Excitatory Glutamatergic Transmission Research Articles

MiR-7 controls glutamatergic transmission and neuronal connectivity in a Cdr1as-dependent manner

The circular RNA (circRNA) Cdr1as is conserved across mammals and highly expressed in neurons, where it directly interacts with microRNA miR-7. However, the biological function of this interaction is unknown. Here, using primary cortical murine neurons, we demonstrate that stimulating neurons by sustained depolarization rapidly induces two-fold transcriptional upregulation of Cdr1as and strong post-transcriptional stabilization of miR-7. Cdr1as loss causes doubling of glutamate release from stimulated synapses and increased frequency and duration of local neuronal bursts. Moreover, the periodicity of neuronal networks increases, and synchronicity is impaired. Strikingly, these effects are reverted by sustained expression of miR-7, which also clears Cdr1as molecules from neuronal projections. Consistently, without Cdr1as, transcriptomic changes caused by miR-7 overexpression are stronger (including miR-7-targets downregulation) and enriched in secretion/synaptic plasticity pathways. Altogether, our results suggest that in cortical neurons Cdr1as buffers miR-7 activity to control glutamatergic excitatory transmission and neuronal connectivity important for long-lasting synaptic adaptations.

Toluene alters the intrinsic excitability and excitatory synaptic transmission of basolateral amygdala neurons.

Inhalant abuse is an important health issue especially among children and adolescents who often encounter these agents in the home. Research into the neurobiological targets of inhalants has lagged behind that of other drugs such as alcohol and psychostimulants. However, studies from our lab and others have begun to reveal how inhalants such as the organic solvent toluene affect neurons in key addiction related areas of the brain including the ventral tegmental area, nucleus accumbens and medial prefrontal cortex. In the present study, we extend these findings and examine the effect of toluene on electrophysiological responses of pyramidal neurons in the basolateral amygdala BLA, a region important for generating emotional and reward based information needed to guide future behavior. Whole-cell patch-clamp electrophysiology recordings of BLA pyramidal neurons in rat brain slices were used to assess toluene effects on intrinsic excitability and excitatory glutamatergic synaptic transmission. Acute application of 3 mM but not 0.3 mM toluene produced a small but significant (~20%) increase in current-evoked action potential (AP) firing that reversed following washout of the toluene containing solution. The change in firing during exposure to 3 mM toluene was accompanied by selective changes in AP parameters including reduced latency to first spike, increased AP rise time and decay and a reduction in the fast after-hyperpolization. To examine whether toluene also affects excitatory synaptic signaling, we expressed channelrhodopsin-2 in medial prefrontal cortex neurons and elicited synaptic currents in BLA neurons via light pulses. Toluene (3 mM) reduced light-evoked AMPA-mediated synaptic currents while a lower concentration (0.3 mM) had no effect. The toluene-induced reduction in AMPA-mediated BLA synaptic currents was prevented by the cannabinoid receptor-1 antagonist AM281. These findings are the first to demonstrate effects of acute toluene on BLA pyramidal neurons and add to existing findings showing that abused inhalants such as toluene have significant effects on neurons in brain regions involved in natural and drug induced reward.

1H-MRS neurometabolite profiles and motor development in school-aged children who are HIV-exposed uninfected: a birth cohort study.

