Amplitude Of Excitatory Postsynaptic Potentials Research Articles

Diffusion-Based Model for Synaptic Molecular Communication Channel.

Computational methods have been extensively used to understand the underlying dynamics of molecular communication methods employed by nature. One very effective and popular approach is to utilize a Monte Carlo simulation. Although it is very reliable, this method can have a very high computational cost, which in some cases renders the simulation impractical. Therefore, in this paper, for the special case of an excitatory synaptic molecular communication channel, we present a novel mathematical model for the diffusion and binding of neurotransmitters that takes into account the effects of synaptic geometry in 3-D space and re-absorption of neurotransmitters by the transmitting neuron. Based on this model we develop a fast deterministic algorithm, which calculates expected value of the output of this channel, namely, the amplitude of excitatory postsynaptic potential (EPSP), for given synaptic parameters. We validate our algorithm by a Monte Carlo simulation, which shows total agreement between the results of the two methods. Finally, we utilize our model to quantify the effects of variation in synaptic parameters, such as position of release site, receptor density, size of postsynaptic density, diffusion coefficient, uptake probability, and number of neurotransmitters in a vesicle, on maximum number of bound receptors that directly affect the peak amplitude of EPSP.

Intravenous self-administration of benzydamine, a non-steroidal anti-inflammatory drug with a central cannabinoidergic mechanism of action.

Benzydamine (BZY) is a non-steroidal anti-inflammatory drug used for the topical treatment of inflammations of the oral and vaginal mucosae. Virtually nothing is known about the central pharmacological actions of BZY. Yet there are reports of voluntary systemic overdosage of BZY in drug addicts, resulting in a euphoric, hallucinatory state. In the present study, we investigated the reinforcing properties of BZY in a rat self-administration paradigm. We found that BZY has a powerful reinforcing effect and that this effect is greatly facilitated in animals that already had substance experience, having previously self-administered heroin and cocaine, indicating cross sensitization between BZY and other common drugs of abuse. We then assessed the effect of BZY on prelimbic cortex-to-nucleus accumbens glutamatergic transmission, using field recordings in rat parasagittal brain slices. BZY dose-dependently reduced both field excitatory post synaptic potential amplitude and paired pulse ratio, suggesting a presynaptic mechanism of action. Similarly to the in vivo paradigm, also the electrophysiological effects of BZY were potentiated in slices from animals that had undergone cocaine and heroin self-administration. Furthermore, BZY-induced Long Term Depression (LTD)-like responses in the prelimbic cortex-to-nucleus accumbens circuitry were significantly reduced in the presence of the CB1 receptor antagonist AM251. These findings provide firm evidence of the abuse liability of BZY and suggest a possible cannabinoidergic mechanism of action. Further research is needed in order to give insights into the molecular mechanism underlying BZY psychoactive and reinforcing effects, to better understand its abuse potential.

Very low concentrations of ethanol suppress excitatory synaptic transmission in rat visual cortex.

Ethanol is one of the most commonly used substances in the world. Behavioral effects of alcohol are well described, however, cellular mechanisms of its action are poorly understood. There is an apparent contradiction between measurable behavioral changes produced by low concentrations of ethanol, and lack of evidence of synaptic changes at these concentrations. Furthermore, effects of ethanol on synaptic transmission in the neocortex are poorly understood. Here, we set to determine effects of ethanol on excitatory synaptic transmission in the neocortex. We show that 1-50mm ethanol suppresses excitatory synaptic transmission to layer 2/3 pyramidal neurons in rat visual cortex in a concentration-dependent manner. To the best of our knowledge, this is the first demonstration of the effects of very low concentrations of ethanol (from 1mm) on synaptic transmission in the neocortex. We further show that a selective antagonist of A1 adenosine receptors, 8-cyclopentyl-1,3-dipropylxanthine (DPCPX), blocks effects of 1-10mm ethanol on synaptic transmission. However, the reduction in excitatory postsynaptic potential amplitude by 50mm ethanol was not affected by DPCPX. We propose that ethanol depresses excitatory synaptic transmission in the neocortex by at least two mechanisms, engaged at different concentrations: low concentrations of ethanol reduce synaptic transmission via A1 R-dependent mechanism and involve presynaptic changes, while higher concentrations activate additional, adenosine-independent mechanisms with predominantly postsynaptic action. Involvement of adenosine signaling in mediating effects of low concentrations of ethanol may have important implications for understanding alcohol's effects on brain function, and provide a mechanistic explanation to the interaction between alcohol and caffeine.

