U34 and U35a ) in adolescent mice produces developmentally smaller hearts. In H9c2 rat cardiomyoblasts, knockdown of Rpl13a snoRNAs by antisense oligonucleotides significantly reduces H9c2 cell size. These concordant effects on organ and cell size suggest that the Rpl13a snoRNAs might be regulating critical pathways that determine cell growth. Using a candidate gene approach, I found that Mtor mRNA and protein expression is significantly reduced in hearts from Rpl13a snoRNA knockout mice. Preliminary results using the RTL-P method suggest that Mtor is subject to snoRNA-guided Nm modification, which is decreased in Rpl13a snoRNA knockout mouse hearts. Conclusion: These results suggest that Rpl13a snoRNAs regulate cardiomyocyte growth, at least in part, by guiding Nm modification of Mtor mRNA.

Pre- and Postsynaptic Activation of M-Channels By a Novel Opener Dampens Neuronal Firing and Transmitter Release

2007 ◽  
Vol 97 (1) ◽  
pp. 283-295 ◽  
Author(s):  
Asher Peretz ◽  
Anton Sheinin ◽  
Cuiyong Yue ◽  
Nurit Degani-Katzav ◽  
Gilad Gibor ◽  
...  
Keyword(s):  
Neuronal Excitability ◽  
Pyramidal Neurons ◽  
Critical Role ◽  
Hippocampal Slices ◽  
Gaba Release ◽  
Neuronal Firing ◽  
Dorsal Root Ganglion Neurons ◽  
Postsynaptic Currents ◽  
M Channels ◽  
Ganglion Neurons

The M-type K+ current (M-current), encoded by Kv7.2/3 (KCNQ2/3) K+ channels, plays a critical role in regulating neuronal excitability because it counteracts subthreshold depolarizations. Here we have characterized the functions of pre- and postsynaptic M-channels using a novel Kv7.2/3 channel opener, NH6, which we synthesized as a new derivative of N-phenylanthranilic acid. NH6 exhibits a good selectivity as it does not affect Kv7.1 and IKS K+ currents as well as NR1/NR2B, AMPA, and GABAA receptor-mediated currents. Superfusion of NH6 increased recombinant Kv7.2/3 current amplitude (EC50 = 18 μM) by causing a hyperpolarizing shift of the voltage activation curve and by markedly slowing the deactivation kinetics. Activation of native M-currents by NH6 robustly reduced the number of evoked and spontaneous action potentials in cultured cortical, hippocampal and dorsal root ganglion neurons. In hippocampal slices, NH6 decreased somatically evoked spike afterdepolarization of CA1 pyramidal neurons and induced regular firing in bursting neurons. Activation of M-channels by NH6, potently reduced the frequency of spontaneous excitatory and inhibitory postsynaptic currents. Activation of M-channels also decreased the frequency of miniature excitatory (mEPSC) and inhibitory (mIPSC) postsynaptic currents without affecting their amplitude and waveform, thus suggesting that M-channels presynaptically inhibit glutamate and GABA release. Our results suggest a role of presynaptic M-channels in the release of glutamate and GABA. They also indicate that M-channels act pre- and postsynaptically to dampen neuronal excitability.

scholarly journals Redox Sensitive Calcium Stores Underlie Enhanced After Hyperpolarization of Aged Neurons: Role for Ryanodine Receptor Mediated Calcium Signaling

2010 ◽  
Vol 104 (5) ◽  
pp. 2586-2593 ◽  
Author(s):  
Karthik Bodhinathan ◽  
Ashok Kumar ◽  
Thomas C. Foster
Keyword(s):  
Neuronal Excitability ◽  
Pyramidal Neurons ◽  
Slow Component ◽  
Ryanodine Receptors ◽  
Calcium Stores ◽  
Memory Decline ◽  
Ca1 Neurons ◽  
Ca1 Pyramidal Neurons ◽  
Age Related ◽  
Intracellular Ca

