Field Excitatory Postsynaptic Potentials Research Articles

The phosphodiesterase-4 and glycine transporter-1 inhibitors enhance in vivo hippocampal theta network connectivity and synaptic plasticity, whereas D-serine does not

Dysfunctional N-methyl-D-aspartate receptors (NMDARs) and cyclic adenosine monophosphate (cAMP) have been associated with deficits in synaptic plasticity and cognition found in neurodegenerative and neuropsychiatric disorders such as Alzheimer’s disease (AD) and schizophrenia. Therapeutic approaches that indirectly enhance NMDAR function through increases in glycine and/or D-serine levels as well as inhibition of phosphodiesterases that reduces degradation of cAMP, are expected to enhance synaptic strength, connectivity and to potentially impact cognition processes. The present in vivo study investigated effects of subcutaneous administration of D-serine, the glycine transporter 1 (GlyT1) inhibitor SSR504734 and the PDE4 inhibitor rolipram, on network oscillations, connectivity and long-term potentiation (LTP) at the hippocampi circuits in Sprague-Dawley rats. In conscious animals, multichannel EEG recordings assessed network oscillations and connectivity at frontal and hippocampal CA1–CA3 circuits. Under urethane anaesthesia, field excitatory postsynaptic potentials (fEPSPs) were measured in the CA1 subfield of the hippocampus after high-frequency stimulation (HFS) of the Schaffer collateral-CA1 (SC) pathway. SSR504734 and rolipram significantly increased slow theta oscillations (4–6.5 Hz) at the CA1–CA3, slow gamma oscillations (30–50 Hz) in the frontal areas and enhanced coherence in the CA1–CA3 network, which were dissociated from motor behaviour. SSR504734 enhanced short-term potentiation (STP) and fEPSP responses were extended into LTP response, whereas the potentiation of EPSP slope was short-lived to STP with rolipram. Unlike glycine, increased levels of D-serine had no effect on network oscillations and limits the LTP induction and expression. The present data support a facilitating role of glycine and cAMP on network oscillations and synaptic efficacy at the CA3–CA1 circuit in rats, whereas raising endogenous D-serine levels had no such beneficial effects.

Optogenetic Manipulation of Postsynaptic cAMP Using a Novel Transgenic Mouse Line Enables Synaptic Plasticity and Enhances Depolarization Following Tetanic Stimulation in the Hippocampal Dentate Gyrus.

cAMP is a positive regulator tightly involved in certain types of synaptic plasticity and related memory functions. However, its spatiotemporal roles at the synaptic and neural circuit levels remain elusive. Using a combination of a cAMP optogenetics approach and voltage-sensitive dye (VSD) imaging with electrophysiological recording, we define a novel capacity of postsynaptic cAMP in enabling dentate gyrus long-term potentiation (LTP) and depolarization in acutely prepared murine hippocampal slices. To manipulate cAMP levels at medial perforant path to granule neuron (MPP-DG) synapses by light, we generated transgenic (Tg) mice expressing photoactivatable adenylyl cyclase (PAC) in DG granule neurons. Using these Tg(CMV-Camk2a-RFP/bPAC)3Koka mice, we recorded field excitatory postsynaptic potentials (fEPSPs) from MPP-DG synapses and found that photoactivation of PAC during tetanic stimulation enabled synaptic potentiation that persisted for at least 30 min. This form of LTP was induced without the need for GABA receptor blockade that is typically required for inducing DG plasticity. The paired-pulse ratio (PPR) remained unchanged, indicating the cAMP-dependent LTP was likely postsynaptic. By employing fast fluorescent voltage-sensitive dye (VSD: di-4-ANEPPS) and fluorescence imaging, we found that photoactivation of the PAC actuator enhanced the intensity and extent of dentate gyrus depolarization triggered following tetanic stimulation. These results demonstrate that the elevation of cAMP in granule neurons is capable of rapidly enhancing synaptic strength and neuronal depolarization. The powerful actions of cAMP are consistent with this second messenger having a critical role in the regulation of synaptic function.