Alterations in regional neurometabolite levels as well as impaired neurodevelopmental outcomes have previously been observed in children who are HIV-exposed uninfected (CHEU). However, little is known about how neurometabolite profiles may relate to their developmental impairment. This study aimed to compare neurometabolite concentrations in school-aged CHEU and children who are HIV-unexposed (CHU) and to explore associations of neurometabolite profiles with functional neurodevelopment in the context of perinatal HIV exposure. We used 3 T single voxel proton magnetic resonance spectroscopy (1H-MRS) to quantify absolute and relative neurometabolites in the parietal gray and parietal white matter in school-aged CHEU and aged- and community-matched CHU. Functional neurodevelopmental outcomes were assessed using the early learning outcome measure (ELOM) tool at 6 years of age. Our study included 152 school-aged children (50% males), 110 CHEU and 42 CHU, with an average age of 74 months at the neuroimaging visit. In an adjusted multiple linear regression analysis, significantly lower glutamate (Glu) concentrations were found in CHEU as compared to CHU in the parietal gray matter (absolute Glu, p = 0.046; Glu/total creatine (Cr+PCr) ratios, p = 0.035) and lower total choline to creatine ratios (GPC+PCh/Cr+PCr) in the parietal white matter (p = 0.039). Using factor analysis and adjusted logistic regression analysis, a parietal gray matter Glu and myo-inositol (Ins) dominated factor was associated with HIV exposure status in both unadjusted (OR 0.55, 95% CI 0.17-0.45, p = 0.013) and adjusted analyses (OR 0.59, 95% CI 0.35-0.94, p = 0.031). With Ins as one of the dominating metabolites, this neurometabolic factor was similar to that found at the age of two years. Furthermore, this factor was also found to be correlated with ELOM scores of gross motor development in CHEU (Pearson's r = -0.48, p = 0.044). In addition, in CHEU, there was a significant association between Ins/Cr+PCr ratios in the parietal white matter and ELOM scores of fine motor coordination and visual motor integration in CHEU (Pearson's r = 0.51, p = 0.032). Reduced Glu concentrations in the parietal gray matter may suggest regional alterations in excitatory glutamatergic transmission pathways in the context of perinatal HIV and/or antiretroviral therapy (ART) exposure, while reduced Cho ratios in the parietal white matter suggest regional myelin loss. Identified associations between neurometabolite profiles and gross and fine motor developmental outcomes in CHEU are suggestive of a neurometabolic mechanism that may underlie impaired motor neurodevelopmental outcomes observed in CHEU.

Inhibitory and excitatory synaptic neuroadaptations in the diazepam tolerant brain

Benzodiazepine (BZ) drugs treat seizures, anxiety, insomnia, and alcohol withdrawal by potentiating γ2 subunit containing GABA type A receptors (GABAARs). BZ clinical use is hampered by tolerance and withdrawal symptoms including heightened seizure susceptibility, panic, and sleep disturbances. Here, we investigated inhibitory GABAergic and excitatory glutamatergic plasticity in mice tolerant to benzodiazepine sedation. Repeated diazepam (DZP) treatment diminished sedative effects and decreased DZP potentiation of GABAAR synaptic currents without impacting overall synaptic inhibition. While DZP did not alter γ2-GABAAR subunit composition, there was a redistribution of extrasynaptic GABAARs to synapses, resulting in higher levels of synaptic BZ-insensitive α4-containing GABAARs and a concomitant reduction in tonic inhibition. Conversely, excitatory glutamatergic synaptic transmission was increased, and NMDAR subunits were upregulated at synaptic and total protein levels. Quantitative proteomics further revealed cortex neuroadaptations of key pro-excitatory mediators and synaptic plasticity pathways highlighted by Ca2+/calmodulin-dependent protein kinase II (CAMKII), MAPK, and PKC signaling. Thus, reduced inhibitory GABAergic tone and elevated glutamatergic neurotransmission contribute to disrupted excitation/inhibition balance and reduced BZ therapeutic power with benzodiazepine tolerance.

Otoferlin as a multirole Ca2+ signaling protein: from inner ear synapses to cancer pathways.

