Changes In Synaptic Plasticity Research Articles

MR imaging central thalamic deep brain stimulation restored autistic-like social deficits in the rat

BackgroundSocial deficit is a core symptom in autism spectrum disorder (ASD). Although deep brain stimulation (DBS) has been proposed as a potential treatment for ASD, an ideal target nucleus is yet to be identified. DBS at the central thalamic nucleus (CTN) is known to alter corticostriatal and limbic circuits, and subsequently increase the exploratory motor behaviors, cognitive performance, and skill learning in neuropsychiatric and neurodegenerative disorders. ObjectiveWe first investigated the ability of CTN-DBS to selectively engage distinct brain circuits and compared the spatial distribution of evoked network activity and modulation. Second, we investigated whether CTN-DBS intervention improves social interaction in a valproic acid–exposed ASD rat offspring model. MethodsBrain regions activated through CTN-DBS by using a magnetic resonance (MR)-compatible neural probe, which is capable of inducing site-selective microstimulations during functional MRI (fMRI), were investigated. We then performed functional connectivity MRI, the three-chamber social interaction test, and Western blotting analyses to evaluate the therapeutic efficacy of CTN-DBS in an ASD rat offspring model. ResultsThe DBS-evoked fMRI results indicated that the activated brain regions were mainly located in cortical areas, limbic-related areas, and the dorsal striatum. We observed restoration of brain functional connectivity (FC) in corticostriatal and corticolimbic circuits after CTN-DBS, accompanied with increased social interaction and decreased social avoidance in the three-chamber social interaction test. The dopamine D2 receptor decreased significantly after CTN-DBS treatment, suggesting changes in synaptic plasticity and alterations in the brain circuits. ConclusionsApplying CTN-DBS to ASD rat offspring increased FC and altered the synaptic plasticity in the corticolimbic and the corticostriatal circuits. This suggests that CTN-DBS could be an effective treatment for improving the social behaviors of individuals with ASD.

Subchronic cerebrolysin treatment alleviates cognitive impairments and dendritic arborization alterations of granular neurons in the hippocampal dentate gyrus of rats with temporal lobe epilepsy

Temporal lobe epilepsy (TLE) is one of the most frequent forms of focal epilepsy; patients with this condition, in addition to exhibiting complex seizures, also exhibit cognitive deficits. In the temporal lobe, the hippocampus, a structure relevant to learning and memory processes, is particularly affected by epilepsy. In animal models of TLE induced by pilocarpine, learning and memory deficiencies associated with changes in synaptic plasticity of the hippocampus have been reported. Cerebrolysin (CBL) is a biologically active mixture of low molecular weight peptides with neuroprotective and neurotrophic effects. The objective of the present study was to determine whether subchronic CBL treatment of rats in the chronic phase of TLE reduces the number and intensity of seizures, and whether CBL treatment can improve cognitive deficits (learning and spatial memory) and dendritic morphology in granular dentate neurons of the hippocampus. Temporal lobe epilepsy (lithium–pilocarpine model) was induced in male Wistar rats (weight, 250–300 g). Two epileptic groups were studied, in which CBL (538 mg/kg) or vehicle was administered intraperitoneally for 5 consecutive days per week for 3 weeks. Respective controls were also included in the study. At the end of treatment, the Barnes maze test (BMT) was used to assess spatial navigational learning and memory. The dendritic morphology of the dentate gyrus was also evaluated using the Golgi–Cox staining method. Results of this study did not support an antiepileptic effect of CBL. Epileptic animals treated with this agent exhibited secondarily generalized seizures similar in frequency and intensity to those of epileptic animals treated only with vehicle. However, when analyzing dendritic morphology of hippocampal granular neurons in these animals, CBL appeared to attenuate dendritic deterioration caused by epilepsy, which was associated with improved cognitive performance of the CBL-treated animals in the BMT compared with vehicle-treated epileptic rats. In conclusion, although CBL did not exert an anticonvulsant effect against secondarily generalized seizures, it can be proposed for use as an add-on therapy in epilepsy management to prevent neuronal alterations, and to improve memory and learning processes.

