Changes In Neuronal Excitability Research Articles

Deep brain stimulation in treatment resistant schizophrenia:post-stimulation PET changes

Introduction: High-frequency DBS of particular brain areas has demonstrated to produce not only local changes in neuronal excitability but also distal effects widespread in the brain [1]. However, no controlled studies have been published in schizophrenia yet. The aim of the present study is to investigate changes in the regional cerebral glucose metabolism in individuals with Treatment Resistant Schizophrenia who underwent DBS treatment.

Effect of kHz electrical stimulation on hippocampal brain slice excitability and network dynamics

Understanding the cellular mechanisms of kHz electrical stimulation is of broad interest in neuromodulation including forms of transcranial electrical stimulation (tES), interferential stimulation, and high-rate spinal cord stimulation (SCS). Yet, the well-established low-pass filtering by neuronal membrane suggests minimal neuronal polarization in response to charge-balanced kHz stimulation. The hippocampal brain slice model is among the most characterized systems in neuroscience and exhaustively studied in screening the effects of electrical stimulation. Testing for changes in neuronal excitability by kHZ electrical stimulation in brain slices is a litmus test for feasibility and mechanism. High-frequency electric field of varied amplitudes (1-120 V/m), waveforms (sinusoidal, symmetrical pule, asymmetrical pulse) and frequencies (1 or 10 kHz) were tested. Single and paired-pulse field excitatory post-synaptic potentials (fEPSP) in CA1 were measured before, during, and after stimulation in radial and tangential direction and for different application time (30 s acute,30 min). Small polarization of individual neurons leads to changes in network dynamic through nonlinear amplification mechanisms at the cellular and/or network level resulting a more sensitive system to an exogenous electric field. Effect of kHZ stimulation on ongoing endogenous network activity was evaluated in carbachol-induced gamma oscillation of CA3a region of rat hippocampal slices. Extracellular local field potential oscillations were recorded and analyzed before, during and after 2s of kHZ stimulation. In order to fully investigate the opportunities in kHZ stimulation, ongoing work on kHz stimulation should consider different mechanisms of action absent in this tested system and different cortical and spinal neurons.

Acute Sleep Deprivation Reduces Oscillatory Network Inhibition in the Young Rat Basolateral Amygdala

The amygdala is concerned with the emotional memory consolidation, and is known as a stress-vulnerable region of the brain. Slow network oscillation is considered to play roles in memory consolidation during sleep. We investigated the relationship between the sleep and oscillation in the basolateral nucleus (BL) of the amygdala, in which burst firing is preferentially observed during sleep and the slow inhibitory oscillation is recorded from projection neuron. We examined whether sleep deprivation (SD) alters the properties of the network inhibition by whole-cell recordings from BL projection neurons and interneurons of the slice preparation of the juvenile rats. The level of the oscillatory network inhibition, measured as summed power of the spectral density between 0.1 and 3 Hz of the synaptic currents in the projection neurons, was significantly attenuated by acute (3 h) SD in older (P20–24) but not in younger (P15–19) animals. This reduction was mainly derived from the reduced peak amplitude of periodic IPSC bursts. In inhibitory interneurons in BL, spontaneous firings were reduced in older SD rats. The spike threshold of interneurons was increased and the power of the periodic excitatory transmission was reduced in the SD rats. Moreover, a reduction in input resistance in projection neurons was observed in SD rats without significant difference in the excitability which was measured by the spike number induced by depolarizing currents. These results suggest that SD stress affects the network oscillatory property accompanied by changes of individual neuronal excitability and synaptic communications.

