bluuebunny/crossref_metadata_2025 huggingface dataset:
Protracted Postnatal Development of Inhibitory Synaptic Transmission in Rat Hippocampal Area CA1 Neurons
Authors: Cohen Akiva S. , Lin Dean D. , Coulter Douglas A.
Published: December 2017

In the CNS, inhibitory synaptic function undergoes profound transformation during early postnatal development. This is due to variations in the subunit composition of subsynaptic GABAAreceptors (GABAARs) at differing developmental stages as well as other factors. These include changes in the driving force for chloride-mediated conductances as well as the quantity and/or cleft lifetime of released neurotransmitter. The present study was undertaken to investigate the nature and time course of developmental maturation of GABAergic synaptic function in hippocampal CA1 pyramidal neurons. In neonatal [postnatal day (P) 1–7] and immature (P8–14) CA1 neurons, miniature inhibitory postsynaptic currents (mIPSCs) were significantly larger, were less frequent, and had slower kinetics compared with mIPSCs recorded in more mature neurons. Adult mIPSC kinetics were achieved by the third postnatal week in CA1 neurons. However, despite this apparent maturation of mIPSC kinetics, significant differences in modulation of mIPSCs by allosteric agonists in adolescent (P15–21) neurons were still evident. Diazepam (1–300 nM) and zolpidem (200 nM) increased the amplitude of mIPSCs in adolescent but not adult neurons. Both drugs increased mIPSC decay times equally at both ages. These differential agonist effects on mIPSC amplitude suggest that in adolescent CA1 neurons, inhibitory synapses operate differently than adult synapses and function as if subsynaptic receptors are not fully occupied by quantal release of GABA. Rapid agonist application experiments on perisomatic patches pulled from adolescent neurons provided additional support for this hypothesis. In GABAAR currents recorded in these patches, benzodiazepine amplitude augmentation effects were evident only when nonsaturating GABA concentrations were applied. Furthermore nonstationary noise analysis of mIPSCs in P15–21 neurons revealed that zolpidem-induced mIPSC augmentation was not due to an increase in single-channel conductance of subsynaptic GABAARs but rather to an increase in the number of open channels responding to a single GABA quantum, further supporting the hypothesis that synaptic receptors may not be saturated during synaptic function in adolescent neurons. These data demonstrate that inhibitory synaptic transmission undergoes a markedly protracted postnatal maturation in rat CA1 pyramidal neurons. In the first two postnatal weeks, mIPSCs are large in amplitude, are slow, and occur infrequently. By the third postnatal week, mIPSCs have matured kinetically but retain distinct responses to modulatory drugs, possibly reflecting continued immaturity in synaptic structure and function persisting through adolescence.
Center-Surround Interactions in the Middle Temporal Visual Area of the Owl Monkey
Authors: Born Richard T.
Published: December 2017

Microelectrode recording and 2-deoxyglucose (2dg) labeling were used to investigate center-surround interactions in the middle temporal visual area (MT) of the owl monkey. These techniques revealed columnar groups of neurons whose receptive fields had opposite types of center-surround interaction with respect to moving visual stimuli. In one type of column, neurons responded well to objects such as a single bar or spot but poorly to large textured stimuli such as random dots. This was often due to the fact that the receptive fields had antagonistic surrounds: surround motion in the same direction as that preferred by the center suppressed responses, thus rendering these neurons unresponsive to wide-field motion. In the second set of complementary, interdigitated columns, neuronal receptive fields had reinforcing surrounds and responded optimally to wide-field motion. This functional organization could not be accounted for by systematic differences in binocular disparity. Within both column types, neurons whose receptive fields exhibited center-surround interactions were found less frequently in the input layers compared with the other layers. Additional tests were done on single units to examine the nature of the center-surround interactions. The direction tuning of the surround was broader than that of the center, and the preferred direction, with respect to that of the center, tended to be either in the same or opposite direction and only rarely in orthogonal directions. Surround motion at various velocities modulated the overall responsiveness to centrally placed moving stimuli, but it did not produce shifts in the peaks of the center's tuning curves for either direction or speed. In layers 3B and 5 of the local motion processing columns, a number of neurons responded only to local motion contrast but did so over a region of the visual field that was much larger than the optimal stimulus size. The central feature of this receptive field type was the generalization of surround antagonism over retinotopic space—a property similar to other “complex” receptive fields described previously. The columnar organization of different types of center-surround interactions may reflect the initial segregation of visual motion information into wide-field and local motion contrast systems that serve complementary functions in visual motion processing. Such segregation appears to occur at later stages of the macaque motion processing stream, in the medial superior temporal area (MST), and has also been described in invertebrate visual systems where it appears to be involved in the important function of distinguishing background motion from object motion.
BK-Type KCaChannels in Two Parasympathetic Cell Types: Differences in Kinetic Properties and Developmental Expression
Authors: Cameron Jill S. , Dryer Stuart E.
Published: December 2017