Inverted U-shaped response of a standardized extract of Centella asiatica (ECa 233) on memory enhancement

The herb Centella asiatica has long been considered a memory tonic. A recent review found no strong evidence for improvement of cognitive function, suggesting negative results were due to limitations in dose, standardization and product variation. We used a standardized extract of C. asiatica (ECa 233) to study behavioral, cellular and molecular effects on learning and memory enhancement. ECa 233 (10, 30, and 100 mg/kg) was given orally to normal rats twice a day for 30 days. We used the Morris water maze to test spatial learning and performed acute brain slice recording to measure changes of synaptic plasticity in the hippocampus, a core brain region for memory formation. Plasticity-related protein expressions (NR2A, NR2B, PSD-95, BDNF and TrkB) in hippocampus was also measured. Rats receiving 10 and 30 mg/kg doses showed significantly enhanced memory retention, and hippocampal long-term potentiation; however, only the 30 mg/kg dose showed increased plasticity-related proteins. There was an inverted U-shaped response of ECa 233 on memory enhancement; 30 mg/kg maximally enhanced memory retention with an increase of synaptic plasticity and plasticity-related proteins in hippocampus. Our data clearly support the beneficial effect on memory retention of a standardized extract of Centella asiatica within a specific therapeutic range.

Proteomic analysis of male rat nucleus accumbens, dorsal hippocampus and amygdala on conditioned place aversion induced by morphine withdrawal

Addiction is characterized by compulsive drug seeking and taking behavior, which is thought to result from persistent neuroadaptations, encoded by changes of gene expression. We previously demonstrated that the changes in synaptic plasticity were required for the formation of aversive memories associated with morphine withdrawal. However, the proteins involved in synaptic plasticity and aversive memory formation have not been well explored. In the present study, we employed a two-dimensional gel electrophoresis (2-DE)-based proteomic technique to detect the changes of protein expression in the nucleus accumbens, amygdala and dorsal hippocampus of the rats that had developed conditioned morphine withdrawal. We found that twenty-three proteins were significantly altered in the amygdala and dorsal hippocampus after conditioned morphine withdrawal. These proteins can be classified into multiple categories, such as energy metabolism, signal transduction, synaptic transmission, cytoskeletal proteins, chaperones, and protein metabolism according to their biological functions. Eight proteins related to synaptic plasticity were further confirmed by western blot analysis. It is very likely that these identified proteins may contribute to conditioned morphine withdrawal-induced neural plasticity and aversive memory formation. Thus, our work will help understand the potential mechanism associated with generation of drug withdrawal memories.

High-Voltage-Activated Calcium Channel in the Afferent Pain Pathway: An Important Target of Pain Therapies.

High-voltage-activated (HVA) Ca2+ channels are widely expressed in the nervous system. They play an important role in pain conduction by participating in various physiological processes such as synaptic transmission, changes in synaptic plasticity, and neuronal excitability. Available evidence suggests that the HVA channel is an important therapeutic target for pain management. In this review, we summarize the changes in different subtypes of HVA channel during pain and present the currently available evidence from the clinical application of HVA channel blockers. We also review novel drugs in various phases of development. Moreover, we discuss the future prospects of HVA channel blockers in order to promote "bench-to-bedside" translation.

Developmental Easing of Short-Term Depression in “Winner” Climbing Fibers

The postnatal development of cerebellar climbing fiber (CF) to Purkinje neuron (PN) synapses is characterized by a substantial pruning during the first 3 weeks after birth, switching from multiple- to single-CF innervation. Previous studies suggested that CF maturation is governed by bidirectional changes of synaptic plasticity. The strengthening of surviving “winner” CFs, which translocate from the PN soma to the dendrite, is thought to be guided by long-term potentiation (LTP), while weakening of to-be-eliminated “loser” CFs, which remain on the soma, was proposed to be due to long-term depression (LTD). However, there are conflicting results from previous studies, whether or not strengthening of winner and weakening of loser CFs during postnatal development is accompanied by changes in short-term plasticity and, thus, whether pre- or postsynaptic forms of LTD and LTP are operational. We, therefore, analyzed the developmental profile of paired-pulse depression (PPD) in “weak” and “strong” CFs in 3–21-day old Igsf9-eGFP mice, which allow visual identification of GFP-labeled CFs. We found that in 3–8-day old mice strong CFs are marked by a stronger PPD compared to weak CFs. Surprisingly, PPD of strong CFs eases during maturation, while PPD in weak CFs remains unchanged. This easing of PPD is neither due to changes in presynaptic influx-release coupling nor to an increased saturation of postsynaptic receptors. Thus, our results imply that synaptic contacts of CFs show distinct features of PPD depending on their affiliation to winner or loser CFs and depending on their somatic or dendritic location.