Neuroplasticity induction using transcranial magnetic stimulation

In this article, we have displayed the results of an analysis of modern scientific data on the induction of neuroplasticity using transcranial magnetic stimulation. We presented the multilevel neuroplastic effects of electromagnetic fields caused by transcranial magnetic stimulation (TMS). The authors of the article determined that transcranial magnetic stimulation uses variable magnetic fields to non-invasively stimulate neurons in the brain. The basis of this method is the modulation of neuroplasticity mechanisms with the subsequent reorganization of neural networks. Repeated TMS (rTMS), which is widely used in neurology, affects neurotransmitters and synaptic plasticity, glial cells and the prevention of neuronal death. The neurotrophic effects of rTMS on dendritic growth, as well as growth and neurotrophic factors, are described. An important aspect of the action of TMS is its effect on neuroprotective mechanisms. A neuroimaging study of patients with Parkinson's disease showed that rTMS increased the concentration of endogenous dopamine in the ipsilateral striatum. After rTMS exposure, the number of β-adrenergic receptors in the frontal and cingulate cortex decreases, but the number of NMDA receptors in the ventromedial thalamus, amygdala, and parietal cortex increases. These processes ultimately lead to the induction of prolonged potentiation. In response to rTMS, neuronal excitability changes due to a shift in ion balance around a population of stimulated neurons; this shift manifests itself as altered synaptic plasticity. Combinations of rTMS treatment and pharmacotherapy (e.g., small doses of memantine) may block the alleviating effect during prolonged potentiation. Studies using models of transient ischemic attack and prolonged ischemia have shown that rTMS protects neurons from death and alters the blood flow and metabolism in the brain. It has been demonstrated that TMS has a proven ability to modulate the internal activity of the brain in a frequency-dependent manner, generate contralateral responses, provide, along with the neuromodulating and neurostimulating effect, affect the brain as a global dynamic system.

Altered A-type potassium channel function in the nucleus tractus solitarii in acquired temporal lobe epilepsy.

Sudden unexpected death in epilepsy (SUDEP) is among the leading causes of death in people with epilepsy. Individuals with temporal lobe epilepsy (TLE) have a high risk for SUDEP because the seizures are often medically intractable. Neurons in the nucleus tractus solitarii (NTS) have been implicated in mouse models of SUDEP and play a critical role in modulating cardiorespiratory and autonomic output. Increased neuronal excitability of inhibitory, GABAergic neurons in the NTS develops during epileptogenesis, and NTS dysfunction has been implicated in mouse models of SUDEP. In this study we used the pilocarpine-induced status epilepticus model of TLE (i.e., pilo-SE mice) to investigate the A-type voltage-gated K+ channel as a potential contributor to increased excitability in GABAergic NTS neurons during epileptogenesis. Compared with age-matched control mice, pilo-SE mice displayed an increase in spontaneous action potential frequency and half-width 9-12 wk after treatment. Activity of GABAergic NTS neurons from pilo-SE mice showed less sensitivity to 4-aminopyridine. Correspondingly, reduced A-type K+ current amplitude was detected in these neurons, with no change in activation or inactivation kinetics. No changes were observed in Kv4.1, Kv4.2, Kv4.3, KChIP1, KChIP3, or KChIP4 mRNA expression. These changes contribute to the increased excitability in GABAergic NTS neurons that develops in TLE and may provide insight into potential mechanisms contributing to the increased risk for cardiorespiratory collapse and SUDEP in this model. NEW & NOTEWORTHY Sudden unexpected death in epilepsy (SUDEP) is a leading cause of death in epilepsy, and dysfunction in central autonomic neurons may play a role. In a mouse model of acquired epilepsy, GABAergic neurons in the nucleus tractus solitarii developed a reduced amplitude of the A-type current, which contributes to the increased excitability seen in these neurons during epileptogenesis. Neuronal excitability changes in inhibitory central vagal circuitry may increase the risk for cardiorespiratory collapse and SUDEP.

The Changes of Intrinsic Excitability of Pyramidal Neurons in Anterior Cingulate Cortex in Neuropathic Pain.