Curcumin modulates long term potentiation in lipopolysaccharide-treated rats

Curcumin is a component of turmeric isolated from the rhizome of Curcuma longa. Natural polyphenols like curcumin have long been used to heal several pathological states. This study aimed to evaluate the effects of curcumin on lipopolysaccharide (LPS)-induced modifications of long-term potentiation (LTP) in rats. Five groups of rats with seven in each were allocated to the experimental groups. The experimental groups were defined as: (1) control, (2) LPS (1 mg/kg), (3) LPS-Cur 5 mg/kg, (4) LPSCur 10 mg/kg, and (5) LPS-Cur 15 mg/kg. Afterward, LTP was recorded from the CA1 region of the hippocampus following high-frequency stimulus application to the Schaffer collateral. Our results indicated that the amplitude and slope components of the field excitatory post-synaptic potential (fEPSP) were reduced after the LPS administration in the control animals. Treatment by the high dose of curcumin (15 mg/kg) restored these parameters in comparison with the LPS-treated group. This investigation suggested that curcumin at a high dose could recover LTP impairments induced by LPS in adult male rats.

Brivaracetam Prevents the Over-expression of Synaptic Vesicle Protein 2A and Rescues the Deficits of Hippocampal Long-term Potentiation In Vivo in Chronic Temporal Lobe Epilepsy Rats.

Patients with temporal lobe epilepsy (TLE) usually suffer from cognitive deficits and recurrent seizures. Brivaracetam (BRV) is a novel anti-epileptic drug (AEDs) recently used for the treatment of partial seizures with or without secondary generalization. Different from other AEDs, BRV has some favorable properties on synaptic plasticity. However, the underlying mechanisms remain elusive. The aim of this study was to explore the neuroprotective mechanism of BRV on synaptic plasticity in experimental TLE rats. The effect of chronic treatment with BRV (10 mg/kg) was assessed on Pilocarpine induced TLE model through measurement of the field excitatory postsynaptic potentials (fEPSPs) in vivo. Differentially expressed synaptic vesicle protein 2A (SV2A) were identified with immunoblot. Then, fast phosphorylation of synaptosomal-associated protein 25 (SNAP-25) during long-term potentiation (LTP) induction was performed to investigate the potential roles of BRV on synaptic plasticity in the TLE model. An increased level of SV2A accompanied by a depressed LTP in the hippocampus was shown in epileptic rats. Furthermore, BRV treatment continued for more than 30 days improved the over-expression of SV2A and reversed the synaptic dysfunction in epileptic rats. Additionally, BRV treatment alleviates the abnormal SNAP-25 phosphorylation at Ser187 during LTP induction in epileptic ones, which is relevant to the modulation of synaptic vesicles exocytosis and voltagegated calcium channels. BRV treatment ameliorated the over-expression of SV2A in the hippocampus and rescued the synaptic dysfunction in epileptic rats. These results identify the neuroprotective effect of BRV on TLE model.

Aging Alters Olfactory Bulb Network Oscillations and Connectivity: Relevance for Aging-Related Neurodegeneration Studies.

The aging process eventually cause a breakdown in critical synaptic plasticity and connectivity leading to deficits in memory function. The olfactory bulb (OB) and the hippocampus, both regions of the brain considered critical for the processing of odors and spatial memory, are commonly affected by aging. Using an aged wild-type C57B/6 mouse model, we sought to define the effects of aging on hippocampal plasticity and the integrity of cortical circuits. Specifically, we measured the long-term potentiation of high-frequency stimulation (HFS-LTP) at the Shaffer-Collateral CA1 pyramidal synapses. Next, local field potential (LFP) spectra, phase-amplitude theta-gamma coupling (PAC), and connectivity through coherence were assessed in the olfactory bulb, frontal and entorhinal cortices, CA1, and amygdala circuits. The OB of aged mice showed a significant increase in the number of histone H2AX-positive neurons, a marker of DNA damage. While the input-output relationship measure of basal synaptic activity was found not to differ between young and aged mice, a pronounced decline in the slope of field excitatory postsynaptic potential (fEPSP) and the population spike amplitude (PSA) were found in aged mice. Furthermore, aging was accompanied by deficits in gamma network oscillations, a shift to slow oscillations, reduced coherence and theta-gamma PAC in the OB circuit. Thus, while the basal synaptic activity was unaltered in older mice, impairment in hippocampal synaptic transmission was observed only in response to HFS. However, age-dependent alterations in neural network appeared spontaneously in the OB circuit, suggesting the neurophysiological basis of synaptic deficits underlying olfactory processing. Taken together, the results highlight the sensitivity and therefore potential use of LFP quantitative network oscillations and connectivity at the OB level as objective electrophysiological markers that will help reveal specific dysfunctional circuits in aging-related neurodegeneration studies.

Monocular Deprivation Affects Visual Cortex Plasticity Through cPKCγ-Modulated GluR1 Phosphorylation in Mice.