Functional Coupling of BK Channels to NMDA Receptors in Hippocampal Dentate Gyrus

The large conductance calcium- and voltage-activated potassium channel (BK channels) is widely expressed in the central nervous system. The physiological roles of BK channels and the calcium sources of their activation in mammalian brain remain not well-understood. Our proteomic and biochemical analyses of BK channels and the calcium-permeable NMDA receptors and have found that they form protein complexes in whole brain and various brain regions, consisting of the obligatory BK channel alpha-subunit and GluN1 subunits and at least the regulatory GluN2A and GluN2B subunits. We examined the functional coupling of BK channels to NMDA receptors in mice hippocampal dentate gyrus. We observed that glutamate evoked outward currents of BK channels in dentate gyrus granule cell soma at potentials more positive than −20 mV which were sensitive to BK channel-specific blocker paxilline and abolished by NMDA receptor antagonist AP-5. We also found that blockade of BK channels by paxilline increased the amplitude of excitatory postsynaptic potential (EPSP) of granule cells evoked by stimulation in the perforant path-granule cell synapses, which was prevented by the presence of AP-5. We thus inferred that BK channels were activated by NMDA receptor-mediated Ca2+ influx in hippocampal dentate gyrus granule cells and the calcium-mediated functional coupling between these two types of channels plays a role in regulation of synaptic transmission.

Age-dependent alterations in neuronal activity in the hippocampus and visual cortex in a mouse model of Juvenile Neuronal Ceroid Lipofuscinosis (CLN3)

Juvenile Neuronal Ceroid Lipofuscinosis (JNCL) is a fatal lysosomal storage disease caused by autosomal recessive mutations in CLN3. JNCL is typified by progressive neurodegeneration that has been suggested to occur from excessive excitatory and impaired inhibitory synaptic input; however, no studies to date have directly evaluated neuronal function. To examine changes in neuronal activity with advancing disease, electrophysiological recordings were performed in the CA1 hippocampus (HPC) and visual cortex (VC) of acute brain slices from Cln3Δex7/8 mice at 1, 4, 8, and 12months of age. Basic electrophysiological parameters, such as field excitatory post-synaptic potential (fePSP) and population spike (PS) amplitudes, were not altered in Cln3Δex7/8 CA1 and VC neurons at any age. However, fiber volley (FV) amplitudes were significantly increased in Cln3Δex7/8 neurons in the HPC at 1month as well as layer II/III of the VC at 1 and 4months, suggesting increased axonal excitability. In older Cln3Δex7/8 mice (8 and 12months), FV amplitude in the CA1 HPC and VC reached levels that were equal to or significantly lower than WT animals. Significant alterations in the synaptic strength of Cln3Δex7/8 CA1 neurons were also linked to age-dependent changes in axonal responses. Additionally, paired-pulse and 12-pulse facilitation responses calculated from PS recordings were significantly decreased in the CA1 HPC and layer II/III of the VC of Cln3Δex7/8 mice at all ages, suggesting permanent alterations in neuronal short-term plasticity. Collectively, our study has identified novel age- and region-dependent alterations in axonal excitability as well as synaptic and non-synaptic neuronal activity in Cln3Δex7/8 mice during disease progression, which may inform neurodegenerative mechanisms in JNCL.

Age- and Sex-Dependent Impact of Repeated Social Stress on Intrinsic and Synaptic Excitability of the Rat Prefrontal Cortex.