To find satisfactory treatment strategies for neuropathic pain syndromes, the cellular mechanisms should be illuminated. Central sensitization is a generator of pain hypersensitivity, and is mainly reflected in neuronal hyperexcitability in pain pathway. Neuronal excitability depends on two components, the synaptic inputs and the intrinsic excitability. Previous studies have focused on the synaptic plasticity in different forms of pain. But little is known about the changes of neuronal intrinsic excitability in neuropathic pain. To address this question, whole-cell patch clamp recordings were performed to study the synaptic transmission and neuronal intrinsic excitability 1 week after spared nerve injury (SNI) or sham operation in male C57BL/6J mice. We found increased spontaneous excitatory postsynaptic currents (sEPSC) frequency in layer II/III pyramidal neurons of anterior cingulate cortex (ACC) from mice with neuropathic pain. Elevated intrinsic excitability of these neurons after nerve injury was also picked up, which was reflected in gain of input-output curve, inter-spike interval (ISI), spike threshold and Refractory period (RP). Besides firing rate related to neuronal intrinsic excitability, spike timing also plays an important role in neural information processing. The precision of spike timing measured by standard deviation of spike timing (SDST) was decreased in neuropathic pain state. The electrophysiological studies revealed the elevated intrinsic excitation in layer II/III pyramidal neurons of ACC in mice with neuropathic pain, which might contribute to central excitation.

Association of mGluR-Dependent LTD of Excitatory Synapses with Endocannabinoid-Dependent LTD of Inhibitory Synapses Leads to EPSP to Spike Potentiation in CA1 Pyramidal Neurons.

The input-output relationships in neural circuits are determined not only by synaptic efficacy but also by neuronal excitability. Activity-dependent alterations of synaptic efficacy have been extensively investigated, but relatively less is known about how the neuronal output is modulated when synaptic efficacy changes are associated with neuronal excitability changes. In this study, we demonstrate that paired pulses of low-frequency stimulation (PP-LFS) induced metabotropic glutamate receptor (mGluR)-dependent LTD at Schaffer collateral (SC)-CA1 synapses in Sprague Dawley rats (both sexes), and this LTD was associated with EPSP to spike (E-S) potentiation, leading to the increase in action potential (AP) outputs. Threshold voltage (Vth) for APs evoked by synaptic stimulation and that by somatic current injection were hyperpolarized significantly after PP-LFS. Blockers of GABA receptors mimicked and occluded PP-LFS effects on E-S potentiation and Vth hyperpolarization, suggesting that suppression of GABAergic mechanisms is involved in E-S potentiation after PP-LFS. Indeed, IPSCs and tonic inhibitory currents were reduced after PP-LFS. The IPSC reduction was accompanied by increased paired-pulse ratio, and abolished by AM251, a blocker for Type 1 cannabinoid receptors, suggesting that PP-LFS suppresses presynaptic GABA release by mGluR-dependent endocannabinoids signaling. By contrast, a Group 1 mGluR agonist, 3, 5-dihydroxyphenylglycine, induced LTD at SC-CA1 synapses but failed to induce significant IPSC reduction and AP output increase. We propose that mGluR signaling that induces LTD coexpression at excitatory and inhibitory synapses regulates an excitation-inhibition balance to increase neuronal output in CA1 neurons.SIGNIFICANCE STATEMENT Long-lasting forms of synaptic plasticity are usually associated with excitability changes, the ability to fire action potentials. However, excitability changes have been regarded to play subsidiary roles to synaptic plasticity in modifying neuronal output. We demonstrate that, when metabotropic glutamate receptor-dependent LTD is induced by paired pulses of low-frequency stimulation, the action potential output in response to a given input paradoxically increases, indicating that increased excitability is more powerful than synaptic depression. This increase is mediated by the suppression of a presynaptic GABA release via metabotropic glutamate receptor-dependent endocannabinoid signaling. Our study shows that neuronal output changes do not always follow the direction of synaptic plasticity at excitatory synapses, highlighting the importance of regulating inhibitory tone via endocannabinoid signaling.