Humans have six members of the ferlin protein family: dysferlin, myoferlin, otoferlin, fer1L4, fer1L5, and fer1L6. These proteins share common features such as multiple Ca2+-binding C2 domains, FerA domains, and membrane anchoring through their single C-terminal transmembrane domain, and are believed to play a key role in calcium-triggered membrane fusion and vesicle trafficking. Otoferlin plays a crucial role in hearing and vestibular function. In this review, we will discuss how we see otoferlin working as a Ca2+-dependent mechanical sensor regulating synaptic vesicle fusion at the hair cell ribbon synapses. Although otoferlin is also present in the central nervous system, particularly in the cortex and amygdala, its role in brain tissues remains unknown. Mutations in the OTOF gene cause one of the most frequent genetic forms of congenital deafness, DFNB9. These mutations produce severe to profound hearing loss due to a defect in synaptic excitatory glutamatergic transmission between the inner hair cells and the nerve fibers of the auditory nerve. Gene therapy protocols that allow normal rescue expression of otoferlin in hair cells have just started and are currently in pre-clinical phase. In parallel, studies have linked ferlins to cancer through their effect on cell signaling and development, allowing tumors to form and cancer cells to adapt to a hostile environment. Modulation by mechanical forces and Ca2+ signaling are key determinants of the metastatic process. Although ferlins importance in cancer has not been extensively studied, data show that otoferlin expression is significantly associated with survival in specific cancer types, including clear cell and papillary cell renal carcinoma, and urothelial bladder cancer. These findings indicate a role for otoferlin in the carcinogenesis of these tumors, which requires further investigation to confirm and understand its exact role, particularly as it varies by tumor site. Targeting this protein may lead to new cancer therapies.

An Insula-Enriched Regulator of Retinoic Acid Marks a New Intersection in the Neural Circuitry of Mouse Social Behavior

An Insula-Enriched Regulator of Retinoic Acid Marks a New Intersection in the Neural Circuitry of Mouse Social Behavior

Alterations in the properties of the glutamatergic system of the rat hippocampus in a lithium-pilocarpine model of temporal lobe epilepsy

Status epilepticus (SE) triggers many pathological changes in the nervous system that are not yet fully understood and may lead to the development of epilepsy. In this work, we studied the effects of SE on the properties of excitatory glutamatergic transmission in the hippocampus in a rat model of lithium-pilocarpine temporal lobe epilepsy. Studies were performed 1 day (acute phase of the model), 3 and 7 days (latent phase), and 30 to 80 days (chronic phase) after SE. Using real-time PCR, we found that in the latent phase there is a decrease in gene expression of GluA1 and GluA2 AMPA receptor subunits, which may also be accompanied by an increased proportion of calcium-permeable AMPA receptors, which play an essential role in the pathogenesis of many CNS diseases. In acute brain slices we found a decrease in the efficiency of excitatory synaptic neurotransmission in all phases of the model when recording field responses in the CA1 region of the hippocampus in response to stimulation of Schaffer collaterals by electric currents of different intensities. However, in the chronic phase we found an increase in the frequency of spontaneous excitatory postsynaptic potentials, indicating an increased background activity of the glutamatergic system in epilepsy. This is also supported by a decrease in the threshold of hind limb extension in the test of maximal electroshock seizure in rats with temporal lobe epilepsy compared to control animals. The results obtained indicate the presence of a number of functional alterations in the glutamatergic system related to epilepsy. These findings can be used to develop antiepileptogenic therapy.

Alterations in the Properties of the Rat Hippocampus Glutamatergic System in the Lithium-Pilocarpine Model of Temporal Lobe Epilepsy

Status epilepticus (SE) triggers many not yet fully understood pathological changes in the nervous system that can lead to the development of epilepsy. In this work, we studied the effects of SE on the properties of excitatory glutamatergic transmission in the hippocampus in the lithium-pilocarpine model of temporal lobe epilepsy in rats. The studies were performed 1 day (acute phase), 3 and 7 days (latent phase), and 30 to 80 days (chronic phase) after SE. According to RT-qPCR data, expression of the genes coding for the AMPA receptor subunits GluA1 and GluA2 was downregulated in the latent phase, which may lead to the increased proportion of calcium-permeable AMPA receptors that play an essential role in the pathogenesis of many CNS diseases. The efficiency of excitatory synaptic neurotransmission in acute brain slices was decreased in all phases of the model, as determined by recording field responses in the CA1 region of the hippocampus in response to the stimulation of Schaffer collaterals by electric current of different strengths. However, the frequency of spontaneous excitatory postsynaptic potentials increased in the chronic phase, indicating an increased background activity of the glutamatergic system in epilepsy. This was also evidenced by a decrease in the threshold current causing hindlimb extension in the maximal electroshock seizure threshold test in rats with temporal lobe epilepsy compared to the control animals. The results suggest a series of functional changes in the properties of glutamatergic system associated with the epilepsy development and can be used to develop the antiepileptogenic therapy.

