Potentiation In Slices Research Articles

Positive Allosteric Modulators of SERCA Pump Restore Dendritic Spines and Rescue Long-Term Potentiation Defects in Alzheimer's Disease Mouse Model.

Alzheimer's disease (AD) is a neurodegenerative disorder that affects memory formation and storage processes. Dysregulated neuronal calcium (Ca2+) has been identified as one of the key pathogenic events in AD, and it has been suggested that pharmacological agents that stabilize Ca2+ neuronal signaling can act as disease-modifying agents in AD. In previous studies, we demonstrated that positive allosteric regulators (PAMs) of the sarco/endoplasmic reticulum Ca2+ ATPase (SERCA) pump might act as such Ca2+-stabilizing agents and exhibit neuroprotective properties. In the present study, we evaluated effects of a set of novel SERCA PAM agents on the rate of Ca2+ extraction from the cytoplasm of the HEK293T cell line, on morphometric parameters of dendritic spines of primary hippocampal neurons in normal conditions and in conditions of amyloid toxicity, and on long-term potentiation in slices derived from 5xFAD transgenic mice modeling AD. Several SERCA PAM compounds demonstrated neuroprotective properties, and the compound NDC-9009 showed the best results. The findings in this study support the hypothesis that the SERCA pump is a potential therapeutic target for AD treatment and that NDC-9009 is a promising lead molecule to be used in the development of disease-modifying agents for AD.

This Month in Anesthesiology

This Month in Anesthesiology

A glibenclamide-sensitive TRPM4-mediated component of CA1 excitatory postsynaptic potentials appears in experimental autoimmune encephalomyelitis

The transient receptor potential melastatin 4 (TRPM4) channel contributes to disease severity in the murine experimental autoimmune encephalomyelitis (EAE) model of multiple sclerosis and to neuronal cell death in models of excitotoxicity and traumatic brain injury. As TRPM4 is activated by intracellular calcium and conducts monovalent cations, we hypothesized that TRPM4 may contribute to and boost excitatory synaptic transmission in CA1 pyramidal neurons of the hippocampus. Using single-spine calcium imaging and electrophysiology, we found no effect of the TRPM4 antagonists 9-phenanthrol and glibenclamide on synaptic transmission in hippocampal slices from healthy mice. In contrast, glibenclamide but not 9-phenanthrol reduced excitatory synaptic potentials in slices from EAE mice, an effect that was absent in slices from EAE mice lacking TRPM4. We conclude that TRPM4 plays little role in basal hippocampal synaptic transmission, but a glibenclamide-sensitive TRPM4-mediated contribution to excitatory postsynaptic responses is upregulated at the acute phase of EAE.

Cntn4, a risk gene for neuropsychiatric disorders, modulates hippocampal synaptic plasticity and behavior

Neurodevelopmental and neuropsychiatric disorders, such as autism spectrum disorders (ASD), anorexia nervosa (AN), Alzheimer’s disease (AD), and schizophrenia (SZ), are heterogeneous brain disorders with unknown etiology. Genome wide studies have revealed a wide variety of risk genes for these disorders, indicating a biological link between genetic signaling pathways and brain pathology. A unique risk gene is Contactin 4 (Cntn4), an Ig cell adhesion molecule (IgCAM) gene, which has been associated with several neuropsychiatric disorders including ASD, AN, AD, and SZ. Here, we investigated the Cntn4 gene knockout (KO) mouse model to determine whether memory dysfunction and altered brain plasticity, common neuropsychiatric symptoms, are affected by Cntn4 genetic disruption. For that purpose, we tested if Cntn4 genetic disruption affects CA1 synaptic transmission and the ability to induce LTP in hippocampal slices. Stimulation in CA1 striatum radiatum significantly decreased synaptic potentiation in slices of Cntn4 KO mice. Neuroanatomical analyses showed abnormal dendritic arborization and spines of hippocampal CA1 neurons. Short- and long-term recognition memory, spatial memory, and fear conditioning responses were also assessed. These behavioral studies showed increased contextual fear conditioning in heterozygous and homozygous KO mice, quantified by a gene-dose dependent increase in freezing response. In comparison to wild-type mice, Cntn4-deficient animals froze significantly longer and groomed more, indicative of increased stress responsiveness under these test conditions. Our electrophysiological, neuro-anatomical, and behavioral results in Cntn4 KO mice suggest that Cntn4 has important functions related to fear memory possibly in association with the neuronal morphological and synaptic plasticity changes in hippocampus CA1 neurons.