The intrinsic electrical properties of identified choroid and ciliary neurons of the chick ciliary ganglion were examined by patch-clamp recording methods. These neurons are derived from a common pool of mesencephalic neural crest precursor cells but innervate different target tissues and have markedly different action potential waveforms and intrinsic patterns of repetitive spike discharge. Therefore it is important to determine whether these cell types express different types of plasma membrane ionic channels, and to ascertain the developmental stages at which these cell types begin to diverge. This study has focused on large-conductance Ca2+-activated K+channels (KCa), which are known to regulate spike waveform and repetitive firing in many cell types. Both ciliary ganglion cell types, identified on the basis of size and somatostatin immunoreactivity, express a robust macroscopic KCacarried by a kinetically homogeneous population of large-conductance (BK-type) KCachannels. However, the kinetic properties of these channels are different in the two cell types. Steady-state fluctuation analyses of macroscopic KCaproduced power spectra that could be fitted with a single Lorentzian curve in both cell types. However, the resulting corner frequency was significantly lower in choroid neurons than in ciliary neurons, suggesting that the underlying KCachannels have a longer mean open-time in choroid neurons. Consistent with fluctuation analyses, significantly slower gating of KCachannels in choroid neurons was also observed during macroscopic activation and deactivation at membrane potentials positive to −30 mV. Differences in the kinetic properties of KCachannels could also be observed directly in single-channel recordings from identified embryonic day 13 choroid and ciliary neurons. The mean open-time of large-conductance KCachannels was significantly greater in choroid neurons than in ciliary neurons in excised inside-out patches. The developmental expression of functional KCachannels appears to be regulated differently in the two cell types. Although both cell types acquire functional KCaat the same developmental stages ( embryonic days 9–13), functional expression of these channels in ciliary neurons requires target-derived trophic factors. In contrast, expression of functional KCachannels proceeds normally in choroid neurons developing in vitro in the absence of target-derived trophic factors. Consistent with this, extracts of ciliary neuron target tissues (striated muscle of the iris/ciliary body) contain KCastimulatory activity. However, KCastimulatory activity cannot be detected in extracts of the smooth muscle targets of choroid neurons.
Dopamine D-1/D-5 Receptor Activation Is Required for Long-Term Potentiation in the Rat Neostriatum In Vitro
Authors: Kerr J.N.D. , Wickens J. R.
Published: December 2017

Dopamine and glutamate are key neurotransmitters involved in learning and memory mechanisms of the brain. These two neurotransmitter systems converge on nerve cells in the neostriatum. Dopamine modulation of activity-dependent plasticity at glutamatergic corticostriatal synapses has been proposed as a cellular mechanism for learning in the neostriatum. The present research investigated the role of specific subtypes of dopamine receptors in long-term potentiation (LTP) in the corticostriatal pathway, using intracellular recording from striatal neurons in a corticostriatal slice preparation. In agreement with previous reports, LTP could be induced reliably under Mg2+-free conditions. This Mg2+-free LTP was blocked by dopamine depletion and by the dopamine D-1/D-5 receptor antagonist SCH 23390 but was not blocked by the dopamine D-2 receptor antagonist remoxipride or the GABAA antagonist picrotoxin. In dopamine-depleted slices, the ability to induce LTP could be restored by bath application of the dopamine D-1/D-5 receptor agonist, SKF 38393. These results show that activation of dopamine D-1/D-5 receptors by either endogenous dopamine or exogenous dopamine agonists is a requirement for the induction of LTP in the corticostriatal pathway. These findings have significance for current understanding of learning and memory mechanisms of the neostriatum and for theoretical understanding of the mechanism of action of drugs used in the treatment of psychotic illnesses and Parkinson's disease.
Effect of Attentive Fixation in Macaque Thalamus and Cortex
Authors: Bender D. B. , Youakim M.
Published: December 2017

Attentional modulation of neuronal responsiveness is common in many areas of visual cortex. We examined whether attentional modulation in the visual thalamus was quantitatively similar to that in cortex. Identical procedures and apparatus were used to compare attentional modulation of single neurons in seven different areas of the visual system: the lateral geniculate, three visual subdivisions of the pulvinar [inferior, lateral, dorsomedial part of lateral pulvinar (Pdm)], and three areas of extrastriate cortex representing early, intermediate, and late stages of cortical processing (V2, V4/PM, area 7a). A simple fixation task controlled transitions among three attentive states. The animal waited for a fixation point to appear (ready state), fixated the point until it dimmed (fixation state), and then waited idly to begin the next trial (idle state). Attentional modulation was estimated by flashing an identical, irrelevant stimulus in a neuron's receptive field during each of the three states; the three responses defined a “response vector” whose deviation from the line of equal response in all three states (the main diagonal) indicated the character and magnitude of attentional modulation. Attentional modulation was present in all visual areas except the lateral geniculate, indicating that modulation was of central origin. Prevalence of modulation was modest (26%) in pulvinar, and increased from 21% in V2 to 43% in 7a. Modulation had a push-pull character (as many cells facilitated as suppressed) with respect to the fixation state in all areas except Pdm where all cells were suppressed during fixation. The absolute magnitude of attentional modulation, measured by the angle between response vector and main diagonal expressed as a percent of the maximum possible angle, differed among brain areas. Magnitude of modulation was modest in the pulvinar (19–26%), and increased from 22% in V2 to 41% in 7a. However, average trial-to-trial variability of response, measured by the coefficient of variation, also increased across brain areas so that its difference among areas accounted for more than 90% of the difference in modulation magnitude among areas. We also measured attentional modulation by the ratio of cell discharge due to attention divided by discharge variability. The resulting signal-to-noise ratio of attention was small and constant, 1.3 ± 10%, across all areas of pulvinar and cortex. We conclude that the pulvinar, but not the lateral geniculate, is as strongly affected by attentional state as any area of visual cortex we studied and that attentional modulation amplitude is closely tied to intrinsic variability of response.
Spatial Receptive Fields of Inferior Colliculus Neurons to Auditory Apparent Motion in Free Field
Authors: Ingham Neil J. , Hart Heledd C. , McAlpine David
Published: December 2017