The Tripod neuron: a minimal structural reduction of the dendritic tree.

Neuron models with explicit dendritic dynamics have shed light on mechanisms for coincidence detection, pathway selection and temporal filtering. However, it is still unclear which morphological and physiological features are required to capture these phenomena. In this work, we introduce the Tripod neuron model and propose a minimal structural reduction of the dendritic tree that is able to reproduce these computations. The Tripod is a three-compartment model consisting of two segregated passive dendrites and a somatic compartment modelled as an adaptive, exponential integrate-and-fire neuron. It incorporates dendritic geometry, membrane physiology and receptor dynamics as measured in human pyramidal cells. We characterize the response of the Tripod to glutamatergic and GABAergic inputs and identify parameters that support supra-linear integration, coincidence-detection and pathway-specific gating through shunting inhibition. Following NMDA spikes, the Tripod neuron generates plateau potentials whose duration depends on the dendritic length and the strength of synaptic input. When fitted with distal compartments, the Tripod encodes previous activity into a dendritic depolarized state. This dendritic memory allows the neuron to perform temporal binding, and we show that it solves transition and sequence detection tasks on which a single-compartment model fails. Thus, the Tripod can account for dendritic computations previously explained only with more detailed neuron models or neural networks. Due to its simplicity, the Tripod neuron can be used efficiently in simulations of larger corticalcircuits. KEY POINTS: We present a neuron model, called the Tripod, with two segregated dendritic branches that are connected to an axosomatic compartment. Each branch implements inhibitory GABAergic and excitatory glutamatergic synaptic transmission, including voltage-gated NMDA receptors. Dendrites are modelled on relevant geometric and physiological parameters measured in human pyramidal cells. The neuron reproduces classical dendritic computations, such as coincidence detection and pathway selection via shunting inhibition, that are beyond the scope of point-neuron models. Under some conditions, dendritic NMDA spikes cause plateau potentials, and we show that they provide a form of short-term memory which is useful for sequence recognition. The dendritic structure of the Tripod neuron is sufficiently simple to be integrated into efficient network simulations and studied in a broad functional context.

Pre- and postsynaptic alterations in the visual cortex of the P23H-1 retinal degeneration rat model.

P23H rats express a variant of rhodopsin with a mutation that leads to loss of visual function with similar properties as human autosomal dominant retinitis pigmentosa (RP). The advances made in different therapeutic strategies to recover visual system functionality reveal the need to know whether progressive retina degeneration affects the visual cortex structure. Here we are interested in detecting cortical alterations in young rats with moderate retinal degeneration, and in adulthood when degeneration is severer. For this purpose, we studied the synaptic architecture of the primary visual cortex (V1) by analyzing a series of pre- and postsynaptic elements related to excitatory glutamatergic transmission. Visual cortices from control Sprague Dawley (SD) and P23H rats at postnatal days 30 (P30) and P230 were used to evaluate the distribution of vesicular glutamate transporters VGLUT1 and VGLUT2 by immunofluorescence, and to analyze the expression of postsynaptic density protein-95 (PSD-95) by Western blot. The amount and dendritic spine distribution along the apical shafts of the layer V pyramidal neurons, stained by the Golgi-Cox method, were also studied. We observed that at P30, RP does not significantly affect any of the studied markers and structures, which suggests in young P23H rats that visual cortex connectivity seems preserved. However, in adult rats, although VGLUT1 immunoreactivity and PSD-95 expression were similar between both groups, a narrower and stronger VGLUT2-immunoreactive band in layer IV was observed in the P23H rats. Furthermore, RP significantly decreased the density of dendritic spines and altered their distribution along the apical shafts of pyramidal neurons, which remained in a more immature state compared to the P230 SD rats. Our results indicate that the most notable changes in the visual cortex structure take place after a prolonged retinal degeneration period that affected the presynaptic thalamocortical VGLUT2-immunoreactive terminals and postsynaptic dendritic spines from layer V pyramidal cells. Although plasticity is more limited at these ages, future studies will determine how reversible these changes are and to what extent they can affect the visual system’s functionality.

