Ethanol Alters the Frequency, Amplitude, and Decay Kinetics of Sr2+-Supported, Asynchronous NMDAR mEPSCs in Rat Hippocampal Slices

2004 ◽  
Vol 91 (6) ◽  
pp. 2568-2577 ◽  
Author(s):  
Adam W. Hendricson ◽  
John R. Sibbald ◽  
Richard A. Morrisett
Keyword(s):  
Pyramidal Neurons ◽  
Hippocampal Slices ◽  
Mean Amplitude ◽  
Long Term Potentiation ◽  
Exponential Fitting ◽  
Decay Kinetics ◽  
Current Decay ◽  
Event Frequency

To discriminate between pre- and postsynaptic effects of ethanol on N-methyl-d-aspartate receptor (NMDAR) signaling in hippocampus, we adapted the technique of Sr2+ substitution to the hippocampal blind slice patch-clamp preparation. Hippocampal slices were isolated from 12- to 20-day-old rats that were killed in accordance with University of Texas Institutional Animal Care and Use Committee guidelines. NMDAR miniature excitatory postsynaptic currents (mEPSCs) were evoked from CA1 pyramidal neurons in the presence of Sr2+ (4 mM), causing the synchronous EPSC observed in the presence of Ca2+ to be supplanted by asynchronous mEPSCs. Amplitudes typically ranged from 5 to 40 pA and responded to the NMDAR antagonist (DL)-APV (50 μM), with a statistically significant reduction in mean amplitude. Ethanol (25, 50, and 75 mM) exerted dose-dependent effects on mEPSC amplitude and frequency. Peak amplitude inhibition was observed at 75 mM ethanol. Notably, ethanol significantly decreased event frequency at 50 and 75 mM ethanol. Ethanol (75 mM) also significantly increased the paired-pulse ratio of NMDAR EPSCs. Cumulative comparisons of decay time constants derived from single-exponential fitting of mEPSCs revealed significantly accelerated current decay kinetics in the presence of 75 mM ethanol. Taken together, these reductions in miniature event frequency and amplitude, concurrent with an increased rate of decay, suggest that the acute effects of ethanol on NMDAR signaling at hippocampal synapses are multifocal in nature. This finding of pre- and postsynaptic effects of ethanol on NMDAR signal strength in a brain region central to cognition is wholly consistent with previous reports of ethanol inhibition of NMDAR–long-term potentiation in vitro and with the profound cognitive deficits associated with binge-level intoxication in vivo.

scholarly journals Preconditioning In Vivo Ischemia Inhibits Anoxic Long-Term Potentiation and Functionally Protects CA1 Neurons in the Gerbil

1998 ◽  
Vol 18 (3) ◽  
pp. 288-296 ◽  
Author(s):  
Kensuke Kawai ◽  
Tadayoshi Nakagomi ◽  
Takaaki Kirino ◽  
Akira Tamura ◽  
Nobufumi Kawai
Keyword(s):  
Nmda Receptor ◽  
Pyramidal Neurons ◽  
Hippocampal Slices ◽  
Long Term Potentiation ◽  
Forebrain Ischemia ◽  
Term Potentiation ◽  
Induced Tolerance

Preconditioning with sublethal ischemia induces tolerance to subsequent lethal ischemia in neurons. We investigated electrophysiologic aspects of the ischemic tolerance phenomenon in the gerbil hippocampus. Gerbils were subjected to 2 minutes of forebrain ischemia (preconditioning ischemia). Some of them were subjected to a subsequent 5 minutes of forebrain ischemia 2 to 3 days after the preconditioning ischemia (double ischemia). Hippocampal slices were prepared from these gerbils subjected to the preconditioning or double ischemia, and field excitatory postsynaptic potentials were recorded from CA1 pyramidal neurons. Capacity for long-term potentiation triggered by tetanic stimulation (tetanic LTP) was transiently inhibited 1 to 2 days after the double ischemia but then recovered. Latency of anoxic depolarization was not significantly different between slices from preconditioned gerbils and those from sham-operated gerbils when these slices were subjected to in vitro anoxia. Postanoxic potentiation of N-methyl-D-aspartate (NMDA) receptor-mediated transmission (anoxic LTP) was inhibited in slices from gerbils 2 to 3 days after the preconditioning ischemia, whereas it was observed in slices from sham-operated gerbils and gerbils 9 days after the preconditioning ischemia. These results suggest that protection by induced tolerance is (1) not only morphologic but also functional, and (2) expressed in inhibiting postischemic overactivation of NMDA receptor-mediated synaptic responses.