We examined responses from 91 single-neurons in the inferior colliculus (IC) of anesthetized guinea pigs to auditory apparent motion in the free field. Apparent motion was generated by presenting 100-ms tone bursts, separated by 50-ms silent intervals, at consecutive speaker positions in an array of 11 speakers, positioned in an arc ±112.5° around midline. Most neurons demonstrated discrete spatial receptive fields (SRFs) to apparent motion in the clockwise and anti-clockwise directions. However, SRFs showed marked differences for apparent motion in opposite directions. In virtually all neurons, mean best azimuthal positions for SRFs to opposite directions occurred at earlier positions in the motion sweep, producing receptive fields to the two directions of motion that only partially overlapped. Despite this, overall spike counts to the two directions were similar for equivalent angular velocities. Responses of 28 neurons were recorded to stimuli with different duration silent intervals between speaker presentations, mimicking different apparent angular velocities. Increasing the stimulus off time increased neuronal discharge rates, particularly at later portions of the apparent motion sweep, and reduced the differences in the SRFs to opposite motion directions. Consequently SRFs to both directions broadened and converged with decreasing motion velocity. This expansion was most obvious on the outgoing side of the each SRF. Responses of 11 neurons were recorded to short (90°) partially overlapping apparent motion sweeps centered at different spatial positions. Nonoverlapping response profiles were recorded in 9 of the 11 neurons tested and confirmed that responses at each speaker position were dependent on the preceding response history. Together these data are consistent with the suggestion that a mechanism of adaptation of excitation contributes to the apparent sensitivity of IC neurons to auditory motion cues. In addition, the data indicate that the sequential activation of an array of speakers to produce apparent auditory motion may not be an optimal stimulus paradigm to separate the temporal and spatial aspects of auditory motion processing.
Vagotomy Decreases Excitability in Primary Vagal Afferent Somata
Authors: Lancaster Eric , Oh Eun Joo , Weinreich Daniel
Published: December 2017

Standard patch-clamp and intracellular recording techniques were used to monitor membrane excitability changes in adult inferior vagal ganglion neurons (nodose ganglion neurons, NGNs) 5 days following section of the vagus nerve (vagotomy). NGNs were maintained in vivo for 5 days following vagotomy, and then in vitro for 2–9 h prior to recording. Vagotomy increased action potential (AP) threshold by over 200% (264 ± 19 pA, mean ± SE, n = 66) compared with control values (81 ± 20 pA, n = 68; P < 0.001). The number of APs evoked by a 3 times threshold 750-ms depolarizing current decreased by >70% (from 8.3 to 2.3 APs, P < 0.001) and the number of APs evoked by a standardized series of (0.1–0.9 nA, 750 ms) depolarizing current steps decreased by over 80% (from 16.9 APs to 2.6 APs, P < 0.001) in vagotomized NGNs. Similar decreases in excitability were observed in vagotomized NGNs in intact ganglia in vitro studied with “sharp” microelectrode techniques. Baseline electrophysiological properties and changes following vagotomy were similar in right and left NGNs. A “sham” vagotomy procedure had no effect on NGN properties at 5 days, indicating that changes were due to severing the vagus nerve itself, not surrounding tissue damage. NGNs isolated after being maintained 17 h in vivo following vagotomy revealed no differences in excitability, suggesting that vagotomy-induced changes occur some time from 1–5 days after injury. Decreased excitability was still observed in NGNs isolated after 20–21 days in vivo following vagotomy. These data indicate that, in contrast to many primary sensory neurons that are thought to become hyperexcitable following section of their axons, NGNs undergo a marked decrease in electrical excitability following vagotomy.
Attenuated LTP in Hippocampal Dentate Gyrus Neurons of Mice Deficient in the PAF Receptor
Authors: Chen Chu , Magee Jeffrey C. , Marcheselli Victor , Hardy Mattie , Bazan Nicolas G.
Published: December 2017

