Hippocampal β2-GABAA receptors mediate LTP suppression by etomidate and contribute to long-lasting feedback but not feedforward inhibition of pyramidal neurons

2021 ◽  
Author(s):  
Alexander G Figueroa ◽  
Claudia Benkwitz ◽  
Gabe Surges ◽  
Nicholas Kunz ◽  
Gregg E Homanics ◽  
...  
Keyword(s):  
Synaptic Plasticity ◽  
Pyramidal Neurons ◽  
Feedback Inhibition ◽  
Brain Slices ◽  
Long Term Potentiation ◽  
Genetically Engineered ◽  
General Anesthetic ◽  
Population Activity ◽  
Genetically Engineered Mice ◽  
Feedforward Inhibition

The general anesthetic etomidate, which acts through GABAA receptors, impairs the formation of new memories under anesthesia. This study addresses the molecular and cellular mechanisms by which this occurs. Here, using a new line of genetically engineered mice carrying the GABAAR β2-N265M mutation, we tested the roles of receptors that incorporate GABAA receptor β2 vs. β3 subunits to suppression of long-term potentiation (LTP), a cellular model of learning and memory. We found that brain slices from β2-N265M mice resisted etomidate suppression of LTP, indicating that the β2-GABAARs are an essential target in this model. As these receptors are most heavily expressed by interneurons in the hippocampus, this finding supports a role for interneuron modulation in etomidate control of synaptic plasticity. Nevertheless, β2 subunits are also expressed by pyramidal neurons, so they might also contribute. Therefore, using a previously established line of β3-N265M mice, we also examined the contributions of β2- vs. β3-GABAARs to GABAA,slow dendritic inhibition, because dendritic inhibition is particularly well suited to controlling synaptic plasticity. We also examined their roles in long-lasting suppression of population activity through feedforward and feedback inhibition. We found both β2- and β3-GABAARs contribute to GABAA,slow inhibition, and that both β2- and β3-GABAARs contribute to feedback inhibition, whereas only β3-GABAARs contribute to feedforward inhibition. We conclude that modulation of β2-GABAARs is essential to etomidate suppression of LTP. Furthermore, to the extent that this occurs through GABAARs on pyramidal neurons, it is through modulation of feedback inhibition.

scholarly journals Altered Short-Term Synaptic Plasticity in Mice Lacking the Metabotropic Glutamate Receptor mGlu7

2002 ◽  
Vol 2 ◽  
pp. 730-737 ◽  
Author(s):  
Trevor J. Bushell ◽  
Gilles Sansig ◽  
Valerie J. Collett ◽  
Herman van der Putten ◽  
Graham L. Collingridge
Keyword(s):  
Synaptic Plasticity ◽  
Molecular Mechanisms ◽  
Pyramidal Neurons ◽  
Metabotropic Glutamate Receptor ◽  
Long Term Potentiation ◽  
Short Term ◽  
Metabotropic Glutamate ◽  
Term Potentiation ◽  
Commissural Pathway ◽  
Frequency Facilitation

Eight subtypes of metabotropic glutamate (mGlu) receptors have been identified of which two, mGlu5 and mGlu7, are highly expressed at synapses made between CA3 and CA1 pyramidal neurons in the hippocampus. This input, the Schaffer collateral-commissural pathway, displays robust long-term potentiation (LTP), a process believed to utilise molecular mechanisms that are key processes involved in the synaptic basis of learning and memory. To investigate the possible function in LTP of mGlu7 receptors, a subtype for which no specific antagonists exist, we generated a mouse lacking this receptor, by homologous recombination. We found that LTP could be induced in mGlu7-/- mice and that once the potentiation had reached a stable level there was no difference in the magnitude of LTP between mGlu7-/- mice and their littermate controls. However, the initial decremental phase of LTP, known as short-term potentiation (STP), was greatly attenuated in the mGlu7-/- mouse. In addition, there was less frequency facilitation during, and less post-tetanic potentiation following, a high frequency train in the mGlu7-/- mouse. These results show that the absence of mGlu7 receptors results in alterations in short-term synaptic plasticity in the hippocampus.