Astrocytes play a critical role in mediating the effect of acute ethanol on central amygdala glutamatergic transmission

The Central Amygdala (CeA) has been heavily implicated in many aspects of alcohol use disorder. Ethanol (EtOH) has been shown to modulate glutamatergic transmission in the lateral subdivision of the CeA, however, the exact mechanism of this modulation is still unclear. EtOH exposure is associated with increased pro-inflammatory cytokines in the CeA, and inhibition of neuroimmune cells (microglia and astrocytes) has previously been shown to reduce EtOH drinking in animal models. Since neuroimmune activation seems to be involved in many of the effects of EtOH, we hypothesized that acute EtOH exposure will increase excitatory glutamatergic transmission in the CeA via modulation of neuroimmune cells. Using ex vivo brain slice whole-cell patch clamp electrophysiology, it was found that a physiologically relevant concentration of EtOH (20 mM) significantly increased presynaptic glutamatergic transmission in the CeA. Pharmacologic and chemogenetic inhibition of astrocyte function significantly reduced the ability of EtOH to modulate CeA glutamatergic transmission with minimal impact of microglia inhibition. This finding prompted additional studies examining whether direct neuroimmune activation through lipopolysaccharide (LPS) might lead to an increase in the glutamatergic transmission in the CeA. It was found that LPS modulation of glutamatergic transmission was limited by microglia activation and required astrocyte signaling. Taken together these results support the hypothesis that acute EtOH enhances lateral CeA glutamatergic transmission through an astrocyte mediated mechanism.This article is part of the special Issue on ‘Neurocircuitry Modulating Drug and Alcohol Abuse'.

Mediators of Neuropathic Pain; Focus on Spinal Microglia, CSF-1, BDNF, CCL21, TNF-α, Wnt Ligands, and Interleukin 1β.

Intractable neuropathic pain is a frequent consequence of nerve injury or disease. When peripheral nerves are injured, damaged axons undergo Wallerian degeneration. Schwann cells, mast cells, fibroblasts, keratinocytes and epithelial cells are activated leading to the generation of an “inflammatory soup” containing cytokines, chemokines and growth factors. These primary mediators sensitize sensory nerve endings, attract macrophages, neutrophils and lymphocytes, alter gene expression, promote post-translational modification of proteins, and alter ion channel function in primary afferent neurons. This leads to increased excitability and spontaneous activity and the generation of secondary mediators including colony stimulating factor 1 (CSF-1), chemokine C-C motif ligand 21 (CCL-21), Wnt3a, and Wnt5a. Release of these mediators from primary afferent neurons alters the properties of spinal microglial cells causing them to release tertiary mediators, in many situations via ATP-dependent mechanisms. Tertiary mediators such as BDNF, tumor necrosis factor α (TNF-α), interleukin 1β (IL-1β), and other Wnt ligands facilitate the generation and transmission of nociceptive information by increasing excitatory glutamatergic transmission and attenuating inhibitory GABA and glycinergic transmission in the spinal dorsal horn. This review focusses on activation of microglia by secondary mediators, release of tertiary mediators from microglia and a description of their actions in the spinal dorsal horn. Attention is drawn to the substantial differences in the precise roles of various mediators in males compared to females. At least 25 different mediators have been identified but the similarity of their actions at sensory nerve endings, in the dorsal root ganglia and in the spinal cord means there is considerable redundancy in the available mechanisms. Despite this, behavioral studies show that interruption of the actions of any single mediator can relieve signs of pain in experimental animals. We draw attention this paradox. It is difficult to explain how inactivation of one mediator can relieve pain when so many parallel pathways are available.