Stress is implicated in psychiatric illnesses that are characterized by impairments in cognitive functions that are mediated by the medial prefrontal cortex (mPFC). Because sex and age determine stress vulnerability, the effects of repeated social stress occurring during early adolescence, mid-adolescence, or adulthood on the cellular properties of male and female rat mPFC Layer V neurons in vitro were examined. Repeated resident–intruder stress produced age- and sex-specific effects on mPFC intrinsic and synaptic excitability. Mid-adolescents were particularly vulnerable to effects on intrinsic excitability. The maximum number of action potentials (APs) evoked by increasing current intensity was robustly decreased in stressed male and female mid-adolescent rats compared with age-matched controls. These effects were associated with stress-induced changes in AP half-width, amplitude, threshold, and input resistance. Social stress at all ages generally decreased synaptic excitability by decreasing the amplitude of spontaneous excitatory postsynaptic potentials. The results suggest that whereas social stress throughout life can diminish the influence of afferents driving the mPFC, social stress during mid-adolescence additionally affects intrinsic characteristics of mPFC neurons that determine excitability. The depressant effects of social stress on intrinsic and synaptic mPFC neurons may underlie its ability to affect executive functions and emotional responses, particularly during adolescence.

α1-Adrenoceptors in the hippocampal dentate gyrus involved in learning-dependent long-term potentiation during active-avoidance learning in rats.

The hippocampus is the key structure for learning and memory in mammals and long-term potentiation (LTP) is an important cellular mechanism responsible for learning and memory. The influences of norepinephrine (NE) on the modulation of learning and memory, as well as LTP, through β-adrenoceptors are well documented, whereas the role of α1-adrenoceptors in learning-dependent LTP is not yet clear. In the present study, we measured extracellular concentrations of NE in the hippocampal dentate gyrus (DG) region using an in-vivo brain microdialysis and high-performance liquid chromatography techniques during the acquisition and extinction of active-avoidance behavior in freely moving conscious rats. Next, the effects of prazosin (an antagonist of α1-adrenoceptor) and phenylephrine (an agonist of the α1-adrenoceptor) on amplitudes of field excitatory postsynaptic potential were measured in the DG region during the active-avoidance behavior. Our results showed that the extracellular concentration of NE in the DG was significantly increased during the acquisition of active-avoidance behavior and gradually returned to the baseline level following extinction training. A local microinjection of prazosin into the DG significantly accelerated the acquisition of the active-avoidance behavior, whereas a local microinjection of phenylephrine retarded the acquisition of the active-avoidance behavior. Furthermore, in all groups, the changes in field excitatory postsynaptic potential amplitude were accompanied by corresponding changes in active-avoidance behavior. Our results suggest that NE activation of α1-adrenoceptors in the hippocampal DG inhibits active-avoidance learning by modulation of synaptic efficiency in rats.

Subchronic metformin pretreatment enhances novel object recognition memory task in forebrain ischemia: behavioural, molecular, and electrophysiological studies.

Metformin exerts its effect via AMP-activated protein kinase (AMPK), which is a key sensor for energy homeostasis that regulates different intracellular pathways. Metformin attenuates oxidative stress and cognitive impairment. In our experiment, rats were divided into 8 groups; some were pretreated with metformin (Met, 200 mg/kg) and (or) the AMPK inhibitor Compound C (CC) for 14 days. On day 14, rats underwent transient forebrain global ischemia. Data indicated that pretreatment of ischemic rats with metformin reduced working memory deficits in a novel object recognition test compared to group with ischemia-reperfusion (I-R) (P < 0.01). Pretreatment of the I-R animals with metformin increased phosphorylated cyclic-AMP response element-binding protein (pCREB) and c-fos levels compared to the I-R group (P < 0.001 for both). The level of CREB and c-fos was significantly lower in ischemic rats pretreated with Met + CC compared to the Met + I-R group. Field excitatory postsynaptic potential (fEPSP) amplitude and slope was significantly lower in the I-R group compared to the sham operation group (P < 0.001). Data showed that fEPSP amplitude and slope was significantly higher in the Met + I-R group compared to the I-R group (P < 0.001). Treatment of ischemic animals with Met + CC increased fEPSP amplitude and slope compared to the Met + I-R group (P < 0.01). We unravelled new aspects of the protective role of AMPK activation by metformin, further emphasizing the potency of metformin pretreatment against cerebral ischemia.