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.

Suppression of Ih Contributes to Propofol-Induced Inhibition of Mouse Cortical Pyramidal Neurons

2005 ◽  
Vol 94 (6) ◽  
pp. 3872-3883 ◽  
Author(s):  
Xiangdong Chen ◽  
Shaofang Shu ◽  
Douglas A. Bayliss
Keyword(s):  
Cortical Neurons ◽  
Pyramidal Neurons ◽  
Brain Slices ◽  
Current Amplitude ◽  
Hcn Channels ◽  
General Anesthetic ◽  
Large Shift ◽  
Fast Kinetics ◽  
Membrane Hyperpolarization ◽  
Cortical Pyramidal Neurons

The contributions of the hyperpolarization-activated current, Ih, to generation of rhythmic activities are well described for various central neurons, particularly in thalamocortical circuits. In the present study, we investigated effects of a general anesthetic, propofol, on native Ih in neurons of thalamus and cortex and on the corresponding cloned HCN channel subunits. Whole cell voltage-clamp recordings from mouse brain slices identified neuronal Ih currents with fast activation kinetics in neocortical pyramidal neurons and with slower kinetics in thalamocortical relay cells. Propofol inhibited the fast-activating Ih in cortical neurons at a clinically relevant concentration (5 μM); inhibition of Ih involved a hyperpolarizing shift in half-activation voltage (Δ V1/2 approximately −9 mV) and a decrease in maximal available current (∼36% inhibition, measured at −120 mV). With the slower form of Ih expressed in thalamocortical neurons, propofol had no effect on current activation or amplitude. In heterologous expression systems, 5 μM propofol caused a large shift in V1/2 and decrease in current amplitude in homomeric HCN1 and linked heteromeric HCN1–HCN2 channels, both of which activate with fast kinetics but did not affect V1/2 or current amplitude of slowly activating homomeric HCN2 channels. With GABAA and glycine receptor channels blocked, propofol caused membrane hyperpolarization and suppressed action potential discharge in cortical neurons; these effects were occluded by the Ih blocker, ZD-7288. In summary, these data indicate that propofol selectively inhibits HCN channels containing HCN1 subunits, such as those that mediate Ih in cortical pyramidal neurons—and they suggest that anesthetic actions of propofol may involve inhibition of cortical neurons and perhaps other HCN1-expressing cells.

Quantal mechanism of long-term potentiation in hippocampal mossy-fiber synapses

1994 ◽  
Vol 71 (6) ◽  
pp. 2552-2556 ◽  
Author(s):  
Z. Xiang ◽  
A. C. Greenwood ◽  
E. W. Kairiss ◽  
T. H. Brown
Keyword(s):  
Pyramidal Neurons ◽  
Mossy Fiber ◽  
Classical Method ◽  
Brain Slices ◽  
Long Term Potentiation ◽  
Quantal Size ◽  
Term Potentiation ◽  
Before And After ◽  
Whole Cell Recordings