scholarly journals Enhanced Neuronal Damage After Ischemic Insults in Mice Lacking Kir6.2-Containing ATP-Sensitive K+ Channels

2006 ◽  
Vol 95 (4) ◽  
pp. 2590-2601 ◽  
Author(s):  
Hong-Shuo Sun ◽  
Zhong-Ping Feng ◽  
Takashi Miki ◽  
Susumu Seino ◽  
Robert J. French
Keyword(s):  
Hippocampal Neurons ◽  
Pyramidal Neurons ◽  
Neuronal Damage ◽  
Focal Cerebral Ischemia ◽  
Hippocampal Slices ◽  
Immunocytochemical Staining ◽  
Sulfonylurea Receptor ◽  
Ca1 Pyramidal Neurons

Adenosine triphosphate (ATP)–sensitive potassium (KATP) channels, incorporating Kir6.x and sulfonylurea receptor subunits, are weak inward rectifiers that are thought to play a role in neuronal protection from ischemic insults. However, the involvement of Kir6.2-containing KATP channel in hippocampus and neocortex has not been tested directly. To delineate the physiological roles of Kir6.2 channels in the CNS, we used knockout (KO) mice that do not express Kir6.2. Immunocytochemical staining demonstrated that Kir6.2 protein was expressed robustly in hippocampal neurons of the wild-type (WT) mice and absent in the KO. To examine neuronal sensitivity to metabolic stress in vitro, and to ischemia in vivo, we 1) exposed hippocampal slices to transient oxygen and glucose deprivation (OGD) and 2) produced focal cerebral ischemia by middle cerebral artery occlusion (MCAO). Both slice and whole animal studies showed that neurons from the KO mice were severely damaged after anoxia or ischemia, whereas few injured neurons were observed in the WT, suggesting that Kir6.2 channels are necessary to protect neurons from ischemic insults. Membrane potential recordings from the WT CA1 pyramidal neurons showed a biphasic response to OGD; a brief hyperpolarization was followed by a small depolarization during OGD, with complete recovery within 30 min after returning to normoxic conditions. By contrast, CA1 pyramidal neurons from the KO mice were irreversibly depolarized by OGD exposure, without any preceding hyperpolarization. These data suggest that expression of Kir6.2 channels prevents prolonged depolarization of neurons resulting from acute hypoxic or ischemic insults, and thus protects these central neurons from the injury.

Background Activity Regulates Excitability of Rat Hippocampal CA1 Pyramidal Neurons by Adaptation of a K+ Conductance

2006 ◽  
Vol 95 (3) ◽  
pp. 2007-2012 ◽  
Author(s):  
Ingrid van Welie ◽  
Johannes A. van Hooft ◽  
Wytse J. Wadman
Keyword(s):  
Neuronal Excitability ◽  
Pyramidal Neurons ◽  
Dynamic Range ◽  
Background Activity ◽  
Hippocampal Slices ◽  
Synaptic Activity ◽  
Input Output ◽  
Ca1 Pyramidal Neurons

In the in vivo brain background synaptic activity has a strong modulatory influence on neuronal excitability. Here we report that in rat hippocampal slices, blockade of endogenous in vitro background activity results in an increased excitability of CA1 pyramidal neurons within tens of minutes. The increase in excitability constitutes a leftward shift in the input–output relationship of pyramidal neurons, indicating a reduced threshold for the induction of action potentials. The increase in excitability results from an adaptive decrease in a sustained K+ conductance, as recorded from somatic cell–attached patches. After 20 min of blockade of background activity, the mean sustained K+ current amplitude in somatic patches was reduced to 46 ± 9% of that in time-matched control patches. Blockade of background activity did not affect fast Na+ conductance. Together, these results suggests that the reduction in K+ conductance serves as an adaptive mechanism to increase the excitability of CA1 pyramidal neurons in response to changes in background activity such that the dynamic range of the input–output relationship is effectively maintained.