P3 - Redox Signaling in the Brain and Antioxidant-Based Therapeutics: Consequences for Hypertension

Over the past two decades, hundreds of studies examining neuronal populations in unique cardiovascular control regions of the brain have revealed a role for reactive oxygen species (ROS) in mediating the elevated sympathetic output known to contribute to the pathogenesis of hypertension. We, and others, have been particularly interested in understanding the involvement of superoxide (O2--) in central neurons in mediating neuronal activation, sympathoexcitation, and hypertensive blood pressures. Numerous studies utilizing viral-mediated overexpression of copper/zinc superoxide dismutase (CuZnSOD) or manganese superoxide dismutase (MnSOD) in cardiovascular control brain regions have clearly identified O2-- as a primary ROS influencing sympathetic drive and systemic blood pressure. Recently, our group has focused on: 1) determining how O2-- mediates changes in neuronal excitability in hypertensive models; and 2) developing clinically relevant and novel antioxidant-based therapeutics to scavenge elevated O2-- levels in the brain for the improved treatment of hypertension. We have demonstrated that increased O2-- levels in neurons stimulated with angiotensin II (AngII), a pro-hypertensive peptide, inhibits outward potassium (K+) current, which contributes to enhanced neuronal firing. Additionally, we have identified redox-sensitive amino acids in neuronal calcium calmodulin kinase II-alpha (CaMKIIa) that mediate its inhibitory action on outward K+ current. In regards to developing novel antioxidant-based therapeutics, we have utilized nanotechnology approaches to create the so-called SOD nanozyme, which consists of CuZnSOD protein bound to poly-l-lysine (PLL50)-polyethylene glycol (PEG) block copolymer. We have shown that SOD nanozyme delivers active SOD protein to neurons and attenuates AngII-induced neuronal signaling. Most importantly, we have observed that central or peripheral (IV) administration of SOD nanozyme significantly decreases hypertensive blood pressures for up to 1 week following a single bolus injection. Collectively, these studies provide new insight into the precise intra-neuronal redox signaling mechanisms influencing blood pressure regulation, and identify novel antioxidant-based therapeutics for the improved treatment of hypertension.

Overexpression of Kcnmb2 in Dorsal CA1 of Offspring Mice Rescues Hippocampal Dysfunction Caused by a Methyl Donor-Rich Paternal Diet

BK channels are known regulators of neuronal excitability, synaptic plasticity, and memory. Our previous study showed that a paternal methyl donor-rich diet reduced the expression of Kcnmb2, which encodes BK channel subunit beta 2, and caused memory deficits in offspring mice. To explore the underlying cellular mechanisms, we investigated the intrinsic and synaptic properties of CA1 pyramidal neurons of the F1 offspring mice whose fathers were fed with either a methyl donor-rich diet (MD) or regular control diet (CD) for 6 weeks before mating. Whole-cell patch-clamp recordings of CA1 pyramidal neurons revealed a decrease in intrinsic excitability and reduced frequency of inhibitory post-synaptic currents in MD F1 mice compared to the CD F1 controls. AAV-based overexpression of Kcnmb2 in dorsal CA1 ameliorated changes in neuronal excitability, synaptic transmission, and plasticity in MD F1 mice. Our findings thus indicate that a transient paternal exposure to a methyl donor-rich diet prior to mating alters Kcnmb2-sensitive hippocampal functions in offspring animals.

Dynamic and Sex-Specific Changes in Gonadotropin-Releasing Hormone Neuron Activity and Excitability in a Mouse Model of Temporal Lobe Epilepsy

Reproductive endocrine disorders are prominent comorbidities of temporal lobe epilepsy (TLE) in both men and women. The neural mechanisms underlying these comorbidities remain unclear, but hypothalamic gonadotropin-releasing hormone (GnRH) neurons may be involved. Here, we report the first direct demonstrations of aberrant GnRH neuron function in an animal model of epilepsy. Recordings of GnRH neuron firing and excitability were made in acute mouse brain slices prepared two months after intrahippocampal injection of kainate (KA) or control saline, a well-established TLE model in which most females develop comorbid estrous cycle disruption. GnRH neurons from control females showed elevated firing and excitability on estrus compared with diestrus. By contrast, cells from KA-injected females that developed prolonged, disrupted estrous cycles (KA-long) showed the reverse pattern. Firing rates of cells from KA-injected females that maintained regular cycles (KA-regular) were not different from controls on diestrus, but were reduced on estrus. In KA-injected males, only GnRH neurons in the medial septum displayed elevated firing. In contrast to the diestrus versus estrus and sex-specific changes in firing, GnRH neuron intrinsic excitability was elevated in all KA-injected groups, indicating a role for afferent synaptic and neuromodulatory inputs in shaping overall changes in firing activity. Furthermore, KA-injected females showed cycle-stage-specific changes in circulating sex steroids on diestrus and estrus that also differed between KA-long and KA-regular groups. Together, these findings reveal that the effects of epilepsy on the neural control of reproduction are dynamic across the estrous cycle, distinct in association with comorbid estrous cycle disruption severity, and sex-specific.

