Excitatory Currents Research Articles

Bifurcations of Negative Responses to Positive Feedback Current Mediated by Memristor in a Neuron Model with Bursting Patterns

In contrast to traditional viewpoint that positive feedback current always enhances neural firing activities, in the present paper, we identify that the excitatory feedback current mediated by memristor can induce negative responses of bursting patterns, which can be well interpreted with bifurcations. For the Hindmarsh–Rose neuron model without memristor, the period-adding bifurcations of bursting patterns and increase of firing frequency can be induced by increasing the excitatory effect of the background current. After introducing a memristor to simulate the biological synapse or electromagnetic induction effect, inverse period-adding or complex bifurcations of bursting patterns are induced by the excitatory feedback current mediated by the memristor. The number of spikes per burst becomes smaller and the firing frequency becomes lower when increasing the positive feedback gain. Such negative responses of bursting patterns to the positive feedback current are demonstrated in a circuit designed with Digital Signal Processor systems of the MatLab software. Furthermore, the underlying bifurcation mechanism of the negative responses to the positive feedback is acquired with fast–slow variable dissection method. With increasing feedback gain, the initial phase of the burst, which corresponds to a saddle-node bifurcation point of the fast subsystem, delays, while the termination phase of the burst, which corresponds to a saddle-homoclinic bifurcation point, remains unchanged. Therefore, the burst becomes narrower with increasing feedback gain, which leads to decrease in the number of spikes within a burst and decrease in firing frequency. The results present a paradoxical nonlinear phenomenon and the dynamical mechanism, which is helpful for understanding the functions of memristor and roles of the electromagnetic induction current.

Integration of Swimming-Related Synaptic Excitation and Inhibition by olig2+ Eurydendroid Neurons in Larval Zebrafish Cerebellum.

The cerebellum influences motor control through Purkinje target neurons, which transmit cerebellar output. Such output is required, for instance, for larval zebrafish to learn conditioned fictive swimming. The output cells, called eurydendroid neurons (ENs) in teleost fish, are inhibited by Purkinje cells and excited by parallel fibers. Here, we investigated the electrophysiological properties of glutamatergic ENs labeled by the transcription factor olig2. Action potential firing and synaptic responses were recorded in current clamp and voltage clamp from olig2+ neurons in immobilized larval zebrafish (before sexual differentiation) and were correlated with motor behavior by simultaneous recording of fictive swimming. In the absence of swimming, olig2+ ENs had basal firing rates near 8 spikes/s, and EPSCs and IPSCs were evident. Comparing Purkinje firing rates and eurydendroid IPSC rates indicated that 1-3 Purkinje cells converge onto each EN. Optogenetically suppressing Purkinje simple spikes, while preserving complex spikes, suggested that eurydendroid IPSC size depended on presynaptic spike duration rather than amplitude. During swimming, EPSC and IPSC rates increased. Total excitatory and inhibitory currents during sensory-evoked swimming were both more than double those during spontaneous swimming. During both spontaneous and sensory-evoked swimming, the total inhibitory current was more than threefold larger than the excitatory current. Firing rates of ENs nevertheless increased, suggesting that the relative timing of IPSCs and EPSCs may permit excitation to drive additional eurydendroid spikes. The data indicate that olig2+ cells are ENs whose activity is modulated with locomotion, suiting them to participate in sensorimotor integration associated with cerebellum-dependent learning.SIGNIFICANCE STATEMENT The cerebellum contributes to movements through signals generated by cerebellar output neurons, called eurydendroid neurons (ENs) in fish (cerebellar nuclei in mammals). ENs receive sensory and motor signals from excitatory parallel fibers and inhibitory Purkinje cells. Here, we report electrophysiological recordings from ENs of larval zebrafish that directly illustrate how synaptic inhibition and excitation are integrated by cerebellar output neurons in association with motor behavior. The results demonstrate that inhibitory and excitatory drive both increase during fictive swimming, but inhibition greatly exceeds excitation. Firing rates nevertheless increase, providing evidence that synaptic integration promotes cerebellar output during locomotion. The data offer a basis for comparing aspects of cerebellar coding that are conserved and that diverge across vertebrates.

Dynamic Recovery from Depression Enables Rate Encoding in Inhibitory Synapses.