PurposeTo determine how visual cortex plasticity changes after monocular deprivation (MD) in mice and whether conventional protein kinase C gamma (cPKCγ) plays a role in visual cortex plasticity.MethodscPKCγ membrane translocation levels were quantified by using immunoblotting to explore the effects of MD on cPKCγ activation. Electrophysiology was used to record field excitatory postsynaptic potential (fEPSP) amplitude with the goal of observing changes in visual cortex plasticity after MD. Immunoblotting was also used to determine the phosphorylation levels of GluR1 at Ser831. Light transmission was analyzed using electroretinography to examine the effects of MD and cPKCγ on mouse retinal function.ResultsMembrane translocation levels of cPKCγ significantly increased in the contralateral visual cortex of MD mice compared to wild-type (WT) mice (P < 0.001). In the contralateral visual cortex, long-term potentiation (LTP) and the phosphorylation levels of GluR1 at Ser 831 were increased in cPKCγ+/+ mice after MD. Interestingly, these levels could be downregulated by cPKCγ knockout compared to cPKCγ+/++MD mice (P < 0.001). Compared to the right eyes of WT mice, the amplitudes of a-waves and b-waves declined in deprived right eyes of mice after MD (P < 0.001). There were no significant differences when comparing cPKCγ+/+ and cPKCγ−/− mice with MD.ConclusionscPKCγ participates in the plasticity of the visual cortex after MD, which is characterized by increased LTP in the contralateral visual cortex, which may be a result of cPKCγ-mediated phosphorylation of GluR1 at Ser 831.

Deep brain stimulation reduces evoked potentials with a dual time course in freely moving rats: Potential neurophysiological basis for intermittent as an alternative to continuous stimulation.

Deep brain stimulation (DBS) is an increasingly applied treatment for various neuropsychiatric disorders including drug-resistant epilepsy, and it may be optimized by rationalizing the stimulation protocol based on increased knowledge of its mechanism of action. We evaluated the effects of minutes to hours of hippocampal DBS on hippocampal evoked potentials (EPs) and local field potentials (LFPs) in freely moving male rats to further investigate some of the previously proposed mechanisms of action. Hippocampal high-frequency (130Hz) DBS was administered for 0, 1, or 6min every 10min for 160min. Stimulation parameter settings were similar to those that had previously been shown to reduce seizures in epileptic rats. EPs and LFPs were recorded in the stimulation-free intervals. We investigated both the immediate temporary effects of 1 or 6min of DBS and the effects of 160min of intermittent DBS. Input specificity was investigated by using two different stimulation electrodes. Relatively low DBS intensities corresponding to only 1.8% of the intensity evoking a maximum EP were required to prevent unintended seizure occurrence in healthy rats. Both 1 and 6min of DBS caused input-specific short-lasting (<60 s) reductions (5%-7%) of the field excitatory postsynaptic potential (fEPSP) slope (P=.005). We observed longer-lasting, input-specific EP reductions during the 160min intermittent DBS, with statistically significant reductions (3%-4%) of the fEPSP slope (P=.009-.018). The LFP spectrogram remained unaltered. Deep brain stimulation induced both acute temporary effects compatible with axonal block and/or synaptic depression, and longer-lasting potentially cumulative EP reductions, suggesting the involvement of homeostatic plasticity or long-term depression. This dual time course may parallel the different temporal patterns of improvement observed in clinical trials. The longer-lasting reductions provide a potential neurophysiological basis for the use of intermittent DBS-as typically used in epilepsy patients-as an alternative to continuous DBS.

MicroRNA-153 impairs presynaptic plasticity by blocking vesicle release following chronic brain hypoperfusion