Flexible resonance in prefrontal networks with strong feedback inhibition.

Oscillations are ubiquitous features of brain dynamics that undergo task-related changes in synchrony, power, and frequency. The impact of those changes on target networks is poorly understood. In this work, we used a biophysically detailed model of prefrontal cortex (PFC) to explore the effects of varying the spike rate, synchrony, and waveform of strong oscillatory inputs on the behavior of cortical networks driven by them. Interacting populations of excitatory and inhibitory neurons with strong feedback inhibition are inhibition-based network oscillators that exhibit resonance (i.e., larger responses to preferred input frequencies). We quantified network responses in terms of mean firing rates and the population frequency of network oscillation; and characterized their behavior in terms of the natural response to asynchronous input and the resonant response to oscillatory inputs. We show that strong feedback inhibition causes the PFC to generate internal (natural) oscillations in the beta/gamma frequency range (>15 Hz) and to maximize principal cell spiking in response to external oscillations at slightly higher frequencies. Importantly, we found that the fastest oscillation frequency that can be relayed by the network maximizes local inhibition and is equal to a frequency even higher than that which maximizes the firing rate of excitatory cells; we call this phenomenon population frequency resonance. This form of resonance is shown to determine the optimal driving frequency for suppressing responses to asynchronous activity. Lastly, we demonstrate that the natural and resonant frequencies can be tuned by changes in neuronal excitability, the duration of feedback inhibition, and dynamic properties of the input. Our results predict that PFC networks are tuned for generating and selectively responding to beta- and gamma-rhythmic signals due to the natural and resonant properties of inhibition-based oscillators. They also suggest strategies for optimizing transcranial stimulation and using oscillatory networks in neuromorphic engineering.

Dopamine Triggers the Maturation of Striatal Spiny Projection Neuron Excitability during a Critical Period

Neural circuits are formed and refined during childhood, including via critical changes in neuronal excitability. Here, we investigated the ontogeny of striatal intrinsic excitability. We found that dopamine neurotransmission increases from the first to the third postnatal week in mice and precedes the reduction in spiny projection neuron (SPN) intrinsic excitability during the fourth postnatal week. In mice developmentally deficient for striatal dopamine, direct pathway D1-SPNs failed to undergo maturation of excitability past P18 and maintained hyperexcitability into adulthood. We found that the absence of D1-SPN maturation was due to altered phosphatidylinositol 4,5-biphosphate dynamics and a consequent lack of normal ontogenetic increases in Kir2 currents. Dopamine replacement corrected these deficits in SPN excitability when provided from birth or during a specific period of juvenile development (P18-P28), but not during adulthood. These results identify a sensitive period of dopamine-dependent striatal maturation, with implications for the pathophysiology and treatment of neurodevelopmental disorders.

Network-Based Drug Discovery: Coupling Network Pharmacology with Phenotypic Screening for Neuronal Excitability

Diseases such as chronic pain with complex etiologies are unlikely to respond to single, target-specific therapeutics but rather require intervention at multiple points within a perturbed disease system. Such approaches are being enabled by the rise of computational methods to identify key points of intervention and by new screening techniques that focus on a relevant condition or phenotype, rather than a specific target. Here we apply an in silico network pharmacology approach to identify small-molecule compounds with the potential to selectively disrupt the structure of a chronic-pain specific disease network, which we validate using a novel phenotypic screen that recapitulates key aspects of neuronal and pain biology by measuring changes in neuronal excitability in native sensory neurons. The combination of network pharmacology with a phenotypic screen is a powerful approach; we show that hit rates increase from 26% to 42%. This represents a rational approach to the discovery of compounds with a poly-pharmacology based therapeutic value, which will be vital for the discovery of treatments for complex disease.