G protein‐coupled estrogen receptor‐1 enhances excitatory synaptic responses in the entorhinal cortex

Activation of estrogen receptors is thought to modulate cognitive function in the hippocampus, prefrontal cortex, and striatum by affecting both excitatory and inhibitory synaptic transmission. The entorhinal cortex is a major source of cortical sensory and associational input to the hippocampus, but it is unclear whether either estrogens or progestogens may modulate cognitive function through effects on synaptic transmission in the entorhinal cortex. This study assessed the effects of the brief application of either 17-β estradiol (E2) or progesterone on excitatory glutamatergic synaptic transmission in the female rat entorhinal cortex in vitro. Rats were ovariectomized on postnatal day (PD) 63 and also received subdermal E2 implants to maintain constant low levels of circulating E2 on par with estrus. Electrophysiological recordings from brain slices were obtained between PD70 and PD86, and field excitatory postsynaptic potentials (fEPSPs) reflecting the activation of the superficial layers of the entorhinal cortex were evoked by the stimulation of layer I afferents. The application of E2 (10nM) for 20 min resulted in a small increase in the amplitude of fEPSPs that reversed during the 30-min washout period. The application of the ERα agonist propylpyrazoletriol (PPT) (100 nM) or the β agonist DPN (1μM) did not significantly affect synaptic responses. However, the application of the G protein-coupled estrogen receptor-1 (GPER1) agonist G1 (100 nM) induced a reversible increase in fEPSP amplitude similar to that induced by E2. Furthermore, the potentiation of responses induced by G1 was blocked by the GPER1 antagonist G15 (1μM). Application of progesterone (100 nM) or its metabolite allopregnanolone (1μM) did not significantly affect synaptic responses. The potentiation of synaptic transmission in the entorhinal cortex induced by the activation of GPER1 receptors may contribute to the modulation of cognitive function in female rats.

Glutamate receptors in the dopamine system – function and role in reinforcement learning

Midbrain dopamine neurons along with the major target of their projections, dopaminoceptive neurons in striatum, regulate reinforcement learning and motivation. The activity and plasticity in the dopamine system are largely dependent on excitatory glutamatergic transmission. The article describes the functional role of N-methyl-D-aspartate (NMDA) receptors in driving the phasic activity in dopamine neurons, and a role of NMDA and metabotropic glutamate 5 (mGluR5) receptors in induction of plasticity in dopaminoceptive striatal medium spiny neurons. Based on published studies on genetically modified mice, the article further discusses how targeted loss of glutamate receptor-dependent signalling in dopamine system affects reinforcement learning and motivational processes. The conclusion of the article is the view that aberrant glutamate signalling in dopamine system may contribute to maladaptive behaviours, which are particularly often observed in mental disorders.

Ampakine Pretreatment Enables One Episode of Hypoxia to Produce Phrenic Motor Facilitation with No Added Benefit of Additional Hypoxic Episodes