SummaryParvalbumin-expressing fast-spiking interneurons (PV-INs) control network firing and the gain of cortical response to sensory stimulation. Crucial for these functions, PV-INs can sustain high-frequency firing with no accommodation. However, PV-INs also exhibit short-term depression (STD) during sustained activation, largely due to the depletion of synaptic resources (vesicles). In most synapses the rate of replenishment of depleted vesicles is constant, determining an inverse relationship between depression levels and the activation rate, which theoretically, severely limits rate-coding capabilities. We examined STD of the PV-IN to pyramidal cell synapse in the mouse visual cortex and found that in these synapses the recovery from depression is not constant but increases linearly with the frequency of use. By combining modeling, dynamic clamp, and optogenetics, we demonstrated that this recovery enables PV-INs to reduce pyramidal cell firing in a linear manner, which theoretically is crucial for controlling the gain of cortical visual responses.

Synaptic balance due to homeostatically self-organized quasicritical dynamics

Recent experiments suggested that homeostatic regulation of synaptic balance leads the visual system to recover and maintain a regime of power-law avalanches. Here we study an excitatory/inhibitory (E/I) mean-field neuronal network that has a critical point with power-law avalanches and synaptic balance. When short term depression in inhibitory synapses and firing threshold adaptation are added, the system hovers around the critical point. This homeostatically self-organized quasi-critical (SOqC) dynamics generates E/I synaptic current cancellation in fast time scales, causing fluctuation-driven asynchronous-irregular (AI) firing. We present the full phase diagram of the model without adaptation varying external input versus synaptic coupling. This system has a rich dynamical repertoire of spiking patterns: synchronous regular (SR), asynchronous regular (AR), synchronous irregular (SI), slow oscillations (SO) and AI. It also presents dynamic balance of synaptic currents, since inhibitory currents try and compensate excitatory currents over time, resulting in both of them scaling linearly with external input. Our model thus unifies two different perspectives on cortical spontaneous activity: both critical avalanches and fluctuation-driven AI firing arise from SOqC homeostatic adaptation, and are indeed two sides of the same coin.

Microglial A20 Protects the Brain from CD8 T-Cell-Mediated Immunopathology

Tumor-necrosis-factor-alpha-induced protein 3 (TNFAIP3), or A20, is a ubiquitin-modifying protein and negative regulator of canonical nuclear factor κB (NF-κB) signaling. Several single-nucleotide polymorphisms in TNFAIP3 are associated with autoimmune diseases, suggesting a role in tissue inflammation. While the role of A20 in peripheral immune cells has been well investigated, less is known about its role in the central nervous system (CNS). Here, we show that microglial A20 is crucial for maintaining brain homeostasis. Without microglial A20, CD8+ Tcells spontaneously infiltrate the CNS and acquire a viral response signature. The combination of infiltrating CD8+ Tcells and activated A20-deficient microglia leads to an increase in VGLUT1+ terminals and frequency of spontaneous excitatory currents. Ultimately, A20-deficient microglia upregulate genes associated with the antiviral response and neurodegenerative diseases. Together, our data suggest that microglial A20 acts as a sensor for viral infection and a master regulator of CNS homeostasis.

Alpha-1 Adrenergic Receptors Modulate Glutamate and GABA Neurotransmission onto Ventral Tegmental Dopamine Neurons during Cocaine Sensitization.

The ventral tegmental area (VTA) plays an important role in the reward and motivational processes that facilitate the development of drug addiction. Presynaptic α1-AR activation modulates glutamate and Gamma-aminobutyric acid (GABA) release. This work elucidates the role of VTA presynaptic α1-ARs and their modulation on glutamatergic and GABAergic neurotransmission during cocaine sensitization. Excitatory and inhibitory currents (EPSCs and IPSCs) measured by a whole cell voltage clamp show that α1-ARs activation increases EPSCs amplitude after 1 day of cocaine treatment but not after 5 days of cocaine injections. The absence of a pharmacological response to an α1-ARs agonist highlights the desensitization of the receptor after repeated cocaine administration. The desensitization of α1-ARs persists after a 7-day withdrawal period. In contrast, the modulation of α1-ARs on GABA neurotransmission, shown by decreases in IPSCs’ amplitude, is not affected by acute or chronic cocaine injections. Taken together, these data suggest that α1-ARs may enhance DA neuronal excitability after repeated cocaine administration through the reduction of GABA inhibition onto VTA dopamine (DA) neurons even in the absence of α1-ARs’ function on glutamate release and protein kinase C (PKC) activation. α1-AR modulatory changes in cocaine sensitization increase our knowledge of the role of the noradrenergic system in cocaine addiction and may provide possible avenues for therapeutics.