Iridium Oxide-Electrodeposited Nanoporous Gold Multielectrode Array with Enhanced Stimulus Efficacy.

A multielectrode array (MEA) was fabricated with electrodes consisting of iridium oxide (IrOx) electrochemically deposited on nanoporous gold (NPG) to improve the moderate charge injection limit (ca. 1 mC cm-2) of NPG MEA. IrOx was electrodeposited by performing cyclic voltammetry with an IrOx deposition solution. The IrOx was electrodeposited on Au (EIROF/Au) and on NPG (EIROF/NPG) MEA, and the samples were analyzed in terms of the charge injection limit, charge storage capacity (CSC), and electrochemical impedance. The charge injection limit of the EIROF(100-cycled)/NPG MEA was estimated to be 2.3 mC cm-2 by measuring the voltage transient, and this value is sufficiently greater than the neural damage threshold (ca. 1 mC cm-2) and is also comparable to that of sputtered IrOx films. Considering the low charge injection limit (<0.1 mC cm-2) for the EIROF(100-cycled)/Au MEA, the high charge injection limit for the EIROF/NPG MEA was explained to be a result of synergetic combination of the inherently large surface area of the NPG and electrically active EIROF. The EIROF(100-cycled)/NPG exhibited an impedance of 9.7 ± 0.45 kΩ at 1 kHz and a CSC of 8 mC/cm-2, respectively, obtained via electrochemical impedance spectroscopy and integration of the cathodic current in a cyclic voltammogram. Scanning transmission electron microscopy and energy-dispersive X-ray spectroscopy are used to conduct an elemental mapping analysis of the cross-sectional structure of the EIROF/NPG and revealed that the EIROF had been uniformly deposited on the surface of the interconnected Au. The efficacy of the improvement in the charge injection limit of the EIROF/NPG MEA was evaluated with rat hippocampal slices. The EIROF/NPG electrodes exhibited a steeper increase in the negative peak amplitude of the field excitatory postsynaptic potentials (fEPSPs), even with an electrical stimulation of a lower amplitude (1-4 V), prolonged negative fEPSPs wave after peak response, and decreased serial reduction of fEPSPs compared to NPG MEA, all of which strongly indicate an improved charge injection for the EIROF/NPG MEA over NPG MEA.

Protein Kinase Cϵ (PKCϵ) Promotes Synaptogenesis through Membrane Accumulation of the Postsynaptic Density Protein PSD-95

Protein kinase Cϵ (PKCϵ) promotes synaptic maturation and synaptogenesis via activation of synaptic growth factors such as BDNF, NGF, and IGF. However, many of the detailed mechanisms by which PKCϵ induces synaptogenesis are not fully understood. Accumulation of PSD-95 to the postsynaptic density (PSD) is known to lead to synaptic maturation and strengthening of excitatory synapses. Here we investigated the relationship between PKCϵ and PSD-95. We show that the PKCϵ activators dicyclopropanated linoleic acid methyl ester and bryostatin 1 induce phosphorylation of PSD-95 at the serine 295 residue, increase the levels of PSD-95, and enhance its membrane localization. Elimination of the serine 295 residue in PSD-95 abolished PKCϵ-induced membrane accumulation. Knockdown of either PKCϵ or JNK1 prevented PKCϵ activator-mediated membrane accumulation of PSD-95. PKCϵ directly phosphorylated PSD-95 and JNK1 in vitro Inhibiting PKCϵ, JNK, or calcium/calmodulin-dependent kinase II activity prevented the effects of PKCϵ activators on PSD-95 phosphorylation. Increase in membrane accumulation of PKCϵ and phosphorylated PSD-95 (p-PSD-95(S295)) coincided with an increased number of synapses and increased amplitudes of excitatory post-synaptic potentials (EPSPs) in adult rat hippocampal slices. Knockdown of PKCϵ also reduced the synthesis of PSD-95 and the presynaptic protein synaptophysin by 30 and 44%, respectively. Prolonged activation of PKCϵ increased synapse number by 2-fold, increased presynaptic vesicle density, and greatly increased PSD-95 clustering. These results indicate that PKCϵ promotes synaptogenesis by activating PSD-95 phosphorylation directly through JNK1 and calcium/calmodulin-dependent kinase II and also by inducing expression of PSD-95 and synaptophysin.