D-Serine Signaling and NMDAR-Mediated Synaptic Plasticity Are Regulated by System A-Type of Glutamine/D-Serine Dual Transporters.

D-serine is a physiologic coagonist of NMDA receptors (NMDARs) required for synaptic plasticity, but mechanisms that terminate D-serine signaling are unclear. In particular, the identity of unidirectional plasma membrane transporters that mediate D-serine reuptake has remained elusive. We report that D-serine and glutamine share the same neuronal transport system, consisting of the classic system A transporters Slc38a1 and Slc38a2. We show that these transporters are not saturated with glutamine in vivo and regulate the extracellular levels of D-serine and NMDAR activity. Glutamine increased the NMDAR-dependent long-term potentiation and the isolated NMDAR potentials at the Schaffer collateral-CA1 synapses, but without affecting basal neurotransmission in male mice. Glutamine did not increase the NMDAR potentials in slices from serine racemase knock-out mice, which are devoid of D-serine, indicating that the effect of glutamine is caused by outcompeting D-serine for a dual glutamine-D-serine transport system. Inhibition of the system A reduced the uptake of D-serine in synaptosomes and neuronal cultures of mice of either sex, while increasing the extracellular D-serine concentration in slices and in vivo by microdialysis. When compared with Slc38a2, the Slc38a1 transporter displayed more favorable kinetics toward the D-enantiomer. Biochemical experiments with synaptosomes from Slc38a1 knock-down mice of either sex further support its role as a D-serine reuptake system. Our study identifies the first concentrative and electrogenic transporters mediating D-serine reuptake in vivo In addition to their classical role in the glutamine-glutamate cycle, system A transporters regulate the synaptic turnover of D-serine and its effects on NMDAR synaptic plasticity.SIGNIFICANCE STATEMENT Despite the plethora of roles attributed to D-serine, the regulation of its synaptic turnover is poorly understood. We identified the system A transporters Slc38a1 and Slc38a2 as the main pathway for neuronal reuptake of D-serine. These transporters are not saturated with glutamine in vivo and provide an unexpected link between the serine shuttle pathway, responsible for regulating D-serine synaptic turnover, and the glutamine-glutamate cycle. Our observations suggest that Slc38a1 and Slc38a2 have a dual role in regulating neurotransmission. In addition to their classical role as the glutamine providers, the system A transporters regulate extracellular D-serine and therefore affect NMDAR-dependent synaptic plasticity. Higher glutamine export from astrocytes would increase extracellular D-serine, providing a feedforward mechanism to increase synaptic NMDAR activation.

Fast, in vivo voltage imaging using a red fluorescent indicator.

Genetically encoded voltage indicators (GEVIs) are emerging optical tools for acquiring brain-wide cell-type-specific functional data at unparalleled temporal resolution. To broaden the application of GEVIs in high-speed multispectral imaging, we used a high-throughput strategy to develop voltage-activated red neuronal activity monitor (VARNAM), a fusion of the fast Acetabularia opsin and the bright red fluorophore mRuby3. Imageable under the modest illumination intensities required by bright green probes (<50 mW mm-2), VARNAM is readily usable in vivo. VARNAM can be combined with blue-shifted optical tools to enable cell-type-specific all-optical electrophysiology and dual-color spike imaging in acute brain slices and live Drosophila. With enhanced sensitivity to subthreshold voltages, VARNAM resolves postsynaptic potentials in slices and cortical and hippocampal rhythms in freely behaving mice. Together, VARNAM lends a new hue to the optical toolbox, opening the door to high-speed in vivo multispectral functional imaging.

Cardiac Arrest Induces Ischemic Long-Term Potentiation of Hippocampal CA1 Neurons That Occludes Physiological Long-Term Potentiation.

Ischemic long-term potentiation (iLTP) is a form of synaptic plasticity that occurs in acute brain slices following oxygen-glucose deprivation. In vitro, iLTP can occlude physiological LTP (pLTP) through saturation of plasticity mechanisms. We used our murine cardiac arrest and cardiopulmonary resuscitation (CA/CPR) model to produce global brain ischemia and assess whether iLTP is induced in vivo, contributing to the functionally relevant impairment of pLTP. Adult male mice were subjected to CA/CPR, and slice electrophysiology was performed in the hippocampal CA1 region 7 or 30 days later. We observed increased miniature excitatory postsynaptic current amplitudes, suggesting a potentiation of postsynaptic AMPA receptor function after CA/CPR. We also observed increased phosphorylated GluR1 in the postsynaptic density of hippocampi after CA/CPR. These data support the in vivo induction of ischemia-induced plasticity. Application of a low-frequency stimulus (LFS) to CA1 inputs reduced excitatory postsynaptic potentials in slices from mice subjected to CA/CPR, while having no effects in sham controls. These results are consistent with a reversal, or depotentiation, of iLTP. Further, depotentiation with LFS partially restored induction of pLTP with theta burst stimulation. These data provide evidence for iLTP following in vivo ischemia, which occludes pLTP and likely contributes to network disruptions that underlie memory impairments.