BackgroundChronic brain hypoperfusion (CBH) is closely related to Alzheimer’s disease (AD) and vascular dementia (VaD). Meanwhile, synaptic pathology plays a prominent role in the initial stage of AD and VaD. However, whether and how CBH impairs presynaptic plasticity is currently unclear.MethodsIn the present study, we performed a battery of techniques, including primary neuronal culture, patch clamp, stereotaxic injection of the lentiviral vectors, morris water maze (MWM), dual luciferase reporter assay, FM1–43 fluorescence dye evaluation, qRT-PCR and western blot, to investigate the regulatory effect of miR-153 on hippocampal synaptic vesicle release both in vivo and in vitro. The CBH rat model was generated by bilateral common carotid artery ligation (2VO).ResultsCompared to sham rats, 2VO rats presented decreased field excitatory postsynaptic potential (fEPSP) amplitude and increased paired-pulse ratios (PPRs) in the CA3-CA1 pathway, as well as significantly decreased expression of multiple vesicle fusion-related proteins, including SNAP-25, VAMP-2, syntaxin-1A and synaptotagmin-1, in the hippocampi. The levels of microRNA-153 (miR-153) were upregulated in the hippocampi of rats following 2VO surgery, and in the plasma of dementia patients. The expression of the vesicle fusion-related proteins affected by 2VO was inhibited by miR-153, elevated by miR-153 inhibition, and unchanged by binding-site mutation or miR masks. FM1–43 fluorescence images showed that miR-153 blunted vesicle exocytosis, but this effect was prevented by either 2′-O-methyl antisense oligoribonucleotides to miR-153 (AMO-153) and miR-masking of the miR-153 binding site in the 3′ untranslated region (3’UTR) of the Snap25, Vamp2, Stx1a and Syt1 genes. Overexpression of miR-153 by lentiviral vector-mediated miR-153 mimics (lenti-pre-miR-153) decreased the fEPSP amplitude and elevated the PPR in the rat hippocampus, whereas overexpression of the antisense molecule (lenti-AMO-153) reversed these changes triggered by 2VO. Furthermore, lenti-AMO-153 attenuated the cognitive decline of 2VO rats.ConclusionsOverexpression of miR-153 controls CBH-induced presynaptic vesicle release impairment by posttranscriptionally regulating the expression of four vesicle release-related proteins by targeting the 3’UTRs of the Stx1a, Snap25, Vamp2 and Syt1 genes. These findings identify a novel mechanism of presynaptic plasticity impairment during CBH, which may be a new drug target for prevention or treatment of AD and VaD.E8TH8SFpmLGUrZnTkkAYxHVideo Graphical abstract

Stereotactically Injected Kv1.2 and CASPR2 Antisera Cause Differential Effects on CA1 Synaptic and Cellular Excitability, but Both Enhance the Vulnerability to Pro-epileptic Conditions.

PurposeWe present a case of voltage-gated potassium channel (VGKC) complex antibody-positive limbic encephalitis (LE) harboring autoantibodies against Kv1.2. Since the patient responded well to immunotherapy, the autoantibodies were regarded as pathogenic. We aimed to characterize the pathophysiological role of this antibody in comparison to an antibody against the VGKC-associated protein contactin-associated protein-2 (CASPR2).MethodsStereotactic injection of patient sera (anti-Kv1.2-associated LE or anti-CASPR2 encephalopathy) and a control subject was performed into the hippocampus of the anesthetized rat in vivo, and hippocampal slices were prepared for electrophysiological purposes. Using extra- and intracellular techniques, synaptic transmission, long-term potentiation (LTP) and vulnerability to pro-epileptic conditions were analyzed.ResultsWe observed that the slope of the field excitatory postsynaptic potential (fEPSP) was significantly increased at Schaffer collateral-CA1 synapses in anti-Kv1.2-treated and anti-CASPR2-treated rats, but not at medial perforant path-dentate gyrus synapses. The increase of the fEPSP slope in CA1 was accompanied by a decrease of the paired-pulse ratio in anti-Kv1.2, but not in anti-CASPR2 tissue, indicating presynaptic site of anti-Kv1.2. In addition, anti-Kv1.2 tissue showed enhanced LTP in CA1, but dentate gyrus LTP remained unaltered. Importantly, LTP in slices from anti-CASPR2-treated animals did not differ from control values. Intracellular recordings from CA1 neurons revealed that the resting membrane potential and a single action potential were not different between anti-Kv1.2 and control tissue. However, when the depolarization was prolonged, the number of action potentials elicited was reduced in anti-Kv1.2-treated tissue compared to both control and anti-CASPR2 tissue. In contrast, polyspike discharges induced by removal of Mg2+ occurred earlier and more frequently in both patient sera compared to control.ConclusionPatient serum containing anti-Kv1.2 facilitates presynaptic transmitter release as well as postsynaptic depolarization at the Schaffer-collateral-CA1 synapse, but not in the dentate gyrus. As a consequence, both synaptic transmission and LTP in CA1 are facilitated and action potential firing is altered. In contrast, anti-CASPR2 leads to increased postsynaptic potentials, but without changing LTP or firing properties suggesting that anti-Kv1.2 and anti-CASPR2 differ in their cellular effects. Both patient sera alter susceptibility to epileptic conditions, but presumably by different mechanisms.