Inhibition of Endocannabinoid Degradation Improves Outcomes from Mild Traumatic Brain Injury: A Mechanistic Role for Synaptic Hyperexcitability.

Traumatic brain injury (TBI) is an increasingly prevalent condition affecting soldiers, athletes, and motor vehicle accident victims. Unfortunately, it currently lacks effective therapeutic interventions. TBI is defined as a primary mechanical insult followed by a secondary cascade involving inflammation, apoptosis, release of reactive oxygen species, and excitotoxicity, all of which can cause synaptic changes, altered neuronal signaling, and, ultimately, behavioral changes. Previously we showed that preventing degradation of the endocannabinoid (EC) 2-acylglycerol (2-AG) with JZL184 after mild TBI attenuated neuroinflammation and improved recovery of neurobehavioral function during the early 24 h post-TBI period. The aim of this study was to extend the timeline of observations to 2 weeks post-injury and to investigate JZL184's impact on synaptic transmission, which we view as a potential mechanism for TBI-induced cellular and behavioral pathology. Adult male rats underwent mild TBI (mTBI) followed by a single intraperitoneal injection of JZL184 or vehicle 30 min post-injury. JZL184 administered-TBI animals showed improved neurobehavioral recovery compared with vehicle-injected TBI animals beginning 24 h post-injury and persisting for 2 weeks. JZL184-treated animals had significantly diminished gray and white matter astrocyte activation when compared with vehicle-treated animals at day 7 post-TBI. JZL184 administration significantly attenuated the increased pGluR1S845/GluR1 and pERK 1/2/ERK and the increases in miniature excitatory postsynaptic potential (mEPSC) frequency and amplitude observed in layer 5 pyramidal neurons at 10 days post-TBI. These results suggest a neuroprotective role for ECs in ameliorating the TBI-induced neurobehavioral, neuroinflammatory, and glutamate dyshomeostasis from mTBI. Further studies elucidating the cellular mechanisms involved are warranted.

Thalamocortical-auditory network alterations following cuprizone-induced demyelination.

BackgroundDemyelination and remyelination are common pathological processes in many neurological disorders, including multiple sclerosis (MS). Clinical evidence suggests extensive involvement of the thalamocortical (TC) system in patients suffering from MS.MethodsUsing murine brain slices of the primary auditory cortex, we investigated the functional consequences of cuprizone-induced de- and remyelination on neuronal activity and auditory TC synaptic transmission in vitro.ResultsOur results revealed an impact of myelin loss and restoration on intrinsic cellular firing patterns, synaptic transmission, and neuronal plasticity in layer 3 and 4 neurons of the auditory TC network. While there was a complex hyper- and depolarizing shift of the resting membrane potential, spontaneous and induced action potential firing was reduced during demyelination and early remyelination. In addition, excitatory postsynaptic potential amplitudes were decreased and induction of LTP was reduced during demyelination.ConclusionsThese data indicate that demyelination-induced impairment of neurons and network activity within the TC system may underlie clinical symptoms observed in demyelinating diseases, corroborating human findings that disease progression is significantly correlated with microstructural tissue damage of the TC system. Further investigation into focal inflammation-induced demyelination models ex vivo and in vivo are needed to understand the functional implication of local and remote lesion formation on TC network activity in MS.