A sodium afterdepolarization in rat superior colliculus neurons and its contribution to population activity.

The mammalian superior colliculus (SC) is a midbrain structure that integrates multimodal sensory inputs and computes commands to initiate rapid eye movements. SC neurons burst with the sudden onset of a visual stimulus, followed by persistent activity that may underlie shifts of attention and decision making. Experiments in vitro suggest that circuit reverberations play a role in the burst activity in the SC, but the origin of persistent activity is unclear. In the present study we characterized an afterdepolarization (ADP) that follows action potentials in slices of rat SC. Population responses seen with voltage-sensitive dye imaging consisted of rapid spikes followed immediately by a second distinct depolarization of lower amplitude and longer duration. Patch-clamp recordings showed qualitatively similar behavior: in nearly all neurons throughout the SC, rapid spikes were followed by an ADP. Ionic and pharmacological manipulations along with experiments with current and voltage steps indicated that the ADP of SC neurons arises from Na(+) current that either persists or resurges following Na(+) channel inactivation at the end of an action potential. Comparisons of pharmacological properties and frequency dependence revealed a clear parallel between patch-clamp recordings and voltage imaging experiments, indicating a common underlying membrane mechanism for the ADP in both single neurons and populations. The ADP can initiate repetitive spiking at intervals consistent with the frequency of persistent activity in the SC. These results indicate that SC neurons have intrinsic membrane properties that can contribute to electrical activity that underlies shifts of attention and decision making.

Realistic simulations of local field potentials in a slice

The two key elements of realistic simulation of LFP are plausible model of neural activity, and the physical properties of the setup, tissue, and electrodes. To reduce the computational burden yet obtain a trustful rendering of LFP in specific experimental context different strategies have been tried. For instance, using total synaptic activity from a population of spiking neurons as a proxy for LFP, or hybrid strategies with network simulations of spiking neurons followed by computation of contributions to LFP from single cells driven by pre-calculated network dynamics. Tests of those strategies are impossible without ground-truth data including all the necessary components. Working towards a framework providing ground truth data for validating methods of analysis of extracellular potentials in cortical slices, we investigated how the use of increasingly detailed physical models of slice tissue affects the resulting model LFPs. Traub's model of thalamo-cortical loop [1] was simulated in NEURON and the extracellular potentials in uniform, homogeneous medium (Vhom) were computed post-hoc from tracked trans-membrane currents. To verify the need for inclusion of experimental setup context we modeled the field in the tissue and saline using finite-element approach (FEM) with FENICS package with mesh generated with gmsh. The slice (yellow parallelogram) was placed in a saline solution (Figure ​(Figure1A)1A) and the cortical column was put in the middle of the slice, and we computed the extracellular potentials it generated at the electrode plane under the slice. Figure 1 A. The mesh in the Petri dish with saline (cylinder), slice is the yellow bar. B. Average L1 norm of difference |k*Vhom - V| as a function of k where V is the potential on the electrode plane in the three cases i)-iii). We modeled 3 different conductivity profiles within the slice and the saline: i) 'no saline' case: slice and saline with the same conductivity of 0.3 mS/cm ii) 'hom+iso+saline': homogeneous and isotropic slice of conductivity 0.3 mS/cm, saline: 3.0 mS/cm iii) 'inhom+anis+saline': inhomogeneous and anisotropic slice with conductivity profiles for the layers taken as mean values from [2]. We see that the inclusion of slice setup noticeably modifies the observed activity as both the amplitude and shape of the potential profile is changed (Figure ​(Figure1B).1B). However, inclusion of inhomogeneity and anisotropy in the computations does not lead to substantial changes of the profile. Indeed, inaccurate estimation of conductivity (see variability of results in [2]) will in general introduce bigger errors than in assuming homogeneous and isotropic tissue.