The ELAV family of RNA-binding proteins in synaptic plasticity and long-term memory.

The mechanisms of de novo gene expression and translation of specific gene transcripts have long been known to support long-lasting changes in synaptic plasticity and behavioral long-term memory. In recent years, it has become increasingly apparent that gene expression is heavily regulated not only on the level of transcription, but also through post-transcriptional gene regulation, which governs the subcellular localization, stability, and likelihood of translation of mRNAs. Specific families of RNA-binding proteins (RBPs) bind transcripts which contain AU-rich elements (AREs) within their 3' UTR and thereby govern their downstream fate. These post-transcriptional gene regulatory mechanisms are coordinated through the same cell signaling pathways that play critical roles in long-term memory formation. In this review, we discuss recent results that demonstrate the roles that these ARE-binding proteins play in LTM formation.

Exercise during abstinence normalizes ultrastructural synaptic plasticity associated with nicotine-seeking following extended access self-administration.

Nicotine-craving progressively increases, or incubates, over abstinence following extended access self-administration. While not yet examined for nicotine, the incubation of cocaine-seeking is accompanied by changes in synaptic plasticity in the nucleus accumbens. Here, we determined whether such changes also accompany enhanced nicotine-seeking following extended access self-administration and abstinence, and whether exercise, a potential intervention for nicotine addiction, may exert its efficacy by normalizing these changes. Given that in humans, tobacco/nicotine use begins during adolescence, we used an adolescent-onset model. Nicotine-seeking was assessed in male rats following extended access nicotine or saline self-administration (23-hr/day, 10days) and 10days of abstinence, conditions known to induce the incubation of nicotine-seeking, using a within-session extinction/cue-induced reinstatement procedure. A subset of rats had 2-hr/day access to a running wheel during abstinence. Ultrastructural alterations of synapses in the nucleus accumbens core and shell were examined using electron microscopy. Nicotine-seeking was elevated following extended access self-administration and abstinence (in sedentary group), and levels of seeking were associated with an increase in the density of asymmetric (excitatory) and symmetric (inhibitory) synapses onto dendrites in the core, as well as longer asymmetric synapses onto spines, a marker of synaptic potentiation, in both the core and shell. Exercise normalized each of these changes; however, in the shell, exercise and nicotine similarly increased the synapse length. Together, these findings indicate an association between nicotine-seeking and synaptic plasticity in the nucleus accumbens, particularly the core, and indicate that the efficacy of exercise to reduce nicotine-seeking may be mediated by reversing these adaptations.

Prophylactic Ketamine Treatment Promotes Resilience to Chronic Stress and Accelerates Recovery: Correlation with Changes in Synaptic Plasticity in the CA3 Subregion of the Hippocampus.

Ketamine is an N-methyl-d-aspartate receptor antagonist that has gained wide attention as a potent antidepressant. It has also been recently reported to have prophylactic effects in animal models of depression and anxiety. Alterations of neuroplasticity in different brain regions; such as the hippocampus; prefrontal cortex; and amygdala; are a hallmark of stress-related disorders; and such changes may endure beyond the treatment of symptoms. The present study investigated whether a prophylactic injection of ketamine has effects on structural plasticity in the brain in mice that are subjected to chronic unpredictable stress followed by an 8-day recovery period. Ketamine administration (3 mg/kg body weight) 1 h before stress exposure increased the number of resilient animals immediately after the cessation of stress exposure and positively influenced the recovery of susceptible animals to hedonic deficits. At the end of the recovery period; ketamine-treated animals exhibited significant differences in dendritic spine density and dendritic spine morphology in brain regions associated with depression compared with saline-treated animals. These results confirm previous findings of the prophylactic effects of ketamine and provide further evidence of an association between the antidepressant-like effect of ketamine and alterations of structural plasticity in the brain

AMPA Receptor Dysregulation and Therapeutic Interventions in a Mouse Model of CDKL5 Deficiency Disorder.