Serotonin modulates the excitatory synaptic transmission in the dentate granule cells.

Serotonergic fibers from the raphe nuclei project to the hippocampal formation, the activity of which is known to modulate the inhibitory interneurons in the dentate gyrus. On the other hand, serotonergic modulation of the excitatory synapses in the dentate gyrus is not well examined. In the present study, we examined the effects of 5-HT on the excitatory postsynaptic potentials (EPSPs) in the dentate granule cells evoked by the selective stimulation of the lateral perforant path (LPP), the medial perforant path (MPP), or the mossy cell fibers (MCF). 5-HT depressed the amplitude of unitary EPSPs (uEPSPs) evoked by the stimulation of LPP or MPP, whereas uEPSPs evoked by MCF stimulation were little affected. The effect was partly explained by the decrease of the resting membrane resistance following the activation of 5-HT1A receptors, which was confirmed by computer simulations. We also found that the probability of evoking uEPSP by LPP stimulation but not MPP or MCF stimulation was reduced by 5-HT and that the paired-pulse ratio of LPP-evoked EPSP but not that of MPP- or MCF-evoked ones was increased by 5-HT. These effects were blocked by 5-HT2 antagonist, suggesting that the transmitter release in the LPP-granule cell synapse is inhibited by the activation of 5-HT2 receptors. The present results suggest that 5-HT can modulate the EPSPs in the dentate granule cells by at least two distinct mechanisms.

Effects of garlic extract on spreading depression: In vitro and in vivo investigations

Objectives: The potential use of garlic for prevention and treatment of different types of headaches has been suggested by several medieval literatures. Cortical spreading depression (CSD), a propagating wave of neuroglial depolarization, was established as a target for anti-migraine drugs. This study was designed to investigate the effect of garlic extract on CSD in adult rats.Methods: CSD was induced by KCl microinjection in the somatosensory cortex. The effects of five different concentrations of garlic oil (1–500 μl/l) were tested on different characteristic features of CSD in necocortical slices. In in vivo experiments, the effects of garlic oil on electrophysiological and morphological changes induced by CSD were investigated.Results: Garlic oil in a dose-dependent manner decreased the amplitude of CSD but not its duration and velocity in neocortical brain slices. Garlic oil at concentration of 500 μl/l reversibly reduced the amplitude of the field excitatory post-synaptic potentials and inhibited induction of long-term potentiation in the third layer of neocortical slices. In in vivo studies, systemic application of garlic oil (1 ml/l) for three consecutive days reduced the amplitude and repetition rate of CSD. Garlic oil also prevented of CSD-induced reactive astrocytosis in the neocortex.Discussion: Garlic oil suppresses CSD, likely via inhibition of synaptic plasticity, and prevents its harmful effects on astrocyte. Further studies are required to identify the exact active ingredient(s) of garlic oil that inhibit CSD and may have the potential to use in treatment of CSD-related disorders.

Lipopolysaccharide-Induced Spatial Memory and Synaptic Plasticity Impairment Is Preventable by Captopril.

Introduction. Renin-angiotensin system has a role in inflammation and also is involved in many brain functions such as learning, memory, and emotion. Neuroimmune factors have been proposed as the contributors to the pathogenesis of memory impairments. In the present study, the effect of captopril on spatial memory and synaptic plasticity impairments induced by lipopolysaccharide (LPS) was investigated. Methods. The rats were divided and treated into control (saline), LPS (1 mg/kg), LPS-captopril (LPS-Capto; 50 mg/kg captopril before LPS), and captopril groups (50 mg/kg) before saline. Morris water maze was done. Long-term potentiation (LTP) from CA1 area of hippocampus was assessed by 100 Hz stimulation in the ipsilateral Schaffer collateral pathway. Results. In the LPS group, the spent time and traveled path to reach the platform were longer than those in the control, while, in the LPS-Capto group, they were shorter than those in the LPS group. Moreover, the slope and amplitude of field excitatory postsynaptic potential (fEPSP) decreased in the LPS group, as compared to the control group, whereas, in the LPS-Capto group, they increased compared to the LPS group. Conclusion. The results of the present study showed that captopril improved the LPS-induced memory and LTP impairments induced by LPS in rats. Further investigations are required in order to better understand the exact responsible mechanism(s).