P112. Modulatory effects of anodal transcranial direct current stimulation on fronto-striatal gain control of the interplay between selective attention and perception

Carrying conversations in public spaces with a plethora of competing sensory inputs demands flexible interactions between attention and perception for selectively processing goal-relevant information. We postulate that the fronto-striatal network plays a key role in regulating this interaction. However, to date the underlying gain control mechanisms are not yet well understood. Neuronal gain control can be fine-tuned by membrane potential regulated changes in neuronal excitability. Anodal transcranial current stimulation (atDCS) has been shown to cause a depolarization of resting membrane potentials, which increases neuronal excitability. In the present study, we applied off-line atDCS over the right inferior frontal gyrus (IFG) in healthy young adults in a single-blinded sham-controlled study to investigate atDCS-induced effects on fronto-striatal gain control of auditory attention. We recorded high-density EEG recordings during a dichotic listening task in which both perceptual saliency and attentional focus were varied, creating conditions of low and high perceptual-attentional conflict. Compared to sham stimulation, pilot results suggest that atDCS enhanced auditory perception and attentional regulation: Specifically, atDCS increased discrimination ability of inter-aural intensity differences and enhanced performance in high conflict conditions. These behavioral effects were reflected by EEG correlates associated with attentional and perceptual processing.

What Happens with the Circuit in Alzheimer's Disease in Mice and Humans?

A major mystery of many types of neurological and psychiatric disorders, such as Alzheimer's disease (AD), remains the underlying, disease-specific neuronal damage. Because of the strong interconnectivity of neurons in the brain, neuronal dysfunction necessarily disrupts neuronal circuits. In this article, we review evidence for the disruption of large-scale networks from imaging studies of humans and relate it to studies of cellular dysfunction in mouse models of AD. The emerging picture is that some forms of early network dysfunctions can be explained by excessively increased levels of neuronal activity. The notion of such neuronal hyperactivity receives strong support from in vivo and in vitro cellular imaging and electrophysiological recordings in the mouse, which provide mechanistic insights underlying the change in neuronal excitability. Overall, some key aspects of AD-related neuronal dysfunctions in humans and mice are strikingly similar and support the continuation of such a translational strategy.

Role of brain-derived neurotrophic factor in the pathogenesis of distention-associated abdominal pain in bowel obstruction.

Previous studies found that visceral sensitivity is increased in bowel obstruction (BO). We hypothesized that mechanical stress-induced expression of BDNF in smooth muscle cells (SMC) of the distended bowel plays a critical role in visceral hypersensitivity in BO by altering voltage-gated K+ channel (Kv ) activity in sensory neurons. Partial colon obstruction was maintained in rats for 7days. Colon-projecting neurons in the dorsal root ganglia (DRG, T13 to L2) were isolated for electrophysiological and gene expression studies. Compared to controls, membrane excitability of colon-projecting DRG neurons was markedly enhanced in BO. The densities of total Kv and transient A-type (IA ) K+ currents, but not sustained delayed IK current, were significantly reduced in the neurons in BO. The mRNA expression of IA subtype Kv 1.4 in colon neurons was down-regulated in BO. Expression of BDNF mRNA and protein was dramatically increased in colonic smooth muscle of the distended segment, but not in the non-distended aboral segment. Mechanical stretch of colon SMC in vitro increased BDNF expression. Treatment with anti-BDNF antibody restored total Kv and IA currents of neurons from BO rats. Administration of Trk B inhibitor ANA-12 blocked BO-associated changes of neuronal excitability, Kv activity and gene expression in obstruction. Mechanical stress-induced expression of BDNF in colon SMC plays a critical role in visceral hypersensitivity in BO by suppressing A-type K+ currents and gene expression in sensory nerve. These findings help to identify therapeutic targets for distention-associated abdominal pain in the gut.