Pathogenic mutations in cyclin-dependent kinase-like 5 (CDKL5) result in CDKL5 deficiency disorder (CDD), a rare disease marked by early-life seizures, autistic behaviors, and intellectual disability. Although mouse models of CDD exhibit dendritic instability and alterations in synaptic scaffolding proteins, studies of glutamate receptor levels and function are limited. Here we used a novel mouse model of CDD, the Cdkl5R59X knock-in mouse (R59X), to investigate changes in synaptic glutamate receptor subunits and functional consequences. Male mice were used for all experiments to avoid the confounding effects of X-inactivation that would be present in female heterozygous mice. We showed that adult male R59X mice recapitulated the behavioral outcomes observed in other mouse models of CDD, including social deficits and memory and learning impairments, and exhibited decreased latency to seizure upon pentylenetetrazol administration. Furthermore, we observed a specific increase in GluA2-lacking α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid)-type glutamate receptors (AMPARs) in the adult R59X hippocampus, which is accompanied electrophysiologically by increased rectification ratio of AMPAR EPSCs and elevated early-phase long term potentiation (LTP). Finally, we showed that acute treatment with the GluA2-lacking AMPAR blocker IEM-1460 decreased AMPAR currents, and rescued social deficits, working memory impairments, and seizure behavior latency in R59X mice.SIGNIFICANCE STATEMENT CDKL5 deficiency disorder (CDD) is a rare disease marked by autistic-like behaviors, intellectual disability, and seizures. While synaptic dysfunction has been observed in mouse models of CDD, there is limited information on how synaptic alterations contribute to behavioral and functional changes in CDD. Here we reveal elevated hippocampal GluA2-lacking AMPAR expression in a novel mouse model of CDD that is accompanied by changes in synaptic AMPAR function and plasticity. We also show, for the first time, that acutely targeting GluA2-lacking AMPAR dysregulation rescues core synaptic and neurobehavioral deficits in CDD.

Differential effect of FHM2 mutation on synaptic plasticity in distinct hippocampal regions.

Familial hemiplegic migraine 2 is a pathology linked to mutation of the ATP1A2 gene producing loss of function of the α2 Na+/K+-ATPase (NKA). W887R/+ knock-in (KI) mice are used to model the familial hemiplegic migraine 2 condition and are characterized by 50% reduced NKA expression in the brain and reduced rate of K+ and glutamate clearance by astrocytes. These alterations might, in turn, produce synaptic changes in synaptic transmission and plasticity. Memory and learning deficits observed in familial hemiplegic migraine patients could be ascribed to a possible alteration of hippocampal neuronal plasticity and measuring possible changes of long-term potentiation in familial hemiplegic migraine 2 KI mice might provide insights to strengthen this link. Here we have investigated synaptic plasticity in distinct hippocampal regions in familial hemiplegic migraine 2 KI mice. We show that the dentate gyrus long-term potentiation of familial hemiplegic migraine 2 mice is abnormally increased in comparison with control animals. Conversely, in the CA1 area, KI and WT mice express long-term potentiation of similar amplitude. The familial hemiplegic migraine 2 KI mice show region-dependent hippocampal plasticity abnormality, which might underlie some of the memory deficits observed in familial migraine.

Different attentional dysfunctions in eEF2K-/- , IL1RAPL1-/- and SHANK3Δ11-/- mice.

A common feature of several psychiatric disorders is the attentional impairment. eEF2K -/- , IL1RAPL1 -/- and SHANK3Δ11 -/- mice were used as animal models consistently linked to changes in synaptic plasticity, learning and memory. All knockout (KO) mice and their corresponding littermates were submitted to the novel object recognition (NOR) and visual object recognition (VOR) tasks. In the NOR, eEF2K-/- mice exhibited a normal performance in terms of mean discrimination index, while SHANK3Δ11-/- and IL1RAPL1 -/- mice were impaired when a delay of 2 and 24 hours was introduced. Surprisingly, when submitted to VOR, where the two objects were replaced with two shapes delivered from two iPods, all the mutant mice performed worse than those in the NOR. In VOR, the application of motion to different shapes, to increase attention, improved performance in eEF2K -/- and IL1RAPL1 -/- but not in SHANK3Δ11 -/- mice. In SHANK3Δ11 -/- mice, attentional deficit was also present even if different motions were applied to the same shapes or when these mice were repeatedly exposed for 5 days to the context. Behavioral analysis showed that eEF2K-/- and IL1RAPL1 -/- mice had a good flexibility tested in the T-maze. eEF2K-/- showed normal self-grooming. On the basis of previous literature data indicating that SHANK3Δ11 -/- showed impaired flexibility and reduced sociability, we identified in this genotype the most exhaustive model showing all the core symptoms of autism spectrum disorder including a heavy visual attention deficit. These findings show the importance of VOR to identify mouse models of autism.