Effects of Hypericum scabrum extract on dentate gyrus synaptic plasticity in high fat diet-fed rats

High-fat diet (HFD) can induce deficits in neural function, oxidative stress, and decrease hippocampal neurogenesis. Hypericum (H.) scabrum extract (Ext) contains compounds that could treat neurological disorders. This study aimed to examine the neuroprotective impacts of the H. scabrum Ext on hippocampal synaptic plasticity in rats that were fed HFD. Fifty-four male Wistar rats (220 ± 10 g) were randomly arranged in six groups: (1) HFD group; (2) HFD + Ext300 group; (3) HFD + Ext100 group; (4) Control group; (5) Ext 300 mg/kg group; (6) Ext 100 mg/kg group. These protocols were administrated for 3 months. After this stage, a stimulating electrode was implanted in the perforant pathway (PP), and a bipolar recording electrode was embedded into the dentate gyrus (DG). Long-term potentiation (LTP) was provoked by high-frequency stimulation (HFS) of the PP. Field excitatory postsynaptic potentials (EPSP) and population spikes (PS) were recorded at 5, 30, and 60 min after HFS. The HFD group exhibited a large and significant decrease in their PS amplitude and EPSP slope as compared to the control and extract groups. In reverse, H. scabrum administration in the HFD + Ext rats reversed the effect of HFD on the PS amplitude and EPSP slope. The results of the study support that H. scabrum Ext can inhibit diminished synaptic plasticity caused by the HFD. These effects are probably due to the extreme antioxidant impacts of the Ext and its capability to scavenge free radicals.

Method of synaptic transmission hidden parameters evaluation based on inhibition analysis data

Nowadays neuroscience strongly demands application of the mathematical methods for description of many neurophysiological and neurochemical processes among which the synaptic transmission outstands. One of the main problems in synaptic transmission modelling is the lack of the accurate values of dynamic parameters of biomolecules and complexes taking part in this process. The goal of this study is to elaborate the method for evaluation of synaptic transmission parameters that cannot be measured directly (so-called hidden parameters) and apply its results for investigation of the main stages of synaptic transmission in neuronets of hippocampus. The method is based on the parametric identification of the synaptic transmission deterministic model, which includes equations for description of inhibitors action on the main biochemical participants. We used three inhibitors: cilnidipine, 1.2- bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid tetrakis(acetoxymethyl ester) (BAPTA-AM), 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX). The parametric identification was performed by minimization of deviation of modeled field excitatory postsynaptic potential from those measured in rat hippocampus slices with microelectrode technique when inhibitors were applied. The results of the parametric identification of proposed model show that the model can adequately describe the generation of field excitatory postsynaptic potentials and their inhibition. The elaborated method afforded to evaluate the numerical meanings of eleven synaptic transmission hidden parameters. Using these parameters we have modelled the key synaptic transmission stages and got the time courses of the main biochemical participants: calcium ions in presynaptic bouton, SNARE complexes, synaptic vesicles in different states, glutamate in the synaptic cleft and open channels of AMPA receptor on the postsynaptic membrane. Thus, we propose method of hidden parameters evaluation that can be applied for different synaptic contacts in the brain of mammalians.

Long-term potentiation enhancing effect of epileptic insult in the CA1 area is dependent on prior-application of primed-burst stimulation.

Herein field recordings were utilized to test the effects of a transient period of pentylenetetrazol (PTZ) treatment on theta-burst long-term potentiation (LTP) at the Schaffer collateral-CA1 synapses as well as RT-PCR was used to investigate the effects of the combination of the pharmacological treatment and the theta-burst LTP induction on the expression of NMDA subunit mRNA in hippocampal slices. The slope of field excitatory postsynaptic potential (fEPSP) was unaffected while the population spike amplitude and area were increased by a transient period of PTZ treatment (3mM, 10min). After a theta burst, a brief PTZ exposure can lead to an enhancement of LTP as documented by fEPSP recording. The effect can be blocked by a selective NMDA receptor antagonist DL-AP5. An increase in the expression of GluN2B and GluN2A subunit mRNAs was also shown due to the combined treatment. The results indicate that the combined treatment increases the degree of NMDA-dependent LTP and are in accord with literature data on the subunit alterations of the hippocampal NMDA receptors. Moreover, our experimental paradigm can be used as a new approach to study the relevance of LTP-like phenomena and epileptic mechanisms.

Exploring the form- And time-dependent effect of low-frequency electromagnetic fields on maintenance of hippocampal long-term potentiation.