Network and cellular mechanisms underlying heterogeneous excitatory/inhibitory balanced states.

Recent work has explored spatiotemporal relationships between excitatory (E) and inhibitory (I) signaling within neural networks, and the effect of these relationships on network activity patterns. Data from these studies have indicated that excitation and inhibition are maintained at a similar level across long time periods and that excitatory and inhibitory currents may be tightly synchronized. Disruption of this balance-leading to an aberrant E/I ratio-is implicated in various brain pathologies. However, a thorough characterization of the relationship between E and I currents in experimental settings is largely impossible, due to their tight regulation at multiple cellular and network levels. Here, we use biophysical neural network models to investigate the emergence and properties of balanced states by heterogeneous mechanisms. Our results show that a network can homeostatically regulate the E/I ratio through interactions among multiple cellular and network factors, including average firing rates, synaptic weights and average neural depolarization levels in excitatory/inhibitory populations. Complex and competing interactions between firing rates and depolarization levels allow these factors to alternately dominate network dynamics in different synaptic weight regimes. This leads to the emergence of distinct mechanisms responsible for determining a balanced state and its dynamical correlate. Our analysis provides a comprehensive picture of how E/I ratio changes when manipulating specific network properties, and identifies the mechanisms regulating E/I balance. These results provide a framework to explain the diverse, and in some cases, contradictory experimental observations on the E/I state in different brain states and conditions.

Determinants of ion selectivity in ASIC1a- and ASIC2a-containing acid-sensing ion channels

Trimeric acid-sensing ion channels (ASICs) contribute to neuronal signaling by converting extracellular acidification into excitatory sodium currents. Previous work with homomeric ASIC1a implicates conserved leucine (L7') and consecutive glycine-alanine-serine (GAS belt) residues near the middle, and conserved negatively charged (E18') residues at the bottom of the pore in ion permeation and/or selectivity. However, a conserved mechanism of ion selectivity throughout the ASIC family has not been established. We therefore explored the molecular determinants of ion selectivity in heteromeric ASIC1a/ASIC2a and homomeric ASIC2a channels using site-directed mutagenesis, electrophysiology, and molecular dynamics free energy simulations. Similar to ASIC1a, E18' residues create an energetic preference for sodium ions at the lower end of the pore in ASIC2a-containing channels. However, and in contrast to ASIC1a homomers, ion permeation through ASIC2a-containing channels is not determined by L7' side chains in the upper part of the channel. This may be, in part, due to ASIC2a-specific negatively charged residues (E59 and E62) that lower the energy of ions in the upper pore, thus making the GAS belt more important for selectivity. This is confirmed by experiments showing that the L7'A mutation has no effect in ASIC2a, in contrast to ASIC1a, where it eliminated selectivity. ASIC2a triple mutants eliminating both L7' and upper charges did not lead to large changes in selectivity, suggesting a different role for L7' in ASIC2a compared with ASIC1a channels. In contrast, we observed measurable changes in ion selectivity in ASIC2a-containing channels with GAS belt mutations. Our results suggest that ion conduction and selectivity in the upper part of the ASIC pore may differ between subtypes, whereas the essential role of E18' in ion selectivity is conserved. Furthermore, we demonstrate that heteromeric channels containing mutations in only one of two ASIC subtypes provide a means of functionally testing mutations that render homomeric channels nonfunctional.

Ampakine pretreatment enables a single brief hypoxic episode to evoke phrenic motor facilitation.