Immediate and delayed decrease of long term potentiation and memory deficits after neonatal intermittent hypoxia

Apnea of prematurity is a common clinical condition that occurs in premature infants and results in intermittent hypoxia (IH) to brain and other organs. While short episodes of apnea are considered of no clinical significance, prolonged apnea with bradycardia and large oxygen desaturation is associated with adverse neurological and cognitive outcome. The mechanisms of cognitive deficits in IH are poorly understood. We hypothesized that brief but multiple episodes of severe oxygen desaturation accompanied by bradycardia may affect early and late synaptic plasticity and produce long-term cognitive deficits.C57BL/6 mouse pups were exposed to IH paradigm consisting of alternating cycles of 5% oxygen for 2.5 min and room air for 5–10 min, 2 h a day from P3 to P7. Long term potentiation (LTP) of synaptic strength in response to high frequency stimulation in hippocampal slices were examined 3 days and 6 weeks after IH. LTP was decreased in IH group relative to controls at both time points. That decrease was associated with deficits in spatial memory on Morris water maze and context fear conditioning test. Hypomyelination was observed in multiple gray and white matter areas on in vivo MRI using micromolecule proton fraction and ex vivo diffusion tensor imaging. No difference in caspase labeling was found between control and IH groups.We conclude that early changes in synaptic plasticity occurring during severe episodes of neonatal IH and persisting to adulthood may represent functional and structural substrate for long term cognitive deficits.

The Virtual Electrode Recording Tool for EXtracellular Potentials (VERTEX) Version 2.0: Modelling in vitro electrical stimulation of brain tissue

Neuronal circuits can be modelled in detail allowing us to predict the effects of stimulation on individual neurons. Electrical stimulation of neuronal circuits in vitro and in vivo excites a range of neurons within the tissue and measurements of neural activity, e.g the local field potential (LFP), are again an aggregate of a large pool of cells. The previous version of our Virtual Electrode Recording Tool for EXtracellular Potentials (VERTEX) allowed for the simulation of the LFP generated by a patch of brain tissue. Here, we extend VERTEX to simulate the effect of electrical stimulation through a focal electric field. We observe both direct changes in neural activity and changes in synaptic plasticity. Testing our software in a model of a rat neocortical slice, we determine the currents contributing to the LFP, the effects of paired pulse stimulation to induce short term plasticity (STP), and the effect of theta burst stimulation (TBS) to induce long term potentiation (LTP).

Identification of key genes, pathways, and miRNA/mRNA regulatory networks of CUMS-induced depression in nucleus accumbens by integrated bioinformatics analysis.

IntroductionMajor depressive disorder (MDD) is a recurrent, devastating mental disorder, which affects >350 million people worldwide, and exerts substantial public health and financial costs to society. Thus, there is a significant need to discover innovative therapeutics to treat depression efficiently. Stress-induced dysfunction in the subtype of neuronal cells and the change of synaptic plasticity and structural plasticity of nucleus accumbens (NAc) are implicated in depression symptomology. However, the molecular and epigenetic mechanisms and stresses to the NAc pathological changes in depression remain elusive.Materials and methodsIn this study, treatment group mice were treated continually with the chronic unpredictable mild stress (CUMS) until expression of depression-like behaviors were found. Depression was confirmed with sucrose preference, novelty-suppressed feeding, forced swimming, and tail suspension tests. We applied high-throughput RNA sequencing to assess microRNA expression and transcriptional profiles in the NAc tissue from depression-like behaviors mice and control mice. The regulatory network of miRNAs/mRNAs was constructed based on the high-throughput RNA sequence and bioinformatics software predictions.ResultsA total of 17 miRNAs and 10 mRNAs were significantly upregulated in the NAc of CUMS-induced mice with depression-like behaviors, and 12 miRNAs and 29 mRNAs were downregulated. A series of bioinformatics analyses showed that these altered miRNAs predicted target mRNA and differentially expressed mRNAs were significantly enriched in the MAPK signaling pathway, GABAergic synapse, dopaminergic synapse, cytokine–cytokine receptor interaction, axon guidance, regulation of autophagy, and so on. Furthermore, dual luciferase report assay and qRT-PCR results validated the miRNA/mRNA regulatory network.ConclusionThe deteriorations of GABAergic synapses, dopaminergic synapses, neurotransmitter synthesis, as well as autophagy-associated apoptotic pathway are associated with the molecular pathological mechanism of CUMS-induced depression.