Excitatory glutamatergic synaptic transmission acting via the α-amino-3-hydro-5-methyl-4-isoxazolepropionate acid receptors (AMPARs) is critical for respiratory rhythmogenesis as well as activation of respiratory motoneurons. A synthetic class of drugs called ampakines can stimulate breathing via positive allosteric modulation of AMPARs which enhances glutamatergic currents. Our laboratory has reported that anesthetized mice pretreated with ampakine CX717 demonstrate enhanced long-term facilitation (LTF) of hypoglossal motor output following repeated bouts of hypoxia. More recently, we reported that ampakine treatment prior to a single bout of hypoxia can produce sustained facilitation of phrenic motor output in anesthetized rats. In the current study, we tested the hypothesis that ampakine pretreatment would enhance the magnitude of phrenic LTF following multiple bouts of hypoxia. Phrenic nerve output, arterial blood pressure and end-tidal CO2 were recorded from urethane-anesthetized, mechanically ventilated and vagotomized adult male Sprague-Dawley rats. Phrenic burst amplitude recorded during the experiments was expressed relative to baseline (pre-treatment) activity (%BL). First, we verified the impact of a single injection of intravenous (iv) dose of ampakine (CX717, 15mg/kg) compared to vehicle solution (10% HPCD). CX717 caused a small and transient increase in phrenic burst amplitude and frequency, confirming previous reports by our group. Phrenic burst amplitude showed a transient increase (70±48%BL after 2 min) that gradually declined and was not different than baseline after 60 min (2±32%BL, n=4). Injection of the HPCD vehicle caused no discernable change in phrenic activity (2 min: 0±15%BL, 60 min: 3±5%Bl, n=4). Second, we investigated if ampakine treatment prior to acute intermittent hypoxia (CX717 + 3 five-minute bouts of hypoxia) would produce a more robust phrenic LTF when compared to ampakine followed by single bout of hypoxia (CX717 + 1 five-minute bout of hypoxia). Similar to our prior report, CX717 + 1 five-minute bout of hypoxia causes a sustained increase in phrenic burst amplitude (60 min: 96±61% Bl, n=8). However, contrary to our hypothesis, little phrenic LTF was observed in the CX717 + 3X hypoxia group (60 min: 24±29%Bl, n=8). Lastly, in a separate series of experiments, we verified the impact of 1 vs. 3 episodes of hypoxia on phrenic motor output, but in the absence of ampakine. Phrenic LTF was present after 3 five-minute bouts of hypoxia (60 min: 88±26%BL, n=3) but not 1 five-minute bout of hypoxia (60 min: 4±1%BL, n=3). These studies of anesthetized and spinal-intact rats indicate that phrenic LTF is not enhanced when ampakine pretreatment is followed by multiple bouts of hypoxia. Rather, the combination of ampakine and a single brief hypoxic episode appears to be ideal for producing sustained increase in phrenic motor output. These findings could have implications for hypoxia-based neurorehabilitation strategies, a method which is gaining traction in spinal cord injury rehabilitation. A single dose of ampakine may serve to “prime” the nervous system such that fewer exposures to hypoxia are required to produce sustained neuroplastic changes.

Cholinergic Signaling, Neural Excitability, and Epilepsy.

Epilepsy is a common brain disorder characterized by recurrent epileptic seizures with neuronal hyperexcitability. Apart from the classical imbalance between excitatory glutamatergic transmission and inhibitory γ-aminobutyric acidergic transmission, cumulative evidence suggest that cholinergic signaling is crucially involved in the modulation of neural excitability and epilepsy. In this review, we briefly describe the distribution of cholinergic neurons, muscarinic, and nicotinic receptors in the central nervous system and their relationship with neural excitability. Then, we summarize the findings from experimental and clinical research on the role of cholinergic signaling in epilepsy. Furthermore, we provide some perspectives on future investigation to reveal the precise role of the cholinergic system in epilepsy.

Glutamatergic plasticity within neurocircuits of the dorsal vagal complex and the regulation of gastric functions.

The meticulous regulation of the gastrointestinal (GI) tract is required for the coordination of gastric motility and emptying, intestinal secretion, absorption, and transit as well as for the overarching management of food intake and energy homeostasis. Disruption of GI functions is associated with the development of severe GI disorders and the alteration of food intake and caloric balance. Functional GI disorders as well as the dysregulation of energy balance and food intake are frequently associated with, or result from, alterations in the central regulation of GI control. The faithful and rapid transmission of information from the stomach and upper GI tract to second-order neurons of the nucleus of the tractus solitarius (NTS) relies on the delicate modulation of excitatory glutamatergic transmission, as does the relay of integrated signals from the NTS to parasympathetic efferent neurons of the dorsal motor nucleus of the vagus (DMV). Many studies have focused on understanding the physiological and pathophysiological modulation of these glutamatergic synapses, although their role in the control and regulation of GI functions has lagged behind that of cardiovascular and respiratory functions. The purpose of this review is to examine the current literature exploring the role of glutamatergic transmission in the DVC in the regulation of GI functions.

Spontaneous synchronous network activity in the neonatal development of mPFC in mice.