Learning and reconsolidation implicate different synaptic mechanisms

Synaptic mechanisms underlying memory reconsolidation after retrieval are largely unknown. Here we report that synapses in projections to the lateral nucleus of the amygdala implicated in auditory fear conditioning, which are potentiated by learning, enter a labile state after memory reactivation, and must be restabilized through a postsynaptic mechanism implicating the mammalian target of rapamycin kinase-dependent signaling. Fear-conditioning-induced synaptic enhancements were primarily presynaptic in origin. Reconsolidation blockade with rapamycin, inhibiting mammalian target of rapamycin kinase activity, suppressed synaptic potentiation in slices from fear-conditioned rats. Surprisingly, this reduction of synaptic efficacy was mediated by post- but not presynaptic mechanisms. These findings suggest that different plasticity rules may apply to the processes underlying the acquisition of original fear memory and postreactivational stabilization of fear-conditioning-induced synaptic enhancements mediating fear memory reconsolidation.

The Inflammatory Chemokine CXCL10 Modulates Synaptic Plasticity and Neuronal Activity in the Hippocampus

Chemokines, a family member of cytokines, have been shown to play a major role in central nervous system inflammation. Among other chemokines, CXCR3 and its ligand CXCL10 are involved in the pathophysiology of several neuroinflammatory conditions. Most of these conditions are also associated with an increased incidence of seizure or epilepsy. Using age-matched wild-type (WT), as well as CXCR3-receptor-deficient (CXCR3-KO) mice, the present study aimed to investigate the effect of the chemokine CXCL10 and its receptor CXCR3 on synaptic plasticity as well as neuronal activities in hippocampal brain slices. Using field potential and intracellular recordings, the effect of exogenous CXCL10 on tetanus-induced long-term potentiation (LTP) as well as the neuronal spike activity was evaluated in hippocampal CA1 area. Exogenous application of CXCL10 enhanced LTP in WT mice, whereas it exerted no significant effect on CXCR3-KO mice. During intracellular recordings of spontaneous spike activity, exogenous application of CXCL10 significantly enhanced the amplitude, duration, and after-hyperpolarization of action potentials in slices obtained from WT mice compared to CXCR3-KO mice. In addition, CXCR3-KO mice exhibited a lower GABAA-mediated excitation in hippocampal CA1 neurons compared to WT mice. These data show that the inflammatory chemokine CXCL10, probably via its receptor CXCR3, modulates neuronal activity and synaptic plasticity in the hippocampus. CXCL10 may be involved in seizures observed during neuroinflammatory diseases such as meningitis and encephalitis.

RAGE and Alzheimer's Disease: A Progression Factor for Amyloid-β-Induced Cellular Perturbation?

Receptor for Advanced Glycation Endproducts (RAGE) is a multiligand member of the immunoglobulin superfamily of cell surface molecules which serves as a receptor for amyloid-beta peptide (Abeta) on neurons, microglia, astrocytes, and cells of vessel wall. Increased expression of RAGE is observed in regions of the brain affected by Alzheimer's disease (AD), and Abeta-RAGE interaction in vitro leads to cell stress with the generation of reactive oxygen species and activation of downstream signaling mechanisms including the MAP kinase pathway. RAGE-mediated activation of p38 MAP kinase in neurons causes Abeta-induced inhibition of long-term potentiation in slices of entorhinal cortex. Increased expression of RAGE in an Abeta-rich environment, using transgenic mouse models, accelerates and accentuates pathologic, biochemical, and behavioral abnormalities compared with mice overexpressing only mutant amyloid-beta protein precursor. Interception of Abeta interaction with RAGE, by infusion of soluble RAGE, decreases Abeta content and amyloid load, as well as improving learning/memory and synaptic function, in a murine transgenic model of Abeta accumulation. These data suggest that RAGE may be a therapeutic target for AD.

The behavioural and electrophysiological effects of CRF in rat frontal cortex

Corticotropin releasing factor (CRF) is a neuropeptide widely distributed in the brain. The role of CRF in the behavioural activity and modulation of anxiety states in several brain structures has been well documented, but its function in the cerebral cortex still remains unknown. The aim of our study was to investigate the effect of CRF injected bilaterally into rat frontal cortex on the locomotor and exploratory activity and anxiety of rats. We also examined the effect of CRF on extracellularly recorded field potentials in rat frontal cortical slices in vitro. Behavioural experiments showed that CRF in doses of 0.05, 0.1, 0.2 microg/1 microl/site decreased locomotor and exploratory activity during a 40-min session in the open field test. In the elevated plus-maze test, CRF in a dose of 0.2 microg/1 microl/site produced a significant anxiolytic-like effect, which was prevented by CRF receptor antagonists (alpha-helicalCRF(9-41) and NBI 27914). Electrophysiological experiments showed that CRF-induced a transient depression of field potentials in slices partly disinhibited by GABA(A) and GABA(B) receptors antagonists. The blockade of NMDA receptors prevented the occurrence of that effect. The obtained results suggest that CRF may have anxiolytic-like effects in the frontal cortex. Moreover, the peptide inhibits locomotor and exploratory activity and depresses excitatory synaptic transmission in a NMDA receptor-dependent manner.