FGF-23 Deficiency Impairs Hippocampal-Dependent Cognitive Function.

Fibroblast growth factor receptor (FGFR) and α-Klotho transduce FGF-23 signaling in renal tubules to maintain systemic phosphate/vitamin D homeostasis. Mice deficient for either the ligand, FGF-23, or the co-receptor, Klotho, are phenocopies with both showing rapid and premature development of multiple aging-like abnormalities. Such similarity in phenotype, suggests that FGF-23 and Klotho have co-dependent systemic functions. Recent reports revealed inverse central nervous system (CNS) effects of Klotho deficiency or Klotho overexpression on hippocampal synaptic, neurogenic, and cognitive functions. However, it is unknown whether FGF-23 deficiency effects function of the hippocampus. We report that, similar to Klotho-deficient mice, FGF-23-deficient mice develop dose-dependent, hippocampal-dependent cognitive impairment. However, FGF-23-deficient brains had no gross structural or developmental defects, no change in hippocampal synaptic plasticity, and only minor impairment to postnatal hippocampal neurogenesis. Together, these data provide evidence that FGF-23 deficiency impairs hippocampal-dependent cognition but otherwise results in a brain phenotype that is distinct from the KL-deficient mouse.

Tripchlorolide May Improve Spatial Cognition Dysfunction and Synaptic Plasticity after Chronic Cerebral Hypoperfusion.

Chronic cerebral hypoperfusion (CCH) is a common pathophysiological mechanism that underlies cognitive decline and degenerative processes in dementia and other neurodegenerative diseases. Low cerebral blood flow (CBF) during CCH leads to disturbances in the homeostasis of hemodynamics and energy metabolism, which in turn results in oxidative stress, astroglia overactivation, and synaptic protein downregulation. These events contribute to synaptic plasticity and cognitive dysfunction after CCH. Tripchlorolide (TRC) is an herbal compound with potent neuroprotective effects. The potential of TRC to improve CCH-induced cognitive impairment has not yet been determined. In the current study, we employed behavioral techniques, electrophysiology, Western blotting, immunofluorescence, and Golgi staining to investigate the effect of TRC on spatial learning and memory impairment and on synaptic plasticity changes in rats after CCH. Our findings showed that TRC could rescue CCH-induced spatial learning and memory dysfunction and improve long-term potentiation (LTP) disorders. We also found that TRC could prevent CCH-induced reductions in N-methyl-D-aspartic acid receptor 2B, synapsin I, and postsynaptic density protein 95 levels. Moreover, TRC upregulated cAMP-response element binding protein, which is an important transcription factor for synaptic proteins. TRC also prevented the reduction in dendritic spine density that is caused by CCH. However, sham rats treated with TRC did not show any improvement in cognition. Because CCH causes disturbances in brain energy homeostasis, TRC therapy may resolve this instability by correcting a variety of cognitive-related signaling pathways. However, for the normal brain, TRC treatment led to neither disturbance nor improvement in neural plasticity. Additionally, this treatment neither impaired nor further improved cognition. In conclusion, we found that TRC can improve spatial learning and memory, enhance synaptic plasticity, upregulate the expression of some synaptic proteins, and increase the density of dendritic spines. Our findings suggest that TRC may be beneficial in the treatment of cognitive impairment induced by CCH.

Sevoflurane anesthesia impairs metabotropic glutamate receptor-dependent long-term depression and cognitive functions in senile mice.