Distinct synaptic loci of Ca2+/calmodulin-dependent protein kinase II necessary for long-term potentiation and depression

1996 ◽  
Vol 76 (3) ◽  
pp. 2097-2101 ◽  
Author(s):  
P. K. Stanton ◽  
A. T. Gage
Keyword(s):  
Pyramidal Neurons ◽  
De Novo ◽  
Hippocampal Slices ◽  
Low Frequency ◽  
Long Term Potentiation ◽  
Term Potentiation ◽  
Bath Application ◽  
Dependent Protein

1. Extracellular bath application of the selective Ca2+/calmodulin-dependent kinase II (CaMKII) inhibitor KN-62 to hippocampal slices in vitro blocked the induction of long-term depression (LTD) by low-frequency Schaffer collateral stimulation (1 Hz/15 min) of the same concentration as has been shown previously to prevent induction of long-term potentiation (LTP) at these synapses. 2. In contrast, postsynaptic intracellular infusion of KN-62 into single CA1 pyramidal neurons did not prevent induction of LTD, although it was quite effective in blocking LTP. 3. We conclude that there is a presynaptic CaMKII that must be activated to induce LTD, whereas postsynaptic CaMKII stimulation is needed to evoke LTP. 4. Bath application of KN-62 also blocked depotentiation by low-frequency stimuli of previously induced LTP, suggesting that induction of depotentiation and de novo LTD may require the same CaMKII-dependent mechanisms.

scholarly journals In vivo and in vitro analyses of amygdalar function reveal a role for copper

2014 ◽  
Vol 111 (10) ◽  
pp. 1927-1939 ◽  
Author(s):  
E. D. Gaier ◽  
R. M. Rodriguiz ◽  
J. Zhou ◽  
M. Ralle ◽  
W. C. Wetsel ◽  
...  
Keyword(s):  
Fear Conditioning ◽  
Secretory Pathway ◽  
Pyramidal Neurons ◽  
Physiological Role ◽  
Long Term Potentiation ◽  
Single Copy ◽  
Inhibitory Effect ◽  
Wild Type

Mice with a single copy of the peptide amidating monooxygenase ( Pam) gene (PAM+/−) are impaired in contextual and cued fear conditioning. These abnormalities coincide with deficient long-term potentiation (LTP) at excitatory thalamic afferent synapses onto pyramidal neurons in the lateral amygdala. Slice recordings from PAM+/− mice identified an increase in GABAergic tone (Gaier ED, Rodriguiz RM, Ma XM, Sivaramakrishnan S, Bousquet-Moore D, Wetsel WC, Eipper BA, Mains RE. J Neurosci 30: 13656–13669, 2010). Biochemical data indicate a tissue-specific deficit in Cu content in the amygdala; amygdalar expression of Atox-1 and Atp7a, essential for transport of Cu into the secretory pathway, is reduced in PAM+/− mice. When PAM+/− mice were fed a diet supplemented with Cu, the impairments in fear conditioning were reversed, and LTP was normalized in amygdala slice recordings. A role for endogenous Cu in amygdalar LTP was established by the inhibitory effect of a brief incubation of wild-type slices with bathocuproine disulfonate, a highly selective, cell-impermeant Cu chelator. Interestingly, bath-applied CuSO4 had no effect on excitatory currents but reversibly potentiated the disynaptic inhibitory current. Bath-applied CuSO4 was sufficient to potentiate wild-type amygdala afferent synapses. The ability of dietary Cu to affect signaling in pathways that govern fear-based behaviors supports an essential physiological role for Cu in amygdalar function at both the synaptic and behavioral levels. This work is relevant to neurological and psychiatric disorders in which disturbed Cu homeostasis could contribute to altered synaptic transmission, including Wilson's, Menkes, Alzheimer's, and prion-related diseases.

scholarly journals Protein kinase D promotes plasticity-induced F-actin stabilization in dendritic spines and regulates memory formation

2015 ◽  
Vol 210 (5) ◽  
pp. 771-783 ◽  
Author(s):  
Norbert Bencsik ◽  
Zsófia Szíber ◽  
Hanna Liliom ◽  
Krisztián Tárnok ◽  
Sándor Borbély ◽  
...  
Keyword(s):  
Synaptic Plasticity ◽  
Protein Kinase ◽  
Dendritic Spines ◽  
Morphological Changes ◽  
Long Term Potentiation ◽  
Memory Formation ◽  
Protein Kinase D