1. The quantal mechanism underlying the expression of long-term potentiation (LTP) was studied in the mossy-fiber (mf) synapses of the rat hippocampus. Whole-cell recordings were used to measure the excitatory postsynaptic currents (EPSCs) before and after LTP induction in brain slices maintained at 31 +/- 1 degrees C. 2. Evoked EPSCs were recorded from 473 CA3 pyramidal neurons. The mf synapses were stimulated using paired pulses (40-ms interpulse interval) repeated every 2–10 s. At least 400 pairs of mf responses were obtained before and during the expression of LTP, which was produced by high-frequency (100 Hz) mf stimulation. Sufficiently stationary data were obtained from five neurons that exhibited LTP and that also satisfied strict criteria and procedures that are necessary for eliciting and identifying unitary mf responses. 3. Three independent lines of evidence implicated a presynaptic component to the mechanism underlying mf LTP. The first was based on a graphical version of the classical method of variance. The graphical variance (GV) method was evaluated by clamping the cell at two different holding potentials during paired-pulse facilitation (PPF). The results indicated that the GV method can distinguish changes in mean quantal content m and mean quantal size q in rat mf synapses. The same analysis, when applied to PPF before and after LTP induction, indicated that both result from an increase in m. 4. The second line of evidence was based on the classical method of failures. Consistent with the inference that mf LTP is due to an increase in m, there was a statistically significant reduction in the number of quantal release failures.(ABSTRACT TRUNCATED AT 250 WORDS)

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 Intersectin 1 is a component of the Reelin pathway to regulate neuronal migration and synaptic plasticity in the hippocampus

2017 ◽  
Vol 114 (21) ◽  
pp. 5533-5538 ◽  
Author(s):  
Burkhard Jakob ◽  
Gaga Kochlamazashvili ◽  
Maria Jäpel ◽  
Aziz Gauhar ◽  
Hans H. Bock ◽  
...  
Keyword(s):  
Synaptic Plasticity ◽  
Neuronal Migration ◽  
Pyramidal Neurons ◽  
Neurological Diseases ◽  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Long Term Potentiation ◽  
Downstream Signaling ◽  
Radial Glial ◽  
Reelin Signaling

Brain development and function depend on the directed and coordinated migration of neurons from proliferative zones to their final position. The secreted glycoprotein Reelin is an important factor directing neuronal migration. Loss of Reelin function results in the severe developmental disorder lissencephaly and is associated with neurological diseases in humans. Reelin signals via the lipoprotein receptors very low density lipoprotein receptor (VLDLR) and apolipoprotein E receptor 2 (ApoER2), but the exact mechanism by which these receptors control cellular function is poorly understood. We report that loss of the signaling scaffold intersectin 1 (ITSN1) in mice leads to defective neuronal migration and ablates Reelin stimulation of hippocampal long-term potentiation (LTP). Knockout (KO) mice lacking ITSN1 suffer from dispersion of pyramidal neurons and malformation of the radial glial scaffold, akin to the hippocampal lamination defects observed in VLDLR or ApoER2 mutants. ITSN1 genetically interacts with Reelin receptors, as evidenced by the prominent neuronal migration and radial glial defects in hippocampus and cortex seen in double-KO mice lacking ITSN1 and ApoER2. These defects were similar to, albeit less severe than, those observed in Reelin-deficient or VLDLR/ ApoER2 double-KO mice. Molecularly, ITSN1 associates with the VLDLR and its downstream signaling adaptor Dab1 to facilitate Reelin signaling. Collectively, these data identify ITSN1 as a component of Reelin signaling that acts predominantly by facilitating the VLDLR-Dab1 axis to direct neuronal migration in the cortex and hippocampus and to augment synaptic plasticity.

scholarly journals Disinhibitory and neuromodulatory regulation of hippocampal synaptic plasticity

2020 ◽  
Author(s):  
Inês Guerreiro ◽  
Zhenglin Gu ◽  
Jerrel L. Yakel ◽  
Boris S. Gutkin
Keyword(s):  
Synaptic Plasticity ◽  
Pyramidal Neurons ◽  
Pyramidal Cells ◽  
General Mechanism ◽  
Excitatory Synapses ◽  
Ca1 Pyramidal Cells ◽  
Ca1 Pyramidal Neurons ◽  
Hippocampal Synaptic Plasticity ◽  
Local Circuitry ◽  
Feedforward Inhibition