Platelet-activating factor (PAF), a bioactive lipid (1- O-alkyl-2-acetyl-sn-glycero-3-phosphocholine) derived from phospholipase A2and other pathways, has been implicated in neural plasticity and memory formation. Long-term potentiation (LTP) can be induced by the application of PAF and blocked by a PAF receptor (PAF-R) inhibitor in the hippocampal CA1 and dentate gyrus. To further investigate the role of PAF in synaptic plasticity, we compared LTP in dentate granule cells from hippocampal slices of adult mice deficient in the PAF-R and their age-matched wild-type littermates. Whole cell patch-clamp recordings were made in the current-clamp mode. LTP in the perforant path was induced by a high-frequency stimulation (HFS) and defined as >20% increase above baseline of the amplitude of excitatory postsynaptic potentials (EPSPs) from 26 to 30 min after HFS. HFS-induced enhancement of the EPSP amplitude was attenuated in cells from the PAF-R-deficient mice (163 ± 14%, mean ± SE; n = 32) when compared with that in wild-type mice (219 ± 17%, n = 32). The incidence of LTP induction was also lower in the cells from the deficient mice (72%, 23 of 32 cells) than in the wild-type mice (91%, 29 of 32 cells). Using paired-pulse facilitation as a synaptic pathway discrimination, it appeared that there were differences in LTP magnitudes in the lateral perforant path but not in the medial perforant path between the two groups. BN52021 (5 μM), a PAF synaptosomal receptor antagonist, reduced LTP in the lateral path in the wild-type mice. However, neither BN52021, nor BN50730 (5 μM), a microsomal PAF-R antagonist, reduced LTP in the lateral perforant path in the receptor-deficient mice. These data provide evidence that PAF-R-deficient mice are a useful model to study LTP in the dentate gyrus and support the notion that PAF actively participates in hippocampal synaptic plasticity.
Natural Substitutions at Highly Conserved T1-Domain Residues Perturb Processing and Functional Expression of Squid Kv1 Channels
Authors: Liu Taylor I. , Lebaric Zora N. , Rosenthal Joshua J. C. , Gilly William F.
Published: December 2017

Shaker-type K-channel α-subunits (SqKv1A, B, D) expressed in neurons of the squid stellate ganglion differ in the length of their N-termini and in the species of amino acid present at several points in the T1 domain, an intracellular region involved in the tetramerization process during channel assembly. Heterologous expression of wild-type SqKv1A, B, and D in Xenopus oocytes reveals large differences in the level of both functional channels (assayed by whole-oocyte voltage clamp) and total channel protein (assayed by immunoblotting). Functional expression is poorest with SqKv1A and by far the best with SqKv1D. Biophysical properties of the three SqKv1 channels are essentially identical (assayed by cell-attached patch clamp). Site-directed mutagenesis was used to determine whether the observed differences in expression level are impacted by two residues in the T1 domain at which SqKv1A and B (but not D) differ from the consensus sequences found in many other taxa. In SqKv1A, glycine is substituted for arginine in an otherwise universally conserved sequence (FFDR in the T1B subdomain). In SqKv1B, glycine replaces serine in a sequence that is conserved within the Kv1 subfamily (SGLR in the T1A subdomain). Restoration of the consensus amino acid at these positions largely accounts for the observed differences in expression level. Analysis of the glycosylation state of aberrant versus restored α-subunits suggests that the anomalous amino acids in SqKv1A and B exert their influence during early steps in channel processing and assembly which take place in the endoplasmic reticulum (ER).
Selection and Coordination of Human Locomotor Forms Following Cerebellar Damage
Authors: Earhart Gammon M. , Bastian Amy J.
Published: December 2017

We have previously shown that control subjects use two distinct temporal strategies when stepping on an inclined surface during walking: one for level and 10° surfaces and another for 20 and 30° surfaces. These two temporal strategies were characterized by systematic shifts in the timing of muscle activity and peak joint angles. We examined whether cerebellar subjects with mild to moderate gait ataxia were impaired in their ability to select these two temporal strategies, adjust peak joint angle amplitudes, and/or adjust one joint appropriately with respect to movements and constraints at another joint. Subjects walked on a level surface and on different wedges (10, 20, and 30°) presented in the context of level walking. In a single trial, a subject walked on a level surface in approach to a wedge, took a single step on the wedge, and continued walking on an elevated level surface beyond the wedge. Cerebellar subjects used two temporal strategies, one for the level and 10° surfaces and another for 20 and 30° surfaces. Cerebellar strategies were similar to those used by controls except for the timing of ankle-joint movement on the steeper wedges. Cerebellar subjects adjusted the peak amplitudes of individual joint angles normally, with the exception of peak ankle plantarflexion. However, they exhibited greater trial-to-trial variability of peak hip and knee joint angles that increased as a function of wedge inclination. The most substantial deficit noted in the cerebellar group was in the relative movement of multiple joints. Cerebellar subjects demonstrated multijoint coordination deficits in all conditions, although these deficits were most pronounced during stance on the steeper wedges. On the 30° wedge, cerebellar subjects showed abnormal relative movement of hip, knee, and ankle joints and the most substantial decomposition of movement. We speculate that to simplify multijoint control, cerebellar subjects decomposed their movement by fixing the ankle joint in a dorsiflexed position on the steepest wedges. Our results suggest that the cerebellum may not be critical in selecting the basic motor patterns for the two temporal strategies because cerebellar subjects produced appropriate timing shifts at most joints. Instead, our data suggest that the cerebellum is most critical for adjusting the relative movement of multiple joints, especially to accommodate external constraints.
Neuronal Restrictive Silencing Element Is Found in the KCC2 Gene: Molecular Basis for KCC2-Specific Expression in Neurons
Authors: Karadsheh Michael F. , Delpire E.
Published: December 2017