Phrenic long-term facilitation (LTF) is a sustained increase in phrenic motor output occurring after exposure to multiple (but not single) hypoxic episodes. Ampakines are a class of drugs that enhance AMPA receptor function. Ampakines can enhance expression of neuroplasticity, and the phrenic motor system is fundamentally dependent on excitatory glutamatergic currents. Accordingly, we tested the hypothesis that combining ampakine pretreatment with a single brief hypoxic exposure would result in phrenic motor facilitation lasting well beyond the period of hypoxia. Phrenic nerve output was recorded in urethane-anesthetized, ventilated, and vagotomized adult Sprague-Dawley rats. Ampakine CX717 (15 mg/kg iv; n = 8) produced a small increase in phrenic inspiratory burst amplitude and frequency, but values quickly returned to predrug baseline. When CX717 was followed 2 min later by a 5-min exposure to hypoxia (n = 8; ~45 mmHg), a persistent increase in phrenic inspiratory burst amplitude (i.e., phrenic motor facilitation) was observed up to 60 min posthypoxia (103 ± 53% increase from baseline). In contrast, when hypoxia was preceded by vehicle injection (10% 2-hydroxypropyl-β-cyclodextrin; n = 8), inspiratory phrenic bursting was similar to baseline values at 60 min. Additional experiments with another ampakine (CX1739, 15 mg/kg) produced comparable results. We conclude that pairing low-dose ampakine treatment with a single brief hypoxic exposure can evoke sustained phrenic motor facilitation. This targeted approach for enhancing respiratory neuroplasticity may have value in the context of hypoxia-based neurorehabilitation strategies.NEW & NOTEWORTHY A single brief episode of hypoxia (e.g., 3-5 min) does not evoke long-lasting increases in respiratory motor output after the hypoxia is concluded. Ampakines are a class of drugs that enhance AMPA receptor function. We show that pairing low-dose ampakine treatment with a single brief hypoxic exposure can evoke sustained phrenic motor facilitation after the acute hypoxic episode.

Spiking Sensory Neurons for Analyzing Electrophysiological Data

Low power consuming biomimetic neurons are considered for use in analyzing electrophysiological data. Starting with a circuit model of a Morris-Lecar inspired spiking neuron, we first investigate the dynamic properties. We demonstrate some of its neuro-computational features including type I and type II excitability, tonic and phasic spiking, spike latency and integration. Electroencephalogram (EEG) signals are then used as excitatory input currents and it is shown that the spiking neurons can provide new insights into brain function. The spike rates of the neurons are employed in a classification task and shown to yield similar performance compared to one using the frequency dependence. We discuss how this circuit has the potential to significantly reduce EEG data, improve privacy and lower power consumption for portable EEG systems.

Nonlinear mechanism of excitatory autapse-induced reduction or enhancement of firing frequency of neuronal bursting

Excitatory and inhibitory effect always induces the enhancement and inhibitory effect of neural electronic activities, which is the common viewpoint of the modulations to the neural firing and plays important roles in the information processing of the nervous system. In the present paper, the Homoclinic/Homoclinic bursting pattern with alternation behavior between burst containing multiple spikes and subthreshold oscillations and the tough value of the burst lower than that of the subthreshold oscillations is chosen as representative, and the excitatory effect on the complex nonlinear dynamics of the representative bursting pattern is studied. For the excitatory autapse with suitable autaptic time delay and strength, the autaptic current pulse applied to the trough of the burst can induce the number of spikes within a burst to decrease and then the average firing frequency to decline, which presents a novel example different from the common viewpoint of the excitatory effect. The excitatory autapse induces the average firing frequency to increase in the remained parameter region of two-parameter plane of the autaptic time delay and strength. With bifurcations acquired by the fast/slow variable dissection method and phase trajectory, the subthreshold oscillations of the bursting correspond to a subthreshold limit cycle of the fast subsystem and the spike within burst corresponds to a suprathreshold limit cycle, and excitatory autaptic current can induce the transition from suprathreshold limit cycle to subthreshold limit cycle, which leads the spike to terminate in advance and is the cause for reducing the average firing frequency. The results is the present paper are compared with the phenomenon and bifurcation mechanism that the excitatory autapse can induce the spike number to decrease within a burst but the average firing frequency to increase as indicated in a recent study on the Fold/Homoclinic bursting. These results enrich the uncommon phenomenon of the neuronal electrical activities, reveal the underlying nonlinear mechanism, provide a new way to regulate the bursting pattern, and disclose the potential functions of the excitatory autapse.

Memristive autapse involving magnetic coupling and excitatory autapse enhance firing

Autapse is the synaptic coupling of a neuron's axon to its own dendrite. Considering recent experimental evidence regarding functional excitatory autapses, we explored how the excitatory autapse influences electrical activity in a neuronal model with ion-channel effects. We found that the excitatory autaptic current is able to enhance firing rates. Based on the chemical features of the autapse, we further proposed a memristive autapse involving magnetic coupling, and compared the memristive autapse and the excitatory autapse using the bifurcation analysis and fast/slow decomposition. Our results identified that both of these two types of autapses exhibit similar geometric dynamic properties in terms of burst regulation. Comparing with the excitatory autapse, the memristive autapse involves in a stronger spiking modulation capability, ensuring the neuron to accommodate strong external inputs. Overall, these findings suggested that the memristive system is expected to be usable to mimic biological synapses for advances in neuromorphic computing.