Dopamine-dependent CB1 receptor dysfunction at corticostriatal synapses in homozygous PINK1 knockout mice

Recessive mutations in the PTEN-induced putative kinase 1 (PINK1) gene cause early-onset Parkinson's disease (PD). We investigated the interaction between endocannabinoid (eCB) and dopaminergic transmission at corticostriatal synapses in PINK1 deficient mice. Whole-cell patch-clamp and conventional recordings of striatal medium spiny neurons (MSNs) were made from slices of PINK1−/−, heterozygous PINK1+/− mice and wild-type littermates (PINK1+/+). In PINK1+/+ mice, CB1 receptor (CB1R) activation reduced spontaneous excitatory postsynaptic currents (sEPSCs). Likewise, CB1R agonists (ACEA, WIN55,212-3 and HU210) induced a dose-dependent reduction of cortically-evoked excitatory postsynaptic potential (eEPSP) amplitude. While CB1R agonists retained their inhibitory effect in heterozygous PINK1+/− mice, conversely, in PINK1−/− mice they failed to modulate sEPSC amplitude. Similarly, CB1R activation failed to reduce eEPSP amplitude in PINK1−/− mice. Parallel biochemical measurements revealed no significant difference in the levels of the two main eCBs, 2-arachidonoylglycerol (2-AG) and anandamide (AEA) in PINK1−/− striata. Similarly, no change was observed in the enzymatic activity of both fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL), responsible for eCB hydrolysis. Instead, a significant reduction of binding ability of CB1R agonists was found in PINK1−/− mice. Notably, the CB1R-dependent inhibition of synaptic activity was restored either by amphetamine or after chronic treatment with the D2 dopamine receptor agonist quinpirole. Additionally, CB1R binding activity returned to control levels after chronic pretreatment with quinpirole.Consistent with the hypothesis of a close interplay with dopaminergic neurotransmission, our findings show a CB1R dysfunction at corticostriatal synapses in PINK1−/−, but not in PINK1+/− mice, and provide a mechanistic link to the distinct plasticity deficits observed in both genotypes.

Differential contribution of Ih to the integration of excitatory synaptic inputs in substantia nigra pars compacta and ventral tegmental area dopaminergic neurons.

The selective vulnerability of substantia nigra pars compacta (SNc) dopaminergic (DA) neurons is an enigmatic trait of Parkinson's disease (PD), especially if compared to the remarkable resistance of closely related DA neurons in the neighboring ventral tegmental area (VTA). Overall evidence indicates that specific electrophysiological, metabolic and molecular factors underlie SNc vulnerability, although many pieces of the puzzle are still missing. In this respect, we recently demonstrated that 1-methyl-4-phenylpyridinium (MPP+), the active metabolite of the parkinsonizing toxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), alters the electrophysiological properties of SNc DA neurons in vitro by inhibiting the hyperpolarization-activated current (Ih). Here, we present an electrophysiological investigation of the functional role of Ih in the integration of synaptic inputs in identified SNc and VTA DA neurons, comparatively, in acute midbrain slices from TH-GFP mice. We show that pharmacological suppression of Ih increases the amplitude and decay time of excitatory postsynaptic potentials, leading to temporal summation of multiple excitatory potentials at somatic level. Importantly, these effects are quantitatively more evident in SNc DA neurons. We conclude that Ih regulates the responsiveness to excitatory synaptic transmission in SNc and VTA DA neurons differentially. Finally, we present the hypothesis that Ih loss of function may be linked to PD trigger mechanisms, such as mitochondrial failure and ATP depletion, and act in concert with SNc-specific synaptic connectivity to promote selective vulnerability.