Low-frequency electromagnetic field (LF-EMF) stimulation is an emerging neuromodulation tool that is attracting more attention because of its non-invasive and well-controlled characteristics. However, the effect of different LF-EMF features including the forms and the time of addition on neuronal activity has not been completely understood. In this study, we used multi-electrode array (MEA) systems to develop a flexible in vitro magnetic stimulation device with plug-and-play features that allows for real-time delivery of LF-EMFs to biological tissues. Crucially, the method enables different forms of LF-EMF to be added at any time to a long-term potentiation (LTP) experiment without interrupting the process of LTP induction. We demonstrated that the slope of field excitatory postsynaptic potentials (fEPSPs) decreased significantly under post or priming uninterrupted sine LF-EMFs. The fEPSPs slope would continue to decline significantly when LF-EMFs were added two times with a 20-min interval. Paired-pulse ratio (PPR) was analyzed and the results reflected that LF-EMFs induced LTP was expressed postsynaptically. The results of pharmacological experiments indicated that AMPA receptor activity was involved in the process of LTP loss caused by post-LF-EMFs. Moreover, the effect of priming sine or Quadripulse stimulation (QPS)-patterned LF-EMFs depended on the time interval between the end of LF-EMF and the beginning of baseline recording. Interestingly, the effect of sine LF-EMFs on LTP would not disappear within 120min, while the impact of QPS-patterned LF-EMFs on LTP might disappear after 90min. These results indicated that LF-EMF might have a form- and time-dependent effect on LTP.

Hippocampal changes in mice lacking an active prohormone convertase 2.

Prohormone convertase 2 (PC2) is essential for the biosynthesis of many neuropeptides, including several of them in hippocampus. In mouse brain, lacking an enzymatically active PC2 (PC2-null) causes accumulation of many neuropeptides in their precursor or intermediate forms. Little is known about how a PC2-null state may affect the function of the hippocampus. In this study, adult PC2-null mice and their wildtype (WT) littermates were subjected to three analyses to determine possible changes associated with PC2-null at physiological, behavioral, and molecular levels, respectively, under normal and stressed conditions. Electrophysiological recordings of hippocampal slices were performed to measure evoked field-excitatory postsynaptic potentials (EPSP), long-term potentiation (LTP), and paired-pulse facilitation (PPF). Morris water maze (MWM) testing was conducted to examine behavioral changes that are indicative of hippocampal integrity. Quantitative mass spectrometry analysis was used to determine changes in the hippocampal proteome in response to a focal cerebral ischemic insult. We found that there were no significant differences in the threshold of evoked EPSPs between PC2-null and WT animals. However, an increase in LTP in both triggering rate and amplitude was observed in PC2-null mice, suggesting that PC2 may be involved in regulating synaptic strength. The PPF, on the other hand, showed a decrease in PC2-null mice, suggesting a presynaptic mechanism. Consistent with changes in LTP, PC2-null mice displayed decreased latencies in finding the escape platform in the MWM test. Further, after distal focal cerebral ischemia, the hippocampal proteomes incurred changes in both WT and PC2-null mice, with a prominent change in proteins associated with neurotransmission, exocytosis, and transport processes seen in the PC2-null but not WT mice. Taken together, our results suggest that PC2 is involved in regulating hippocampal synaptic plasticity, learning, and memory behaviors, as well as the hippocampal response to stresses originating in other regions of the brain.

Altered Cognitive Flexibility and Synaptic Plasticity in the Rat Prefrontal Cortex after Exposure to Low (≤15 cGy) Doses of 28Si Radiation.

This study has established the impact that 1-15 cGy 600 MeV/n 28Si radiation had on cognitive flexibility performance, glutamatergic synaptic transmission and plasticity in the prelimbic area (PrL) of the medial prefrontal cortex (mPFC) of ∼10-month-old (at the time of irradiation) male Wistar rats. Exposure to 1 cGy 600 MeV/n 28Si ions resulted in significantly impaired performance in the simple (SD) and compound discrimination (CD) stages of the attentional set shifting (ATSET) task. However, there was a pronounced non-linear dose response for cognitive impairment. Should similar effects occur in astronauts, the impairment of SD performance would result in a decreased ability to identify and learn the "rules" required to respond to new tasks/situations, while the impaired CD performance would result in a decreased ability to identify and maintain focus on relevant aspects of the task being conducted. The irradiated rats were also screened for performance in a task for unconstrained cognitive flexibility (UCFlex), often referred to as creative problem solving. Exposure to 1, 5 and 10 cGy resulted in a significant reduction in UCFlex performance, in an apparent all-or-none responsive manner. Importantly, performance in the ATSET test was not indicative of UCFlex performance. From a risk assessment perspective, these findings suggest that a value based on a single behavioral end point may not fully represent the cognitive deficits induced by space radiation, even within the cognitive flexibility domain. After completion of the cognitive flexibility testing, in vitro electrophysiological assessments of glutamatergic synaptic transmission and plasticity were performed in slices of the PrL cortex of 10 cGy irradiated rats. Extracellular recordings of field excitatory postsynaptic potentials revealed that radiation significantly decreased long-term depression in layer L5. Patch-clamp whole cell recordings in pyramidal neurons of the L2-3 revealed reduced frequency of spontaneous excitatory postsynaptic currents indicating alterations in presynaptic glutamate release and impaired neuronal spiking (e.g., decreased action potential amplitudes) in irradiated neurons. However, there was no obvious correlation between magnitudes of these electrophysiological decrements and the cognitive performance status of the irradiated rats. These data suggest that while radiation-induced changes in synaptic plasticity in the PrL cortex may be associated with cognitive impairment, they are most likely not the sole determinant of the incidence and severity of such impairments.