Spontaneous Synchronous Network Activity (SSA) is a hallmark of neurodevelopment found in numerous central nervous system structures, including neocortex. SSA occurs during restricted developmental time‐windows, commonly referred to as critical periods in sensory neocortex. Although part of the neocortex, the critical period for SSA in the medial prefrontal cortex (mPFC) and the underlying mechanisms for generation and propagation are unknown. Using Ca2+ imaging and whole‐cell patch‐clamp in an acute mPFC slice mouse model, the development of spontaneous activity and SSA was investigated at cellular and network levels during the two first postnatal weeks. The data revealed that developing mPFC neuronal networks are spontaneously active and exhibit SSA in the first two postnatal weeks, with peak synchronous activity at postnatal days (P)8–9. Networks remain active but are desynchronized by the end of this 2‐week period. SSA was driven by excitatory ionotropic glutamatergic transmission with a small contribution of excitatory GABAergic transmission at early time points. The neurohormone oxytocin desynchronized SSA in the first postnatal week only without affecting concurrent spontaneous activity. By the end of the second postnatal week, inhibiting GABAA receptors restored SSA. These findings point to the emergence of GABAA receptor‐mediated inhibition as a major factor in the termination of SSA in mouse mPFC.

Homeostatic Recovery of Embryonic Spinal Activity Initiated by Compensatory Changes in Resting Membrane Potential.

When baseline activity in a neuronal network is modified by external challenges, a set of mechanisms is prompted to homeostatically restore activity levels. These homeostatic mechanisms are thought to be profoundly important in the maturation of the network. It has been shown that blockade of either excitatory GABAergic or glutamatergic transmission in the living chick embryo transiently blocks the movements generated by spontaneous network activity (SNA) in the spinal cord. However, the embryonic movements then begin to recover by 2 h and are completely restored by 12 h of persistent receptor blockade. It remains unclear what mechanisms mediate this early recovery (first hours) after neurotransmitter blockade, or even if the same mechanisms are triggered following GABAergic and glutamatergic antagonists. Here we find two distinct mechanisms that could underlie this homeostatic recovery. First, we see a highly robust compensatory mechanism observed shortly after neurotransmitter receptor blockade. In the first 2 h of GABAergic or glutamatergic blockade in vitro, there was a clear depolarization of resting membrane potential (RMP) in both motoneurons and interneurons. These changes reduced threshold current and were observed in the continued presence of the antagonist. Therefore, it appears that fast changes in RMP represent a key fast homeostatic mechanism for the maintenance of network activity. Second, we see a less consistent compensatory change in the absolute threshold voltage in the first several hours of in vitro and in vivo neurotransmitter blockade. These mechanisms likely contribute to the homeostatic recovery of embryonic movements following neurotransmitter blockade.

Ginsenoside Rg1 alleviates repeated alcohol exposure-induced psychomotor and cognitive deficits

BackgroundChronic alcohol consumption disrupts psychomotor and cognitive functions, most of which are subserved by the dysfunction of hippocampus. Dysregulated excitatory glutamatergic transmission is implicated in repeated alcohol induced psychomotor and cognitive impairment. Ginsenoside Rg1, one of the main active ingredient of the traditional tonic medicine Panax ginseng C.A. Meyer (Araliaceae), has been used to treat cognitive deficits. Particularly, Rg1 has been demonstrated to improve hippocampus-dependent learning in mice and attenuate glutamate-induced excitotoxicity in vitro. Thus, in the present research, we sought to investigate the therapeutic effects of Ginsenoside Rg1 on repeated alcohol induced psychomotor and cognitive deficits in hippocampal-dependent behavioral tasks and unravel the underpinnings of its neuroprotection.MethodsMale ICR (CD-1) mice were consecutively intragastrically treated with 20% (w/v) alcohol for 21 days. Then, behavior tests were conducted to evaluate repeated alcohol induced psychomotor and cognitive deficits. Histopathological changes, and biochemical and molecular alterations were assessed to determine the potential neuroprotective mechanism of Rg1.ResultsThe results suggested that Rg1, at the optimal dose of 6 mg/kg, has the potential to ameliorate repeated alcohol induced cognitive deficits by regulating activities of NR2B containing NMDARs and excitotoxic signaling.ConclusionOur findings further provided a new strategy to treat chronic alcohol exposure induced adverse consequences.