Activation of alpha-1 adrenergic receptors increases cytosolic calcium in neurones of the paraventricular nucleus of the hypothalamus.

Norepinephrine (NE) activates adrenergic receptors (ARs) in the hypothalamic paraventricular nucleus (PVN) to increase excitatory currents, depolarise neurones and, ultimately, augment neuro-sympathetic and endocrine output. Such cellular events are known to potentiate intracellular calcium ([Ca2+ ]i ); however, the role of NE with respect to modulating [Ca2+ ]i in PVN neurones and the mechanisms by which this may occur remain unclear. We evaluated the effects of NE on [Ca2+ ]i of acutely isolated PVN neurones using Fura-2 imaging. NE induced a slow increase in [Ca2+ ]i compared to artificial cerebrospinal fluid vehicle. NE-induced Ca2+ elevations were mimicked by the α1 -AR agonist phenylephrine (PE) but not by α2 -AR agonist clonidine (CLON). NE and PE but not CLON also increased the overall number of neurones that increase [Ca2+ ]i (ie, responders). Elimination of extracellular Ca2+ or intracellular endoplasmic reticulum Ca2+ stores abolished the increase in [Ca2+ ]i and reduced responders. Blockade of voltage-dependent Ca2+ channels abolished the α1 -AR induced increase in [Ca2+ ]i and number of responders, as did inhibition of phospholipase C inhibitor, protein kinase C and inositol triphosphate receptors. Spontaneous phasic Ca2+ events, however, were not altered by NE, PE or CLON. Repeated K+ -induced membrane depolarisation produced repetitive [Ca2+ ]i elevations. NE and PE increased baseline Ca2+ , whereas NE decreased the peak amplitude. CLON also decreased peak amplitude but did not affect baseline [Ca2+ ]i . Taken together, these data suggest receptor-specific influence of α1 and α2 receptors on the various modes of calcium entry in PVN neurones. They further suggest Ca2+ increase via α1 -ARs is co-dependent on extracellular Ca2+ influx and intracellular Ca2+ release, possibly via a phospholipase C inhibitor-mediated signalling cascade.

Excitatory electromagnetic induction current enhances coherence resonance of the FitzHugh–Nagumo neuron

The effect of electromagnetic induction on neural firing activities has been widely investigated and has also been related to neural information coding. In this study, electromagnetic induction and Gaussian white noise (GWN) are introduced to the FitzHugh–Nagumo neuron, and the effect of induction current on GWN-induced coherence resonance (CR) is investigated. For an appropriate value of bias voltage source, the induction current is excitatory (respectively, inhibitory) when the gain of induction current is positive (respectively, negative). When the induction current is excitatory, the degree of CR is enhanced. When the induction current is inhibitory, however, the degree of CR is weakened. Furthermore, by varying the value of bias voltage source, we show that the degree of CR increases with the increase in the gain of induction current. Bifurcation analysis shows that the supercritical Hopf bifurcation point gets close to the resting state with the increase in the gain of induction current, which causes the increase in the degree of CR. The results of this study show that excitatory electromagnetic induction current can enhance noise-induced CR. This finding provides a possible way to modulate CR of the nervous system.

Cyclooxygenase-2 inhibition reduces anxiety-like behavior and normalizes enhanced amygdala glutamatergic transmission following chronic oral corticosterone treatment

Chronic stress increases the probability of receiving an anxiety, depression, or chronic illness diagnosis. Pharmacological interventions that reduce the behavioral and physiological effects of chronic stress in animal models may represent novel approaches for the treatment of stress-related psychiatric disorders. Here, we examined the effects of cyclooxygenase-2 (COX-2) inhibition on anxiety-like behaviors and amygdala glutamatergic signaling after chronic non-invasive oral corticosterone (CORT) administration in mice. Treatment with the highly selective COX-2 inhibitor Lumiracoxib (LMX) reversed anxiety-like behavior induced by chronic CORT. Specifically, acute and repeated administration of LMX 5 mg kg−1 reduced chronic CORT-induced anxiety-like behavior measured using the elevated-plus maze, elevated-zero maze, and light-dark box tests. In contrast, LMX did not affect anxiety-like behaviors in naïve mice. Ex vivo electrophysiology studies revealed that repeated LMX treatment normalized chronic CORT-induced increases in spontaneous excitatory glutamatergic currents recorded from anterior, but not posterior, basolateral amygdala neurons. These data indicate COX-2 inhibition can reverse chronic CORT-induced increases in anxiety-like behaviors and amygdala glutamatergic signaling, and support further clinical investigation of selective COX-2 inhibitors for the treatment of affective and stress-related psychiatric disorders.