Neuronal nitric oxide synthase has a role in the detrimental effects of lipopolysaccharide on spatial memory and synaptic plasticity in rats.

The role of neuronal nitric oxide synthase (nNOS) in lipopolysaccharide (LPS)-induced memory and synaptic plasticity impairment was investigated. The rats were divided and treated as follows: (1) control (saline), (2) LPS, (3) 7NI (7-nitroindazole as a nNOS inhibitor)-LPS and (4) 7NI. In a Morris water maze, the LPS group took a longer amount of time and traveled a greater distance to reach the platform, this was prevented by 7NI. Malondialdehyde (MDA) and nitric oxide (NO) metabolites in the hippocampus of the LPS group were higher while the total thiol, superoxide dismutase and catalase were lower than that of the controlled specimen. Pre-treatment using 7NI prevented the changes in the biochemical criteria. The slope and amplitude of the field excitatory post-synaptic potential (fEPSP) in the LPS group decreased, whereas in 7NI-LPS group they increased. It is suggested that inhibition of nNOS by 7NI improves the deleterious effects of LPS by reducing NO metabolites and the brain tissues oxidative damage.

Radix Angelica Sinensis Promotes Synaptic Plasticity During Cognitive Recovery in Chronically Stressed Rats.

The accumulation of chronic stress is associated with cognitive dysfunction. Radix Angelica Sinensis (RAS) has been shown to have neuroprotective potential for treating Alzheimer's disease and vascular dementia. However, the impact of RAS on cognitive impairment induced by chronic stress has not been studied. In the present study, RAS significantly alleviated cognitive deficits in rats subjected to chronic restraint stress. This neuroprotective effect was associated with enhancement of synaptic efficacy by improving field excitatory postsynaptic potential amplitudes, alleviating adverse alterations in the structure of synapses and neurons in the hippocampus, and increasing the levels of brain-derived neurotrophic factor, microtubule-associated protein-2, and synaptophysin in the hippocampus. These findings provide initial evidence for the therapeutic potential of RAS for the treatment of neuronal deterioration caused by chronic stress.

Vitamin C reverses lead-induced deficits in hippocampal synaptic plasticity in rats.

Lead (Pb) is a neurotoxic metal that is widely distributed in the environment. In experimental animals, chronic exposure to this neurotoxicant resulted in impaired synaptic plasticity and cognitive function. In this study, we examined the protective effects of vitamin C (ascorbic acid) against Pb exposure-induced impairment of long-term potentiation (LTP). Forty-four adult male Wistar rats were divided into six groups and subjected to the following treatments for three months: (1) vehicle (distilled water); (2) Pb; (3) ascorbic acid; (4) Pb+ascorbic acid; (5) Pb (two months) followed by ascorbic acid; and (6) ascorbic acid (one month) followed by Pb. After treatment, the population spike (PS) amplitude and slope of excitatory postsynaptic potentials (EPSP) were measured in the dentate gyrus(DG) of rats in vivo. Following these measurements, blood samples were collected for the following biochemical assays: malondialdehyde (MDA), total antioxidant capacity (TAC), and total oxidant status (TOS). There was a significant increase in plasma MDA and TOS in the Pb-intoxicated group compared to the control group. There was a significant increase in TAC levels in the ascorbic acid group. Our results also show that Pb exposure caused a decrease in the EPSP slope and PS amplitude when compared with the control group, whereas vitamin C increased these parameters. Co-administration of Pb with vitamin C inhibited the effects of Pb. These findings suggested that Pb exposure caused impairment in LTP, that may have been mediated through oxidative damage. Vitamin C ameliorated the Pb-induced impairment of synaptic plasticity in the DG via antioxidant activity.