Treadmill exercise restores memory and hippocampal synaptic plasticity impairments in ovalbumin-sensitized juvenile rats: Involvement of brain-derived neurotrophic factor (BDNF)

Studies demonstrate that asthma, especially during childhood, affects the functions of the brain including learning and memory. Exercise is well known for its neuroprotective functions and for its beneficial effects on asthma. We aimed to assess the effects of exercise on cognitive function, synaptic plasticity, and hippocampal brain-derived neurotrophic factor (BDNF) levels in ovalbumin (OVA) sensitized juvenile rats. Rats were sensitized by intraperitoneal administration and inhaled OVA. Animals were subjected to treadmill running exercise during the OVA-challenged period. T-helper type 2 (Th2) cytokine [interleukin (IL)-4], Th1 cytokine (INF-γ) levels, and INF-γ/IL-4 (Th1/Th2) ratio in bronchoalveolar lavage fluid (BALF), and tracheal response to methacholine and OVA were measured. Further, memory behaviors and BDNF levels were measured in the hippocampus as well as long-term potentiation (LTP) was assessed by recording field excitatory postsynaptic potentials (fEPSPs) in the hippocampus. The levels of IL-4 and TGF-β were decreased but INF-γ level and INF-γ/IL-4 ratio increased in the BALF due to exercise in the OVA-sensitized animals. In addition, exercise improved OVA-sensitization induced cognitive impairments, increased BDNF levels, and enhanced hippocampal LTP in OVA-sensitized rats. Exercise is not only effective in the alleviation of airway inflammation by restoring Th1/Th2 cytokines balance, but also is a candidate for improvement of memory and synaptic plasticity deficits partially through increasing the levels of hippocampal BDNF in OVA-sensitized rats.

Exposure to 1-bromopropane vapors during pregnancy enhances the development of hippocampal neuronal excitability in rat pups during lactation.

ObjectivesAlthough 1‐Bromopropane (1‐BP) exposure has been reported to cause neurotoxicity in adult humans and animals, its effects on the development of the central nervous system remain unclear. Recently, we reported delayed developmental neurotoxicity (DNT) upon 1‐BP exposure in rats. Here we aimed to study the effect of prenatal 1‐BP exposure on the hippocampal excitability in the juvenile offspring.MethodsPregnant Wistar rats were exposed to vaporized 1‐BP for 20 days (6 h/d) with concentrations of 0 (control), 400, or 700 ppm. Hippocampal slices were prepared from male offspring during postnatal days (PNDs) 13, 14, and 15. Field excitatory postsynaptic potential (fEPSP) and population spike (PS) were recorded simultaneously from the CA1 region.ResultsIn the exposed groups, the stimulation/response relationships of fEPSP slope and PS amplitude were enhanced more than in the control group at PND 14. Analysis of fEPSP‐spike coupling demonstrated increased values of Top and Eslope50 in the exposed groups. Real‐time PCR analysis showed a significant increase in the mRNA levels of the adult type Nav1.1 Na+ channel subunit and the GluR1 glutamate receptor subunit in the hippocampus of the 700 ppm group at PND 14.ConclusionsOur results provide evidence that prenatal exposure to 1‐BP accelerates developmental enhancement of hippocampal excitability in the pups before eye‐opening. The current study suggests that our evaluation method of DNT is applicable to the industrial chemical 1‐BP.