Postoperative cognitive dysfunction is often observed in older patients. Previous reports described the link between postoperative cognitive dysfunction and general anesthetics, such as sevoflurane, but the exact mechanism remains unclear. We therefore sought to characterize the effects of sevoflurane on hippocampal-dependent cognitive functions, as well as hippocampal plasticity, and to delineate the underlying mechanisms. Behavioral assays including the novel object recognition test and the Morris water maze test were carried out to assess the cognitive performance of control and sevoflurane-exposed mice. Electrophysiological recordings were carried out to evaluate the sevoflurane-induced changes of synaptic plasticity in the hippocampus. Furthermore, western blot assay was utilized to quantitatively assess the altered protein expression resulting from sevoflurane exposure. Sevoflurane anesthesia impaired cognitive functions, as well as metabotropic glutamate receptor-dependent long-term depression, through elevated surface expression of small conductance calcium-activated potassium type 2 channels. Blockage of calcium-activated potassium type 2 channels reversed the sevoflurane-induced deficits at both cellular and behavioral levels. Sevoflurane anesthesia impaired metabotropic glutamate receptor-dependent long-term depression and thereby affected cognitive functions in old mice. Inhibitory modulators of calcium-activated potassium type 2 channels might prevent cognitive decline elicited by sevoflurane. Geriatr Gerontol Int 2019; 19: 357-362.

Experimental pediatric stroke shows age-specific recovery of cognition and role of hippocampal Nogo-A receptor signaling

Ischemic stroke is a leading cause of death worldwide and clinical data suggest that children may recover from stroke better than adults; however, supporting experimental data are lacking. We used our novel mouse model of experimental juvenile ischemic stroke (MCAO) to characterize age-specific cognitive dysfunction following ischemia. Juvenile and adult mice subjected to 45-min MCAO, and extracellular field recordings of CA1 neurons were performed to assess hippocampal synaptic plasticity changes after MCAO, and contextual fear conditioning was performed to evaluate memory and biochemistry used to analyze Nogo-A expression. Juvenile mice showed impaired synaptic plasticity seven days after MCAO, followed by full recovery by 30 days. Memory behavior was consistent with synaptic impairments and recovery after juvenile MCAO. Nogo-A expression increased in ipsilateral hippocampus seven days after MCAO compared to contralateral and sham hippocampus. Further, inhibition of Nogo-A receptors reversed MCAO-induced synaptic impairment in slices obtained seven days after juvenile MCAO. Adult MCAO-induced impairment of LTP was not associated with increased Nogo-A. This study demonstrates that stroke causes functional impairment in the hippocampus and recovery of behavioral and synaptic function is more robust in the young brain. Nogo-A receptor activity may account for the impairments seen following juvenile ischemic injury.

Abstract TP588: Underlying Mechanisms Of Preconditioning Against Stroke: Lack Of Ischemic Neuroprotectant Sirt1 Increases Long-term Potentiation Induction In Mice

Sirt1 has been implicated to play a major role in ischemic preconditioning (IPC)—a phenomenon whereby a sublethal episode of ischemia induces tolerance to a subsequent prolonged ischemic insult, such as stroke. Both IPC and pharmacological mimetics (i.e. resveratrol) upregulate Sirt1 activity and expression. Since Sirt1 is thought to regulate the expression of proteins involved in synaptic plasticity, neuroprotection afforded by Sirt1 may be explained by changes in these processes. For this reason, we investigated the effects of Sirt1 deficiency on long-term potentiation (LTP). Using inducible, neuronal-specific Sirt1 knockout mice, acute brain slices were prepared and extracellular field recordings were taken in the CA1 region of the hippocampus. Sirt1 deficiency significantly increased LTP induction (2.08 ± 0.065 fold change relative to a 1.46 ± 0.054 change in wild-type mice; n = 10-11, p = 0.022), suggesting Sirt1 may function to repress the transcription of genes associated with LTP. Paired-pulse facilitation was also significantly increased, where neuronal Sirt1 knockout mice had a 2.10 ± 0.047 fold increase in the paired-pulse response after LTP compared to that of the wild-type control (1.60 ± 0.040; n = 10-11, p = 0.001). These changes were indicative of presynaptic involvement. To test whether similar changes in plasticity occur during the late phase of preconditioning, wild-type mice were treated with resveratrol or a vehicle control and subjected to electrophysiological recordings ex vivo 48 hours later. However, no differences in LTP induction or paired-pulse facilitation were observed. Thus, it is unclear whether protection mediated by resveratrol preconditioning involves changes in synaptic plasticity. Since Sirt1 is capable of deacetylating many histone and non-histone proteins, its effects on transcription and gene expression may vary depending on its activity and period of activation. It is probable that during the extended window of ischemic tolerance, Sirt1 may exert different effects than that of the early or classical late phase. Thus, future studies investigating the effects of Sirt1 on plasticity across different time windows of IPC may shed light on new, more direct targets that can mimic or facilitate preconditioning.