KCC2 is one of four known isoforms of the K-Cl cotransporter with an expression pattern restricted to neurons. It mediates efflux of Cl− across neuronal membranes and plays an important role in GABAergic and glycinergic neurotransmission. To understand the molecular basis for neuronal specificity of KCC2 expression, we isolated and sequenced portions of the KCC2 gene, including some of its 5′ flanking (control) region. We found a 21-bp sequence, within intron 1, that shares 80% homology to the consensus site for neuronal-restrictive silencing factor binding. We demonstrated that this specific sequence of the KCC2 gene promotes transcriptional regulation by showing that nuclear proteins isolated from a mouse neural progenitor cell line interact with this 21-bp element and by establishing that this element silences reporter gene expression in nonneuronal cells.
Context Dependency in the Globus Pallidus Internal Segment During Targeted Arm Movements
Authors: Gdowski Martha J. , Miller Lee E. , Parrish Todd , Nenonene Emmanuel K. , Houk James C.
Published: December 2017

Extracellular discharges from single neurons in the internal segment of the globus pallidus (GPi) were recorded and analyzed for rate changes associated with visually guided forearm rotations to four different targets. We sought to examine how GPi neurons contribute to movement preparation and execution. Unit discharge from 108 GPi neurons recorded in 35 electrode penetrations was aligned to the time of various behavioral events, including the onset of cued and return movements. In total, 39 of 108 GPi neurons (36%) were task-modulated, demonstrating statistically significant changes in discharge rate at various times between the presentation of visual cues and movement generation. Most often, strong modulation in discharge rate occurred selectively during either the cued ( n = 32) or return ( n = 2) phases of the task, although a few neurons ( n = 5) were well-modulated during both movement phases. Of the 34 neurons that were modulated exclusively during cued or return movements, 50% ( n = 17) were modulated similarly in association with movements to any target. The remaining 17 neurons exhibited considerable diversity in their discharge properties associated with movements to each target. Cued phases of behavior were always rewarded if executed correctly, whereas return phases were never rewarded. Overall, these data reveal that many GPi neurons discharged in a context-dependent manner, being modulated during cued, rewarded movements, but not during similar self-paced, unrewarded movements. When considered in the light of other observations, the context-dependence we have observed seems likely to be influenced by the animal's expectation of reward.
Differential Regulation of Cutaneous and H-Reflexes During Leg Cycling in Humans
Authors: Zehr E. Paul , Hesketh Kathryn L. , Chua Romeo
Published: December 2017

Reflexes undergo modulation according to task and timing during standing, walking, running, and leg cycling in humans. Both cutaneous and Hoffman (H-) reflexes are modulated by movement and task. However, recent evidence suggests that the modulation pattern for cutaneous and H-reflexes may be different. We sought to clarify this issue by reducing the effect of movement phase and altering the level of background muscle activation (low and high) in static and dynamic (leg cycling) conditions. Electromyography was recorded from the ankle extensors soleus and medial gastrocnemius (MG) and the knee extensor vastus lateralis (VL). Reflexes were evoked during the downstroke of stationary leg cycling. Cutaneous reflexes were evoked with trains of 5 × 1.0 ms pulses at 300 Hz delivered to the distal tibial nerve, whereas H-reflexes were evoked in soleus by stimulation with single 1.0-ms pulses. There were two main observations in this study: 1) middle latency cutaneous reflexes were facilitatory during static contraction but were dramatically attenuated or reversed to suppressive responses during cycling (task-dependent modulation); 2) soleus H-reflexes were larger in the high muscle activation condition but were unaffected by task (no task-dependent modulation). Thus opposite results were obtained in the two reflex pathways. It is concluded that cutaneous and H-reflexes are modulated by different mechanisms during active locomotor-like movements.
Dendritic Glutamate Autoreceptors Modulate Signal Processing in Rat Mitral Cells
Authors: Salin Paul-Antoine , Lledo Pierre-Marie , Vincent Jean-Didier , Charpak Serge
Published: December 2017

It has been shown recently that in mitral cells of the rat olfactory bulb, N-methyl-d-aspartate (NMDA) autoreceptors are activated during mitral cell firing. Here we consider in more details the mechanisms of mitral cell self-excitation and its physiological relevance. We show that both ionotropic NMDA and non-NMDA autoreceptors are activated by glutamate released from primary and secondary dendrites. In contrast to non-NMDA autoreceptors, NMDA autoreceptors are almost exclusively located on secondary dendrites and their activation generates a large and sustained self-excitation. Both intracellularly evoked and miniature NMDA-R mediated synaptic potentials are blocked by intracellular bis-( o-aminophenoxy)- N,N,N′,N′-tetraacetic acid (BAPTA) and result from a calcium-dependent release of glutamate. Self-excitation can be produced by a single spike, and trains of spikes result in frequency facilitation. Thus activation of excitatory autoreceptors is a major function of action potentials backpropagating in mitral cell dendrites, which results in an immediate positive feedback counteracting recurrent inhibition and increasing the signal-to-noise ratio of olfactory inputs.
Extracellular Calcium Fluctuations and Intracellular Potentials in the Cortex During the Slow Sleep Oscillation
Authors: Massimini Marcello , Amzica Florin
Published: December 2017