AbstractHippocampal synaptic plasticity, particularly in the Schaffer collateral (SC) to CA1 pyramidal excitatory transmission, is considered as the cellular mechanism underlying learning. The CA1 pyramidal neurons are embedded in an intricate local circuitry that contains a variety of interneurons. The roles these interneurons play in the regulation of the excitatory synaptic plasticity remains largely understudied. Our recent experiments showed that repeated cholinergic activation of α7 nACh receptors expressed in oriens-lacunosum-moleculare (OLMα2) interneurons could induce LTP in SC-CA1 synapses, likely through disinhibition by inhibiting stratum radiatum (s.r.) interneurons that provide feedforward inhibition onto CA1 pyramidal neurons, revealing a potential mechanism for local interneurons to regulate SC-CA1 synaptic plasticity. Here, we pair in vitro studies with biophysically-based modeling to uncover the mechanisms through which cholinergic-activated GABAergic interneurons can disinhibit CA1 pyramidal cells, and how repeated disinhibition modulates hippocampal plasticity at the excitatory synapses. We found that α7 nAChR activation increases OLM activity. OLM neurons, in turn inhibit the fast-spiking interneurons that provide feedforward inhibition onto CA1 pyramidal neurons. This disinhibition, paired with tightly timed SC stimulation, can induce potentiation at the excitatory synapses of CA1 pyramidal neurons. Our work further describes the pairing of disinhibition with SC stimulation as a general mechanism for the induction of hippocampal synaptic plasticity.Disinhibition of the excitatory synapses, paired with SC stimulation, leads to increased NMDAR activation and intracellular calcium concentration sufficient to upregulate AMPAR permeability and potentiate the synapse. Repeated paired disinhibition of the excitatory synapse leads to larger and longer lasting increases of the AMPAR permeability. Our study thus provides a novel mechanism for inhibitory interneurons to directly modify glutamatergic synaptic plasticity. In particular, we show how cholinergic action on OLM interneurons can down-regulate the GABAergic signaling onto CA1 pyramidal cells, and how this shapes local plasticity rules. We identify paired disinhibition with SC stimulation as a general mechanism for the induction of hippocampal synaptic plasticity.

scholarly journals Neurotoxicity of NMDA antagonists: a glutamatergic theory of schizophrenia based on selective impairment of local inhibitory feedback circuits

2000 ◽  
Vol 2 (3) ◽  
pp. 287-298
Keyword(s):  
Pyramidal Neurons ◽  
Brain Slices ◽  
Nmda Antagonist ◽  
Long Term Potentiation ◽  
Normal Function ◽  
Recurrent Inhibition ◽  
Resting Membrane Potential ◽  
Nmda Antagonists ◽  
Inhibitory Feedback

Modulation of recurrent inhibition is critical not only for the normal function of highly excitable regions of the brain, especially the limbic system, but may also be a primary determining factor for the viability of neurons in these regions. Standard extracellular and intracellular recordings from in vitro brain slices of rat hippocampi were employed to show that recurrent inhibition onto CA1 neurons can be modulated by N-methyl-D-aspartate (NMDA) antagonists. Besides reducing the amplitude of inhibitory postsynaptic potentials (IPSPs) at resting membrane potential conditions, different NMDA antagonists, including the endogenous substance N-acetyl-L-aspartyl-L-glutamic acid (NAAG), are able to block long-term potentiation (LIP) of recurrent inhibition completely at concentrations that are not sufficient to block LTP of the excitatory drive onto pyramidal neurons. This LTP of recurrent inhibition may play a significant role in stimulus discrimination and learning, as simulated in a biophysical computer model of a basic neuronal circuit. Both the amplitude of the IPSP and LTP of the recurrent inhibitory circuit also undergo developmental changes showing their highest expression and vulnerability to chronic NMDA antagonist injections in juvenile rats. Finally, blocking NMDA receptor-dependent transmission in the recurrent inhibition loop may lead to an overall increased excitability of the neuronal network. This may resemble the positive schizophrenic symptoms observed in man, presumably caused by elevated levels of the endogenous NMDA antagonist NAAG.