Is the Selective Serotonin Reuptake Inhibitor Fluoxetine a Fountain of Youth?

Evaluation of: Maya Vetencourt JF, Sale A, Viegi A et al.: The antidepressant fluoxetine restores plasticity in the adult visual cortex. Science 320, 385–288 (2008). The potential for synaptic strength to be regulated by experience is high early in postnatal life, and declines thereafter. The constraint of synaptic plasticity in the adult visual system is thought to underlie the resistance to therapy for the treatment of amblyopia. However, a recent report by Maya Vetencourt et al. demonstrates that systemic administration of the popular antidepressant fluoxetine reactivates synaptic plasticity in the visual system of adult rats, and enables the recovery of function in an eye chronically deprived of vision. Fluoxetine administration stimulated a decrease in basal levels of extracellular GABA, an increase in the level of BDNF and the return of long-term potentiation in slices of visual cortex. The ability to reactivate robust synaptic plasticity in the adult mammalian visual system has clear therapeutic potential for the treatment of amblyopia in adults.

An Essential Role for PICK1 in NMDA Receptor-Dependent Bidirectional Synaptic Plasticity

PICK1 is a calcium-sensing, PDZ domain-containing protein that interacts with GluR2 and GluR3 AMPA receptor (AMPAR) subunits and regulates their trafficking. Although PICK1 has been principally implicated in long-term depression (LTD), PICK1 overexpression in CA1 pyramidal neurons causes a CaMK- and PKC-dependent potentiation of AMPAR-mediated transmission and an increase in synaptic GluR2-lacking AMPARs, mechanisms associated with NMDA receptor (NMDAR)-dependent long-term potentiation (LTP). Here, we directly tested whether PICK1 participates in both hippocampal NMDAR-dependent LTP and LTD. We show that the PICK1 potentiation of AMPAR-mediated transmission is NMDAR dependent and fully occludes LTP. Conversely, blockade of PICK1 PDZ interactions or lack of PICK1 prevents LTP. These observations demonstrate an important role for PICK1 in LTP. In addition, deletion of PICK1 or blockade of PICK1 PDZ binding prevented NMDAR-dependent LTD. Thus, PICK1 plays a critical role in bidirectional NMDAR-dependent long-term synaptic plasticity in the hippocampus.

Dynamics of the readily releasable pool during post‐tetanic potentiation in the rat calyx of Held synapse

The size of the readily releasable pool (RRP) of vesicles was measured in control conditions and during post-tetanic potentiation (PTP) in a large glutamatergic terminal called the calyx of Held. We measured excitatory postsynaptic currents evoked by a high frequency train of action potentials in slices of 4-11-day-old rats. After a tetanus the cumulative release during such a train was enlarged by approximately 50%, indicating that the size of the RRP was increased. The amount of enhancement depended on the duration and frequency of the tetanus and on the age of the rat. After the tetanus, the size of the RRP decayed more slowly (t(1/2)=10 versus 3 min) back to control values than the release probability. This difference was mainly due to a very fast initial decay of the release probability, which had a time constant compatible with an augmentation phase (tau approximately 30 s). The overall decay of PTP at physiological temperature was not different from room temperature, but the increase in release probability (P(r)) was restricted to the first minute after the tetanus. Thereafter PTP was dominated by an increase in the size of the RRP. We conclude that due to the short lifetime of the increase in release probability, the contribution of the increase in RRP size during post-tetanic potentiation is more significant at physiological temperature.

Effect of hypobaric hypoxia on the development of long-term posttetanic potentiation in slices of rat olfactory cortex: Correction with hypoxic preconditioning

We studied the effect of in vivo hypobaric hypoxia on the development (after 3 h) of in vitro long-term posttetanic potentiation in Wistar rats. Severe hypoxia suppressed induction of posttetanic potentiation in slices of the olfactory cortex. Preconditioning exposure (moderate hypobaric hypoxia) prevented inhibition of posttetanic potentiation induced by severe hypoxia.