Actin turnover in dendritic spines influences spine development, morphology, and plasticity, with functional consequences on learning and memory formation. In nonneuronal cells, protein kinase D (PKD) has an important role in stabilizing F-actin via multiple molecular pathways. Using in vitro models of neuronal plasticity, such as glycine-induced chemical long-term potentiation (LTP), known to evoke synaptic plasticity, or long-term depolarization block by KCl, leading to homeostatic morphological changes, we show that actin stabilization needed for the enlargement of dendritic spines is dependent on PKD activity. Consequently, impaired PKD functions attenuate activity-dependent changes in hippocampal dendritic spines, including LTP formation, cause morphological alterations in vivo, and have deleterious consequences on spatial memory formation. We thus provide compelling evidence that PKD controls synaptic plasticity and learning by regulating actin stability in dendritic spines.

Effect of Common Anesthetics on Dendritic Properties in Layer 5 Neocortical Pyramidal Neurons

2008 ◽  
Vol 99 (3) ◽  
pp. 1394-1407 ◽  
Author(s):  
Sarah Potez ◽  
Matthew E. Larkum
Keyword(s):  
High Frequency ◽  
Pyramidal Neurons ◽  
Animal Experiments ◽  
Apical Dendrite ◽  
Network Activity ◽  
Calcium Spikes ◽  
Firing Properties ◽  
The Impact

Understanding the impact of active dendritic properties on network activity in vivo has so far been restricted to studies in anesthetized animals. However, to date no study has been made to determine the direct effect of the anesthetics themselves on dendritic properties. Here, we investigated the effects of three types of anesthetics commonly used for animal experiments (urethane, pentobarbital and ketamine/xylazine). We investigated the generation of calcium spikes, the propagation of action potentials (APs) along the apical dendrite and the somatic firing properties in the presence of anesthetics in vitro using dual somatodendritic whole cell recordings. Calcium spikes were evoked with dendritic current injection and high-frequency trains of APs at the soma. Surprisingly, we found that the direct actions of anesthetics on calcium spikes were very different. Two anesthetics (urethane and pentobarbital) suppressed dendritic calcium spikes in vitro, whereas a mixture of ketamine and xylazine enhanced them. Propagation of spikes along the dendrite was not significantly affected by any of the anesthetics but there were various changes in somatic firing properties that were highly dependent on the anesthetic. Last, we examined the effects of anesthetics on calcium spike initiation and duration in vivo using high-frequency trains of APs generated at the cell body. We found the same anesthetic-dependent direct effects in addition to an overall reduction in dendritic excitability in anesthetized rats with all three anesthetics compared with the slice preparation.

Neuroprotective properties of mitochondria-targeted antioxidants of the SkQ-type

2016 ◽  
Vol 27 (8) ◽  
pp. 849-855 ◽  
Author(s):  
Nickolay K. Isaev ◽  
Elena V. Stelmashook ◽  
Elisaveta E. Genrikhs ◽  
Galina A. Korshunova ◽  
Natalya V. Sumbatyan ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Brain Area ◽  
Hippocampal Slices ◽  
Amyloid Β ◽  
Long Term Potentiation ◽  
Term Potentiation ◽  
Neuroprotective Action

AbstractIn 2008, using a model of compression brain ischemia, we presented the first evidence that mitochondria-targeted antioxidants of the SkQ family, i.e. SkQR1 [10-(6′-plastoquinonyl)decylrhodamine], have a neuroprotective action. It was shown that intraperitoneal injections of SkQR1 (0.5–1 μmol/kg) 1 day before ischemia significantly decreased the damaged brain area. Later, we studied in more detail the anti-ischemic action of this antioxidant in a model of experimental focal ischemia provoked by unilateral intravascular occlusion of the middle cerebral artery. The neuroprotective action of SkQ family compounds (SkQR1, SkQ1, SkQTR1, SkQT1) was manifested through the decrease in trauma-induced neurological deficit in animals and prevention of amyloid-β-induced impairment of long-term potentiation in rat hippocampal slices. At present, most neurophysiologists suppose that long-term potentiation underlies cellular mechanisms of memory and learning. They consider inhibition of this process by amyloid-β1-42as anin vitromodel of memory disturbance in Alzheimer’s disease. Further development of the above studies revealed that mitochondria-targeted antioxidants could retard accumulation of hyperphosphorylated τ-protein, as well as amyloid-β1-42, and its precursor APP in the brain, which are involved in developing neurodegenerative processes in Alzheimer’s disease.

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