scholarly journals NMDA receptor–BK channel coupling regulates synaptic plasticity in the barrel cortex

2021 ◽  
Vol 118 (35) ◽  
pp. e2107026118 ◽  
Author(s):  
Ricardo Gómez ◽  
Laura E. Maglio ◽  
Alberto J. Gonzalez-Hernandez ◽  
Belinda Rivero-Pérez ◽  
David Bartolomé-Martín ◽  
...  
Keyword(s):  
Synaptic Plasticity ◽  
Pyramidal Neurons ◽  
Barrel Cortex ◽  
Feedback Inhibition ◽  
Bk Channels ◽  
Bk Channel ◽  
Spike Timing ◽  
Ability To Act ◽  
Nmdar Activation ◽  
Molecular Context

Postsynaptic N-methyl-D-aspartate receptors (NMDARs) are crucial mediators of synaptic plasticity due to their ability to act as coincidence detectors of presynaptic and postsynaptic neuronal activity. However, NMDARs exist within the molecular context of a variety of postsynaptic signaling proteins, which can fine-tune their function. Here, we describe a form of NMDAR suppression by large-conductance Ca2+- and voltage-gated K+ (BK) channels in the basal dendrites of a subset of barrel cortex layer 5 pyramidal neurons. We show that NMDAR activation increases intracellular Ca2+ in the vicinity of BK channels, thus activating K+ efflux and strong negative feedback inhibition. We further show that neurons exhibiting such NMDAR–BK coupling serve as high-pass filters for incoming synaptic inputs, precluding the induction of spike timing–dependent plasticity. Together, these data suggest that NMDAR-localized BK channels regulate synaptic integration and provide input-specific synaptic diversity to a thalamocortical circuit.

scholarly journals TRPM4 Expression During Postnatal Developmental of Mouse CA1 Pyramidal Neurons

2021 ◽  
Vol 15 ◽  
Author(s):  
Denise Riquelme ◽  
Oscar Cerda ◽  
Elias Leiva-Salcedo
Keyword(s):  
Membrane Potential ◽  
Patch Clamp ◽  
Postnatal Development ◽  
Pyramidal Neurons ◽  
Brain Slices ◽  
Long Term Potentiation ◽  
Neuronal Firing ◽  
Resting Membrane Potential ◽  
Ca1 Pyramidal Neurons ◽  
Apical Dendrites

TRPM4 is a non-selective cation channel activated by intracellular calcium and permeable to monovalent cations. This channel participates in the control of neuronal firing, neuronal plasticity, and neuronal death. TRPM4 depolarizes dendritic spines and is critical for the induction of NMDA receptor-dependent long-term potentiation in CA1 pyramidal neurons. Despite its functional importance, no subcellular localization or expression during postnatal development has been described in this area. To examine the localization and expression of TRPM4, we performed duplex immunofluorescence and patch-clamp in brain slices at different postnatal ages in C57BL/6J mice. At P0 we found TRPM4 is expressed with a somatic pattern. At P7, P14, and P35, TRPM4 expression extended from the soma to the apical dendrites but was excluded from the axon initial segment. Patch-clamp recordings showed a TRPM4-like current active at the resting membrane potential from P0, which increased throughout the postnatal development. This current was dependent on intracellular Ca2+ (ICAN) and sensitive to 9-phenanthrol (9-Ph). Inhibiting TRPM4 with 9-Ph hyperpolarized the membrane potential at P14 and P35, with no effect in earlier stages. Together, these results show that TRPM4 is expressed in CA1 pyramidal neurons in the soma and apical dendrites and associated with a TRPM4-like current, which depolarizes the neurons. The expression, localization, and function of TRPM4 throughout postnatal development in the CA1 hippocampal may underlie an important mechanism of control of membrane potential and action potential firing during critical periods of neuronal development, particularly during the establishment of circuits.

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