During slow wave sleep the main activity of cortical neurons consists of synchronous and rhythmic alternations of the membrane potential between depolarized and hyperpolarized values. The latter are long-lasting (200–600 ms) periods of silence. The mechanisms responsible for this periodical interruption of cortical network activity are unknown. Here we report a decrease of ∼20% in the extracellular calcium concentration ([Ca]out) progressively taking place in the cortex between the onset and the offset of the depolarizing phase of the slow sleep oscillation. Since [Ca]outexerts a high gain modulation of synaptic transmission, we estimated the associated transmitter release probability and found a corresponding 50% drop. Thus the periods of silence occurring in the cortical network during slow wave sleep are promoted by recurrent [Ca]out depletions.
GABA Uptake and Heterotransport Are Impaired in the Dentate Gyrus of Epileptic Rats and Humans With Temporal Lobe Sclerosis
Authors: Patrylo Peter R. , Spencer Dennis D. , Williamson Anne
Published: December 2017

In vivo dialysis and in vitro electrophysiological studies suggest that GABA uptake is altered in the dentate gyrus of human temporal lobe epileptics characterized with mesial temporal sclerosis (MTLE). Concordantly, anatomical studies have shown that the pattern of GABA-transporter immunoreactivity is also altered in this region. This decrease in GABA uptake, presumably due to a change in the GABA transporter system, may help preserve inhibitory tone interictally. However, transporter reversal can also occur under several conditions, including elevations in [K+]o, which occurs during seizures. Thus GABA transporters could contribute to seizure termination and propagation through heterotransport. To test whether GABA transport is compromised in both the forward (uptake) and reverse (heterotransport) direction in the sclerotic epileptic dentate gyrus, the physiological effects of microapplied GABA and nipecotic acid (NPA; a compound that induces heterotransport) were examined in granule cells in hippocampal slices from kainate (KA)-induced epileptic rats and patients with temporal lobe epilepsy (TLE). GABA- and NPA-induced responses were prolonged in granule cells from epileptic rats versus controls (51.3 and 31.3% increase, respectively) while the conductance change evoked with NPA microapplication was reduced by 40%. Furthermore the ratio of GABA/NPA conductance, but not duration, was significantly >1 in epileptic rats but not controls, suggesting a compromise in transporter function in both directions. Similar changes were observed in tissue resected from epileptic patients with medial temporal sclerosis but not in those without the anatomical changes associated with MTLE. These data suggest that the GABA transporter system is functionally compromised in both the forward and reverse directions in the dentate gyrus of chronically epileptic tissue characterized by mesial temporal sclerosis. This alteration may enhance inhibitory tone interically yet be permissive for seizure propagation due to a decreased probability for GABA heterotransport during seizures.
Neuroplasticity Induced by Tooth Pulp Stimulation in Trigeminal Subnucleus Oralis Involves NMDA Receptor Mechanisms
Authors: Park Soo Joung , Chiang Chen Yu , Hu James W. , Sessle Barry J.
Published: December 2017

We have recently demonstrated that application of the mustard oil (MO), a small-fiber excitant and inflammatory irritant, to the rat maxillary molar tooth pulp induces significant increases in jaw muscle electromyographic (EMG) activity and neuroplastic changes in trigeminal (V) subnucleus caudalis. Since subnucleus oralis (Vo) as well as caudalis receives projections from molar pulp afferents and is also an integral brain stem relay of afferent input from orofacial structures, we tested whether MO application to the exposed pulp induces neuroplastic changes in oralis neurons and whether microinjection of MK-801, a noncompetitive NMDA antagonist, into the Vo influences the pulp/MO-induced neuroplastic changes in chloralose/urethan-anesthetized rats. Single neuronal activity was recorded in Vo, and neurons classified as low-threshold mechanoreceptive (LTM), wide dynamic range (WDR), nociceptive-specific (NS), deep (D), or skin/mucosa and deep (S + D). The spontaneous activity, mechanoreceptive field (RF) size, mechanical threshold, and response to suprathreshold mechanical stimuli applied to the neuronal RF were assessed prior to and throughout a 40- to 60-min period after MO application to the maxillary molar pulp. In animals pretreated with saline microinjection (0.3 μl) into the Vo, MO application to the pulp produced a significant increase in spontaneous activity, expansion of the pinch or deep RF, decrease in the mechanical threshold, and increase in response to suprathreshold mechanical stimuli of the nociceptive (WDR, NS, and S + D) neurons except for those nociceptive neurons having their RF only in the intraoral region. The pulpal application of MO did not produce any significant neuroplastic changes in LTM neurons. Furthermore, in animals pretreated with MK-801 microinjection (3 μg/0.3 μl) into the Vo, MO application to the pulp did not produce any significant changes in the RF and response properties of nociceptive neurons. In other animals pretreated with saline (0.3 μl) or MK-801 (3 μg/0.3 μl) microinjected into the Vo, mineral oil application to the pulp did not produce any significant changes in RF and response properties of nociceptive neurons. These findings indicate that the application of MO to the tooth pulp can induce significant neuroplastic changes in oralis nociceptive neurons and that central NMDA receptor mechanisms may be involved in these neuroplastic changes.
Serotonin Increases the Incidence of Primary Afferent-Evoked Long-Term Depression in Rat Deep Dorsal Horn Neurons
Authors: Garraway Sandra M. , Hochman Shawn
Published: December 2017