The neuropeptide GsMTx4 inhibits a mechanosensitive BK channel through the voltage-dependent modification specific to mechano-gating

The cardiac mechanosensitive BK (Slo1) channels are gated by Ca2+, voltage, and membrane stretch. The neuropeptide GsMTx4 is a selective inhibitor of mechanosensitive (MS) channels. It has been reported to suppress stretch-induced cardiac fibrillation in the heart, but the mechanism underlying the specificity and even the targeting channel(s) in the heart remain elusive. Here, we report that GsMTx4 inhibits a stretch-activated BK channel (SAKcaC) in the heart through a modulation specific to mechano-gating. We show that membrane stretching increases while GsMTx4 decreases the open probability (Po) of SAKcaC. These effects were mostly abolished by the deletion of the STREX axis-regulated (STREX) exon located between RCK1 and RCK2 domains in BK channels. Single-channel kinetics analysis revealed that membrane stretch activates SAKcaC by prolonging the open-time duration (τO) and shortening the closed-time constant (τC). In contrast, GsMTx4 reversed the effects of membrane stretch, suggesting that GsMTx4 inhibits SAKcaC activity by interfering with mechano-gating of the channel. Moreover, GsMTx4 exerted stronger efficacy on SAKcaC under membrane-hyperpolarized/resting conditions. Molecular dynamics simulation study revealed that GsMTx4 appeared to have the ability to penetrate deeply within the bilayer, thus generating strong membrane deformation under the hyperpolarizing/resting conditions. Immunostaining results indicate that BK variants containing STREX are also expressed in mouse ventricular cardiomyocytes. Our results provide common mechanisms of peptide actions on MS channels and may give clues to therapeutic suppression of cardiac arrhythmias caused by excitatory currents through MS channels under hyper-mechanical stress in the heart.

Altered Synaptic Drive onto Birthdated Dentate Granule Cells in Experimental Temporal Lobe Epilepsy.

Dysregulated adult hippocampal neurogenesis occurs in many temporal lobe epilepsy (TLE) models. Most dentate granule cells (DGCs) generated in response to an epileptic insult develop features that promote increased excitability, including ectopic location, persistent hilar basal dendrites (HBDs), and mossy fiber sprouting. However, some appear to integrate normally and even exhibit reduced excitability compared to other DGCs. To examine the relationship between DGC birthdate, morphology, and network integration in a model of TLE, we retrovirally birthdated either early-born [EB; postnatal day (P)7] or adult-born (AB; P60) DGCs. Male rats underwent pilocarpine-induced status epilepticus (SE) or sham treatment at P56. Three to six months after SE or sham treatment, we used whole-cell patch-clamp and fluorescence microscopy to record spontaneous excitatory and inhibitory currents from birthdated DGCs. We found that both AB and EB populations of DGCs recorded from epileptic rats received increased excitatory input compared with age-matched controls. Interestingly, when AB populations were separated into normally integrated (normotopic) and aberrant (ectopic or HBD-containing) subpopulations, only the aberrant populations exhibited a relative increase in excitatory input (amplitude, frequency, and charge transfer). The ratio of excitatory-to-inhibitory input was most dramatically upregulated for ectopically localized DGCs. These data provide definitive physiological evidence that aberrant integration of post-SE, AB DGCs contributes to increased synaptic drive and support the idea that ectopic DGCs serve as putative hub cells to promote seizures.SIGNIFICANCE STATEMENT Adult dentate granule cell (DGC) neurogenesis is altered in rodent models of temporal lobe epilepsy (TLE). Some of the new neurons show abnormal morphology and integration, but whether adult-generated DGCs contribute to the development of epilepsy is controversial. We examined the synaptic inputs of age-defined populations of DGCs using electrophysiological recordings and fluorescent retroviral reporter birthdating. DGCs generated neonatally were compared with those generated in adulthood, and adult-born (AB) neurons with normal versus aberrant morphology or integration were examined. We found that AB, ectopically located DGCs exhibit the most pro-excitatory physiological changes, implicating this population in seizure generation or progression.