Involvement of extrasynaptic glutamate in physiological and pathophysiological changes of neuronal excitability.

Glutamate is the most abundant neurotransmitter of the central nervous system, as the majority of neurons use glutamate as neurotransmitter. It is also well known that this neurotransmitter is not restricted to synaptic clefts, but found in the extrasynaptic regions as ambient glutamate. Extrasynaptic glutamate originates from spillover of synaptic release, as well as from astrocytes and microglia. Its concentration is magnitudes lower than in the synaptic cleft, but receptors responding to it have higher affinity for it. Extrasynaptic glutamate receptors can be found in neuronal somatodendritic location, on astroglia, oligodendrocytes or microglia. Activation of them leads to changes of neuronal excitability with different amplitude and kinetics. Extrasynaptic glutamate is taken up by neurons and astrocytes mostly via EAAT transporters, and astrocytes, in turn metabolize it to glutamine. Extrasynaptic glutamate is involved in several physiological phenomena of the central nervous system. It regulates neuronal excitability and synaptic strength by involving astroglia; contributing to learning and memory formation, neurosecretory and neuromodulatory mechanisms, as well as sleep homeostasis.The extrasynaptic glutamatergic system is affected in several brain pathologies related to excitotoxicity, neurodegeneration or neuroinflammation. Being present in dementias, neurodegenerative and neuropsychiatric diseases or tumor invasion in a seemingly uniform way, the system possibly provides a common component of their pathogenesis. Although parts of the system are extensively discussed by several recent reviews, in this review I attempt to summarize physiological actions of the extrasynaptic glutamate on neuronal excitability and provide a brief insight to its pathology for basic understanding of the topic.

Two novel forms of ERG oscillation in Drosophila: age and activity dependence

Over an animal’s lifespan, neuronal circuits and systems often decline in an inherently heterogeneous fashion. To compare the age-dependent progression of changes in visual behavior with alterations in retinal physiology, we examined phototaxis and electroretinograms (ERGs) in a wild-type D. melanogaster strain (Canton-S) across their lifespan. In aged flies (beyond 50% median lifespan), we found a marked decline in phototaxis, while motor coordination was less disrupted, as indicated by relatively stronger negative geotaxis. These aged flies displayed substantially reduced ERG transient amplitudes while the receptor potentials (RP) remained largely intact. Using a repetitive light flash protocol, we serendipitously discovered two forms of activity-dependent oscillation in the ERG waveforms of young flies: ‘light-off’ and ‘light-on’ oscillations. After repeated 500 ms light flashes, light-off oscillations appeared during the ERG off-transients (frequency: 50–120 Hz, amplitude: ∼1 mV). Light-on oscillations (100–200 Hz, ∼0.3 mV) were induced by a series of 50 ms flashes, and were evident during the ERG on-transients. Both forms of oscillation were observed in other strains of D. melanogaster (Oregon-R, Berlin), additional Drosophila species (D. funerbris, D. euronotus, D. hydei, D. americana), and were evoked by a variety of light sources. Both light-off and light-on oscillations were distinct from previously described ERG oscillations in the visual mutant rosA in terms of location within the waveform and frequency. However, within rosA mutants, light-off oscillations, but not light-on oscillations could be recruited by the repetitive light flash protocol. Importantly though, we found that both forms of oscillation were rarely observed in aged flies. Although the physiological bases of these oscillations remain to be elucidated, they may provide important clues to age-related changes in neuronal excitability and synaptic transmission.