5-hydroxytryptamine (5-HT) is released in spinal cord by descending systems that modulate somatosensory transmission and can potently depress primary afferent-evoked synaptic responses in dorsal horn neurons. Since primary afferent activity-induced long-term potentiation (LTP) may contribute to central sensitization of nociception, we studied the effects of 5-HT on the expression of sensory-evoked LTP and long-term depression (LTD) in deep dorsal horn (DDH) neurons. Whole cell, predominantly current clamp, recordings were obtained from DDH neurons in transverse slices of neonatal rat lumbar spinal cord. The effect of 5-HT on dorsal-root stimulation-evoked synaptic responses was tested before, during, or after high-frequency conditioning stimulation (CS). In most cells (80%), 5-HT caused a depression of the naı̈ve synaptic response. Even though 5-HT depressed evoked responses, CS in the presence of 5-HT was not only still capable of inducing LTD but also increased its incidence from 54% in controls to 88% ( P < 0.001). Activation of ligands selective for 5-HT1A/1B and 5-HT1B, but not 5-HT2A/2C or 5-HT3receptors, best reproduced these actions. 5-HT also potently depressed postconditioning synaptic responses regardless of whether the induced plasticity was LTP or LTD. Our results demonstrate that in addition to depressing the amplitude of evoked sensory input, 5-HT can also control the direction of its long-term modifiability, favoring the expression of LTD. These findings demonstrate cellular mechanisms that may contribute to the descending serotonergic control of nociception.
Positive Allosteric Modulators of AMPA Receptors Reduce Proton-Induced Receptor Desensitization in Rat Hippocampal Neurons
Authors: Lei Saobo , Orser Beverley A. , Thatcher Gregory R. L. , Reynolds James N. , MacDonald John F.
Published: December 2017

Whole-cell or outside-out patch recordings were used to investigate the effects of protons and positive modulators of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors on the desensitization of glutamate-evoked AMPA receptor currents in isolated hippocampal CA1 neurons. Protons inhibited glutamate-evoked currents (IC50 of 6.2 pH units) but also enhanced the apparent rate and extent of AMPA receptor desensitization. The proton-induced enhancement of desensitization could not be attributed to a reduction in the rate of recovery from desensitization or to a change in the kinetics of deactivation. Non-stationary variance analysis indicated that protons reduced maximum open probability without changing the conductance of AMPA channels. The positive modulators of AMPA receptor desensitization, cyclothiazide and GT-21-005 (an organic nitrate), reduced the proton sensitivity of AMPA receptor desensitization, which suggests that they interact with protons to diminish desensitization. In contrast, the effects of wheat germ agglutinin and aniracetam on AMPA receptor desensitization were independent of pH. These results demonstrate that a reduction in the proton sensitivity of receptor desensitization contributes to the mechanism of action of some positive modulators of AMPA receptors.
H2O2 Is a Novel, Endogenous Modulator of Synaptic Dopamine Release
Authors: Chen Billy T. , Avshalumov Marat V. , Rice Margaret E.
Published: December 2017

Recent evidence suggests that reactive oxygen species (ROS) might act as modulators of neuronal processes, including synaptic transmission. Here we report that synaptic dopamine (DA) release can be modulated by an endogenous ROS, H2O2. Electrically stimulated DA release was monitored in guinea pig striatal slices using carbon-fiber microelectrodes with fast-scan cyclic voltammetry. Exogenously applied H2O2reversibly inhibited evoked release in the presence of 1.5 mM Ca2+. The effectiveness of exogenous H2O2, however, was abolished or decreased by conditions that enhance Ca2+ entry, including increased extracellular Ca2+ concentration ([Ca2+]o; to 2.4 mM), brief, high-frequency stimulation, and blockade of inhibitory D2 autoreceptors. To test whether DA release could be modulated by endogenous H2O2, release was evoked in the presence of the H2O2-scavenging enzyme, catalase. In the presence of catalase, evoked [DA]o was 60% higher than after catalase washout, demonstrating that endogenously generated H2O2 can also inhibit DA release. Importantly, the Ca2+ dependence of the catalase-mediated effect was opposite to that of H2O2: catalase had a greater enhancing effect in 2.4 mM Ca2+ than in 1.5 mM, consistent with enhanced H2O2 generation in higher [Ca2+]o. Together these data suggest that H2O2production is Ca2+ dependent and that the inhibitory mechanism can be saturated, thus preventing further effects from exogenous H2O2. These findings show for the first time that endogenous H2O2 can modulate vesicular neurotransmitter release, thus revealing an important new signaling role for ROS in synaptic transmission.
KT3.2 and KT3.3, Two Novel Human Two-Pore K+Channels Closely Related to TASK-1
Authors: Vega-Saenz de Miera Eleazar , Lau David H. P. , Zhadina Maria , Pountney David , Coetzee William A. , Rudy Bernardo
Published: December 2017