Temperature modifies potentiation but not depotentiation in bidirectional hippocampal plasticity of Syrian hamsters ( Mesocricetus auratus)

Previous studies have shown that one form of neuroplasticity, population spike (PS) potentiation, can be established in the hamster hippocampus at temperatures above 20 °C. Here, we tested three related hypotheses; namely, that in Syrian hamsters: (1) PS potentiation can be elicited below 20 °C and that at any constant temperature, potentiation can be described by a pair of sigmoidal functions matched to input/output curves; (2) potentiation can be partially reversed by depotentiation (a second and distinctive form of neuroplasticity); and (3) tetanus evokes long-term potentiation in slices from animals housed under conditions corresponding to various stages of the annual hibernation cycle. To test these hypotheses, we measured PS amplitudes and fEPSP slopes in CA1 pyramidal cells in hippocampal slices. We found that sigmoidal functions before and after tetanus showed PS enhancement at 18 °C and a larger enhancement at 28 °C, thereby supporting hypothesis 1. We also found that low-frequency stimulation reduced the amplitude of the potentiated PS by ∼29% at both 18 °C and 28 °C, consistent with hypothesis 2; and that slices from nonhibernating hamsters on long and short photoperiods and from hamsters in hibernation all showed at least 40% increases in fEPSP slope following tetanus at a slice temperature of 23 °C, supporting hypothesis 3. Thus, bidirectional plasticity is present in hamsters. That is, both potentiation and depotentiation were readily evoked at 28 °C; potentiation was muted, while depotentiation (the reversal of the potentiation) remained robust at 18 °C. Moreover, potentiated responses could be elicited in slices from animals housed under diverse conditions.

Two-Deoxyglucose-Induced Long-Term Potentiation in Slices of Rat Dentrate Gyrus

In keeping with previous observations in the CA1 and the somatosensory neocortex of the brain of rat, 20-min applications of 2-deoxy-D-glucose (2DG; 10 mM, replacing glucose) induced a long-term potentiation (LTP)-like enhancement of field excitatory synaptic potentials (fEPSPs) in the dentate region of hippocampal slices. The effects of 2DG were not identical at synapses of medial and lateral perforant paths (MPP and LPP). At MPP synapses, there was no post-2DG early depression of fEPSPs and the potentiation reached +78.6 +/- 5.7 % (+/- standard error of the mean) 40 min after the return to glucose. In the presence of 50 microM D-amino-phosphono valerate (APV; an N-methyl-D-aspartate [NMDA] receptor antagonist), a marked post-2DG depression appeared and the subsequent LTP was reduced to +34.7 +/- 2.8 % (for both 2DG- and APV-treatment P<0.001 by ANOVA-2W). At LPP synapses, even under control conditions, there was a sharp post-2DG depression followed by LTP (+62.2 +/- 5.7 %) and APV had little effect on either the post-2DG depression or LTP, reducing the latter by only 24 % [the 2DG treatment was very significant (P<0.001) but not the APV treatment]. Thus, 2DG evokes both NMDAR-dependent and -independent components of LTP in the perforant pathways. In view of these findings, the consumption of 2DG could have significant effects on synaptic plasticity and cognitive function.

Ca3 neuronal activities of dorsal and ventral hippocampus are differentially altered in rats after prolonged post-ischemic survival

The aim of the present study is to explore the potential hyper-excitability of hippocampal CA3 neurons in rats after prolonged post-ischemic survival. We conducted 15-min four-vessel-occlusion ischemic episodes in rats, allowed these animals to survive for approximately 8 months and then examined the basic morphological features and population synaptic activities of CA3 neurons. In fixed tissue sections obtained from dorsal hippocampi of post-ischemic rats, we observed a complete loss of the CA1 neurons together with a shrunken CA1 sector. Extracellular recordings in slices revealed that the overall synaptic activities of dorsal hippocampal CA3 neurons were decreased in post-ischemic rats compared with sham-operated controls. Both sham control and post-ischemic ventral hippocampal neurons were capable of exhibiting intermittent spontaneous field potentials in slices. These spontaneous field potentials spread from the CA3 to the CA1 area and their generation relied on the activity of glutamate alpha-amino-3-hydroxy-5-methyl-4 isoxazole proprionic acid (AMPA) receptors. The propensity for displaying these spontaneous field potentials appeared to be greater in post-ischemic slices than sham control slices. Our data suggest that the hyper-excitability of the post-ischemic hippocampus, if it occurs, may preferentially take place in the ventral CA3 circuitry.