MicroRNA134 of Ventral Hippocampus Is Involved in Cocaine Extinction-Induced Anxiety-like and Depression-like Behaviors in Mice

We previously found that cocaine abuse could increase microRNA134 (miR134) levels in the hippocampus; yet the roles of miR134 in cocaine-related abnormal psychiatric outcomes remain unknown. In this study, using the cocaine-induced conditioned place preference (CPP) mice model, we found that mice exhibit enhanced anxiety-like and depression-like behaviors during the cocaine extinction (CE) period of CPP, accompanied by obviously increased miR134 levels and decreased levels of 19 genes that are associated with synaptic plasticity, glia activity, and neurochemical microenvironments, in the ventral hippocampus (vHP). Knockdown of miR134 in vHP in vivo reversed the changes in 15 of 19 potential gene targets of miR134 and rescued the abnormal anxiety-like and depression-like behavioral outcomes in CE mice. In parallel, knockdown of miR134 reversed CE-induced changes in dendritic spines and synaptic proteins and increased the field excitatory postsynaptic potential (fEPSP) of CA1 pyramidal neurons in the vHP of CE mice. In addition, knockdown of miR134 suppressed the CE-enhanced microglia activity, inflammatory, apoptotic, and oxidative stress statuses in the vHP. With the data taken together, miR134 may be involved in cocaine-associated psychiatric problems, potentially via regulating the expressions of its gene targets that are related to synaptic plasticity and neurochemical microenvironments.

Effect of Electroacupuncture at GV20 on Sleep Deprivation-Induced Depression-Like Behavior in Mice.

Accumulating evidence suggests that sleep deprivation (S-Dep) is a critical risk factor for depression. Electroacupuncture (EA) treatment has been reported to ameliorate posttraumatic stress disorder- (PSTD-) like behavior and enhance hippocampal neurogenesis. However, whether EA treatment has any beneficial effect on S-Dep-induced depression-like behavior is still unknown. In the present study, we focused on whether EA at Baihui (GV20) can ameliorate the deterioration effect of S-Dep in mice. Mice were randomly divided into normal, S-Dep, S-Dep + EA, and S-Dep + sham EA groups. Cognitive behavior test and in vitro assay were performed separately to avoid the influence of behavior test on synaptic transmission and protein expression. Depression-like behaviors were determined by forced swimming test (FST), tail suspension test (TST), and Morris water maze (MWM). Neurogenesis was identified by BrdU, DCX, and NeuN immunofluorescence staining. In vitro long-term potentiation was detected by high frequency stimulation (HFS) at Schaffer collateral-CA1 synapses in hippocampal slices. Brain-derived neurotropic factor (BDNF) and tropomyosin receptor kinase B (TrkB) protein expression level were assayed by western blot. Our results indicated that D-Sep mice demonstrated depression-like behaviors determined by prolonged immobility duration in FST and TST; D-Sep mice also manifested spatial memory retention deficit in MWM. Furthermore, EA treatment ameliorated D-Sep-induced depression-like behaviors and spatial memory retention deficit. Mechanically, EA treatment alleviated neuron progenitor cell proliferation and differentiation, ameliorated the field excitatory postsynaptic potentials (fEPSPs) slope impaired by S-Dep, and elevated BDNF/TrkB protein expression. Taken together, our data suggested that EA treatment has a protective effect on S-Dep-induced depression-like behavior and cognitive impairment, which may be through regulating BDNF/TrkB protein expression.

Alteration of the neurogenesis and long term potential of olfactory bulb in an animal model of PTSD

Failure of extinction of fear-conditioned traumatic memory is the main pathology behind post-traumatic stress disorder (PTSD). Functional and structural dysfunctions in the olfactory system are implicated by studies in PTSD patients. However, little is known regarding the neurobiological networks of trauma‑related odor sensitivity in PTSD. Male Wistar rats were exposed with a female cat for 10 min and long-term stress was evaluated by behavioral tests, containing open field (OF) and elevated plus maze (EPM). To prove the PTSD model, the serum level of cortisol was evaluated and compared with the control group. Local field potential (LFP) was applied to compare the electrophysiology of the OB in two groups. To assess neurogenesis, the expression of nestin, and doublecortin were evaluated. Data from EPM revealed a significant increase in spent time in the closed arms in PTSD group. We observed a significant reduction in OF parameters in terms of the total distance traveled, the time spent in the central zone, and the number of crossing the central zone in PTSD group compared to the control group. The mean serum cortisol level was significantly higher in the PTSD group than the control group. In LFP recording, the slope and the amplitude of field excitatory postsynaptic potential (fEPSP) in the PTSD group were significantly higher than that of the control group. Our results also showed that the mRNA expression level of nestin as a neural progenitor marker and doublecortin, as an immature neuron marker, significantly decreased in the PTSD group compared to the control group. This study has shown that PTSD can disrupt the OB function through decreasing neurogenesis. More information on PTSD and OB would help us to establish a greater degree of accuracy on this matter.