Second hand smoke exposure depresses neuronal excitability and enhances 4‐AP sensitive channel function of cardiac vagal neurons in the nucleus ambiguus

BACKGROUNDSecond hand smoke (SHS) is a significant risk factor for cardiac dysfunction including arrhythmias and sudden cardiac death. Previously we showed that environmentally relevant concentrations of SHS reduce heart rate variability (HRV), an index of autonomic function. We also showed that SHS exposure significantly reduces cardiac vagal neuronal excitability in the nucleus ambiguus (NA), the final vagal cardiac output regulating HRV. We further showed that SHS‐induced attenuation of SK channel activity that may serve as a partial compensatory mechanism to the reduction in overall neuronal excitability. Here, we sought to test the hypothesis that SHS exposure, at an environmentally relevant concentration that reduces HRV, depresses neuronal excitability of cardiac vagal neurons in the NA by enhancing 4‐AP sensitive potassium channel function.METHODSAdult male C57BL6/J mice underwent open chest surgeries to retrograde label cardiac vagal neurons by applying a fluorescent dye (DiI) to the sinoatrial node. After two weeks of recovery from surgery, mice were randomly assigned to either filtered air (FA) or SHS (3 mg/m3, 6 hr/d, 5 d/wk) for 4‐, 8‐ or 12‐weeks. Whole‐cell current clamp recordings in brainstem slices were performed on anatomically identified cardiac vagal neurons in the NA with fluorescent labeling.RESULTSSHS exposure significantly (p < 0.05) reduced spiking response to depolarizing current injections after 4‐ and 12‐weeks – but not 8‐weeks – of exposure. Perfusion with 1 mM of 4‐AP, a voltage‐activated potassium channel blocker, similarly increased spiking response by 5–10 spikes/s across all time points. The 4‐AP induced changes in spiking responses were not different between SHS and FA (p > 0.05). SHS exposure also significantly (p < 0.05) increased voltage and current threshold for action potential generation for all time points tested (4‐, 8‐, and 12‐weeks). 4‐AP significantly lowered the voltage threshold; these effects were significantly (p < 0.05) bigger in the SHS group (−1.2 ± 0.5 mV vs. −3.7 ± 0.4 mV, FA vs. SHS respectively). In contrast, 4‐AP similarly lowered current threshold for action potential generation in both FA and SHS groups (−80 ± 13 pA vs. −103 ± 12 pA, FA vs. SHS, respectively).CONCLUSIONSWe conclude that environmentally relevant SHS exposure induces time‐dependent changes in neuronal excitability of cardiac vagal neurons. Some of these changes may be the result of increased voltage‐activated potassium channel function.Support or Funding InformationR01 ES025229; T32 HL086350This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Lysozyme over‐expression during nerve injury excites Aδ & C fibres in a fibre specific manner to incite neuropathic pain

Human lysozyme is one of the most extensively studied proteins yet its exact physiological functions still remain a mystery. Here, we highlight a hitherto unrecognized role of lysozyme in neuropathic pain and neuronal excitability. Injection of lysozyme alone in healthy rats leads to heightened sensitivity in them towards both mechanical and thermal pain stimuli. Also, in rat models of neuropathic pain, lysozyme is over – expressed and its down – regulation by siRNA or inhibition of its activity by its disaccharide inhibitor ‐ chitobiose relieves pain confirming a causal role of lysozyme in neuropathic pain. Moreover, as the catalytically incompetent lysozyme or its chemically inhibited counterparts fail to provoke pain indicate that it deploys its catalytic site for eliciting pain. Bath application of lysozyme remarkably increased both the spontaneous excitatory potentials and currents (sEPSPs & sEPSCs) and the amplitudes of afferent mediated evoked excitatory synaptic inputs (eFPSPs & eEPSCs) in Aδ fibres in a fibre specific manner in the dorsal horn neurons. It also increased paired pulsed ratio only in the C‐fibres. When complexed with chitobiose it does not lead to any change in neuronal excitability. Thus, lysozyme excites neurons by deploying its catalytic region in a fibre specific manner. Further, we show that it deploys its catalytic site to recruit Annexin A2 to transduce TLR4→NFkβ signaling pathway which may culminate in the fusion of neurotransmitter vesicles at the synapse to manifest neuronal excitability and eventually pain. Thus, glycan inhibitors of lysozyme and antagonists of the pathway recruited by it to inflict pain pave not only the way for novel approaches for dissecting the molecular mechanism of neuropathic pain but also for treating this unmet medical need efficaciously.Support or Funding InformationCouncil of Scientific and Industrial Research, India to ASThis abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.