SAT-361 Rapid Glucocorticoid Regulation of Adrenoreceptor Trafficking Desensitizes CRH Neurons to Noradrenergic Activation

Stress activates the hypothalamic-pituitary-adrenal (HPA) axis via excitatory noradrenergic projections from the brainstem to corticotropin releasing hormone (CRH) neurons in the hypothalamic paraventricular nucleus (PVN). The resulting systemic release of glucocorticoids feeds back to the hypothalamus to rapidly suppress HPA activation. Patch-clamp electrophysiology experiments revealed a strong increase in excitatory currents via alpha 1 adrenoreceptor (AR1a) activation, which was desensitized after acute restraint stress or glucocorticoid application. This rapid desensitization was reversed by inhibiting endocytosis, suggesting that desensitization was achieved by AR1a internalization. Live cell imaging of AR1a-GFP in a hypothalamic cell line (mHypoE-N42) revealed a glucocorticoid facilitation of norepinephrine (NE)-induced AR1a internalization. FRET interactions between AR1a-GFP and endocytic markers labeled with dsRed revealed that glucocorticoids prevent rapid recycling of AR1a to the plasma membrane, forcing the receptor further down the endocytic pathway. Glucocorticoid treatment also caused an increase in ubiquitination of the trafficking protein beta arrestin, without affecting phosphorylation of the beta arrestin or AR1a. Thus, glucocorticoids likely cause rapid ubiquitin modifications to beta arrestin that shuttle AR1a to the late endosome and prevent it from recycling to the membrane, desensitizing the neurons to NE. The desensitization was found to last at least 4 hours in both ex vivo slice preparations and in vivo stressed animals with elevated blood corticosterone levels. Long term desensitization specifically to noradrenergic inputs could contribute to a systemic stressor-selective negative feedback regulation of the HPA axis.

Structure of auditory nerve synapses in normal and in hearing impaired

The neurons of the cochlear nuclei in the brainstem are the first central processors of auditory information, and they provide inputs to all the major brainstem and midbrain auditory nuclei. The synaptic connectivity pattern of neural networks in each part of the cochlear nuclear complex is an essential determinant of their role in information processing. The synapse of the auditory nerve on principal neurons in the cochlear nucleus is biophysically and anatomically specialized for the fast conduction of excitatory currents into the auditory pathway. A growing interest in the field is to determine how auditory nerve synapses adapt to fluctuations in the sound environment. In this paper, we will discuss novel findings related to the structural and molecular responses of auditory nerve synapses and enwrapping astrocytes in the normal hearing and in the hearing impaired.Support or Funding InformationNIDCD/NIH: R01DC013048; R56DC013048This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Phase Coherent Currents Underlying Neocortical Seizure-Like State Transitions.

In the epileptic brain, phase amplitude cross-frequency coupling (CFC) features have been used to objectively classify seizure-related states, and the inter-seizure state has been demonstrated as being random, in contrast to the seizure state being predictable; however, the excitatory and inhibitory networks underlying their dynamics remain unclear. Therefore, the objectives of this study are to classify the dynamics of seizure sub-states labeling seizure-like event (SLE) onset and termination intervals using CFC features and to obtain their underlying excitatory/inhibitory cellular correlates. SLEs were induced in mouse neocortical brain slices using a low-magnesium perfusate, and were recorded in Layer II/III using simultaneous local field potential (LFP) and whole-cell voltage clamp electrodes. Classification of onset and termination of SLE transitions was investigated using CFC features in conjunction with an unsupervised two-state hidden Markov model (HMM). γ-Distributions of their durations indicated that both are predictable. Furthermore, omitting 4 Hz from the HMM classifier switched both SLE sub-states from statistically deterministic to random without changing the dynamics of the SLE state. These results were generalized to 4-aminopyridine (4-AP)-induced SLEs and human seizure traces. Only during these sub-states, both excitatory and inhibitory currents coupled with the field. Where excitatory currents phase locked to a broad range of frequencies between 1 and 12 Hz, inhibitory currents dominantly phase locked at 4 Hz. We conclude that inhibition underlies the predictability of neocortical CFC-defined SLE transition sub-states.