We report the cloning of human KT3.2 and KT3.3 new members of the two-pore K+channel (KT) family. Based on amino acid sequence and phylogenetic analysis, KT3.2, KT3.3, and TASK-1 constitute a subfamily within the KT channel mammalian family. When Xenopus oocytes were injected with KT3.2 cRNA, the resting membrane potential was brought close to the potassium equilibrium potential. At low extracellular K+concentrations, two-electrode voltage-clamp recordings revealed the expression of predominantly outward currents. With high extracellular K+(98 mM), the current-voltage relationship exhibited weak outward rectification. Measurement of reversal potentials at different [K+]orevealed a slope of 48 mV per 10-fold change in K+concentration as expected for a K+-selective channel. Unlike TASK-1, which is highly sensitive to changes of pH in the physiological range, KT3.2 currents were relatively insensitive to changes in intracellular or extracellular pH within this range due to a shift in the pH dependency of KT3.2 of 1 pH unit in the acidic direction. On the other hand, the phorbol ester phorbol 12-myristate 13-acetate (PMA), which does not affect TASK-1, produces strong inhibition of KT3.2 currents. Human KT3.2 mRNA expression was most prevalent in the cerebellum. In rat, KT3.2 is exclusively expressed in the brain, but it has a wide distribution within this organ. High levels of expression were found in the cerebellum, medulla, and thalamic nuclei. The hippocampus has a nonhomogeneous distribution, expressing at highest levels in the lateral posterior and inferior portions. Medium expression levels were found in neocortex. The KT3.2 gene is located at chromosome 8q24 1–3, and the KT3.3 gene maps to chromosome 20q13.1.
Synaptic Drive to Motoneurons During Fictive Swimming in the Developing Zebrafish
Authors: Buss Robert R. , Drapeau Pierre
Published: December 2017

The development of swimming behavior and the correlated activity patterns recorded in motoneurons during fictive swimming in paralyzed zebrafish larvae were examined and compared. Larvae were studied from when they hatch (after 2 days) and are first capable of locomotion to when they are active swimmers capable of capturing prey (after 4 days). High-speed (500 Hz) video imaging was used to make a basic behavioral characterization of swimming. At hatching and up to day 3, the larvae swam infrequently and in an undirected fashion. They displayed sustained bursts of contractions (‘burst swimming’) at an average frequency of 60–70 Hz that lasted from several seconds to a minute in duration. By day 4 the swimming had matured to a more frequent and less erratic “beat-and-glide” mode, with slower (∼35 Hz) beats of contractions for ∼200 ms alternating with glides that were twice as long, lasting from just a few cycles to several minutes overall. In whole cell current-clamp recordings, motoneurons displayed similar excitatory synaptic activity and firing patterns, corresponding to either fictive burst swimming (day 2–3) or beat-and-glide swimming (day 4). The resting potentials were similar at all stages (about −70 mV) and the motoneurons were depolarized (to about −40 mV) with generally non-overshooting action potentials during fictive swimming. The frequency of sustained inputs during fictive burst swimming and of repetitive inputs during fictive beat-and glide swimming corresponded to the behavioral contraction patterns. Fictive swimming activity patterns were eliminated by application of glutamate antagonists (kynurenic acid or 6-cyano-7-nitroquinoxalene-2,3-dione anddl-2-amino-5-phosphonovaleric acid) and were modified but maintained in the presence of the glycinergic antagonist strychnine. The corresponding synaptic currents underlying the synaptic drive to motoneurons during fictive swimming could be isolated under voltage clamp and consisted of cationic [glutamatergic postsynaptic currents (PSCs)] and anionic inputs (glycinergic PSCs). Either sustained or interrupted patterns of PSCs were observed during fictive burst or beat-and-glide swimming, respectively. During beat-and-glide swimming, a tonic inward current and rhythmic glutamatergic PSCs (∼35 Hz) were observed. In contrast, bursts of glycinergic PSCs occurred at a higher frequency, resulting in a more tonic pattern with little evidence for synchronized activity. We conclude that a rhythmic glutamatergic synaptic drive underlies swimming and that a tonic, shunting glycinergic input acts to more closely match the membrane time constant to the fast synaptic drive.
Cannabinoid-Induced Presynaptic Inhibition of Glutamatergic EPSCs in Substantia Gelatinosa Neurons of the Rat Spinal Cord
Authors: Morisset Valerie , Urban Laszlo
Published: December 2017

The effect of cannabinoids on excitatory transmission in the substantia gelatinosa was investigated using intracellular recording from visually identified neurons in a transverse slice preparation of the juvenile rat spinal cord. In the presence of strychnine and bicuculline, perfusion of the cannabinoid receptor agonist WIN55,212-2 reduced the frequency and the amplitude of spontaneous excitatory postsynaptic currents (sEPSCs). Furthermore, the frequency of miniature EPSCs (mEPSCs) was also decreased by WIN55,212-2, whereas their amplitude was not affected. Similar effects were reproduced using the endogenous cannabinoid ligand anandamide. The effects of both agonists were blocked by the selective CB1 receptor antagonist SR141716A. Electrical stimulation of high-threshold fibers in the dorsal root evoked a monosynaptic EPSC in lamina II neurons. In the presence of WIN55,212-2, the amplitude of the evoked EPSC (eEPSCs) was reduced, and the paired-pulse ratio was increased. The reduction of the eEPSC following CB1 receptor activation was unlikely to have a postsynaptic origin because the response to AMPA, in the presence of 1 μM TTX, was unchanged. To investigate the specificity of this synaptic inhibition, we selectively activated the nociceptive C fibers with capsaicin, which induced a strong increase in the frequency of EPSCs. In the presence of WIN55,212-2, the response to capsaicin was diminished. In conclusion, these results strongly suggest a presynaptic location for CB1 receptors whose activation results in inhibition of glutamate release in the spinal dorsal horn. The strong inhibitory effect of cannabinoids on C fibers may thereby contribute to the modulation of the spinal excitatory transmission, thus producing analgesia at the spinal level.