A decrease in the excitability of CA1 pyramidal neurons contributes to the age related decrease in hippocampal function and memory decline. Decreased neuronal excitability in aged neurons can be observed as an increase in the Ca2+- activated K+- mediated post burst afterhyperpolarization (AHP). In this study, we demonstrate that the slow component of AHP (sAHP) in aged CA1 neurons (aged-sAHP) is decreased ∼50% by application of the reducing agent dithiothreitol (DTT). The DTT-mediated decrease in the sAHP was age specific, such that it was observed in CA1 pyramidal neurons of aged (20–25 mo), but not young (6–9 mo) F344 rats. The effect of DTT on the aged-sAHP was blocked following depletion of intracellular Ca2+ stores (ICS) by thapsigargin or blockade of ryanodine receptors (RyRs) by ryanodine, suggesting that the age-related increase in the sAHP was due to release of Ca2+ from ICS through redox sensitive RyRs. The DTT-mediated decrease in the aged-sAHP was not blocked by inhibition of L-type voltage gated Ca2+ channels (L-type VGCC), inhibition of Ser/Thr kinases, or inhibition of the large conductance BK potassium channels. The results add support to the idea that a shift in the intracellular redox state contributes to Ca2+ dysregulation during aging.

scholarly journals Metformin Enhances Excitatory Synaptic Transmission onto Hippocampal CA1 Pyramidal Neurons

2020 ◽  
Vol 10 (10) ◽  
pp. 706
Author(s):  
Wen-Bing Chen ◽  
Jiang Chen ◽  
Zi-Yang Liu ◽  
Bin Luo ◽  
Tian Zhou ◽  
...  
Keyword(s):  
Synaptic Transmission ◽  
Neuronal Excitability ◽  
Pyramidal Neurons ◽  
Glutamate Release ◽  
Hippocampal Slices ◽  
Hippocampal Pyramidal Neurons ◽  
Beneficial Effects ◽  
Ca1 Pyramidal Neurons ◽  
Postsynaptic Currents ◽  
Hippocampal Ca1

Metformin (Met) is a first-line drug for type 2 diabetes mellitus (T2DM). Numerous studies have shown that Met exerts beneficial effects on a variety of neurological disorders, including Alzheimer’s disease (AD), Parkinson’s disease (PD) and Huntington’s disease (HD). However, it is still largely unclear how Met acts on neurons. Here, by treating acute hippocampal slices with Met (1 μM and 10 μM) and recording synaptic transmission as well as neuronal excitability of CA1 pyramidal neurons, we found that Met treatments significantly increased the frequency of miniature excitatory postsynaptic currents (mEPSCs), but not amplitude. Neither frequency nor amplitude of miniature inhibitory postsynaptic currents (mIPSCs) were changed with Met treatments. Analysis of paired-pulse ratios (PPR) demonstrates that enhanced presynaptic glutamate release from terminals innervating CA1 hippocampal pyramidal neurons, while excitability of CA1 pyramidal neurons was not altered. Our results suggest that Met preferentially increases glutamatergic rather than GABAergic transmission in hippocampal CA1, providing a new insight on how Met acts on neurons.

scholarly journals A Review and Rationale for the Use of Genetically Engineered Animals in the Study of Traumatic Brain Injury

2001 ◽  
Vol 21 (11) ◽  
pp. 1241-1258 ◽  
Author(s):  
Luca Longhi ◽  
Kathryn E. Saatman ◽  
Ramesh Raghupathi ◽  
Helmut L. Laurer ◽  
Philipp M. Lenzlinger ◽  
...  
Keyword(s):  
Traumatic Brain Injury ◽  
Dna Damage ◽  
Cell Death ◽  
Brain Injury ◽  
Human Head ◽  
Genetically Engineered ◽  
Cellular Mechanisms ◽  
Cell Dysfunction ◽  
Damage Repair ◽  
Genetically Engineered Mice

The mechanisms underlying secondary cell death after traumatic brain injury (TBI) are poorly understood. Animal models of TBI recapitulate many clinical and pathologic aspects of human head injury, and the development of genetically engineered animals has offered the opportunity to investigate the specific molecular and cellular mechanisms associated with cell dysfunction and death after TBI, allowing for the evaluation of specific cause-effect relations and mechanistic hypotheses. This article represents a compendium of the current literature using genetically engineered mice in studies designed to better understand the posttraumatic inflammatory response, the mechanisms underlying DNA damage, repair, and cell death, and the link between TBI and neurodegenerative diseases.

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