Electrophysiological Properties Of Neurons Research Articles

Electrical Low Frequency Stimulation of the Kindling Site Preserves the Electrophysiological Properties of the Rat Hippocampal CA1 Pyramidal Neurons From the Destructive Effects of Amygdala Kindling: The Basis for a Possible Promising Epilepsy Therapy

BackgroundDeep brain stimulation (DBS) has emerged as a potential therapeutic strategy in the treatment of neurological disorders including epilepsy. However, the cellular mechanism responsible for the effects of DBS remains largely undefined. Therefore, using electrophysiological approach, we aimed to determine the antiepileptic effects and restorative potential of low frequency stimulation (LFS) on amygdala kindling-induced changes in electrophysiological properties of rat hippocampal CA1 pyramidal neurons. MethodsAnimals were kindled by electrical stimulation of amygdala in a rapid kindling manner (12 times per day). In one group of animals, immediately after termination of daily 12 rapid kindling stimulations, the kindling site was subjected to 4 packages of LFS at intervals of 5 min (each package contained 200 monophasic square-wave pulses, 0.1 ms pulse duration at 1 Hz). Whole cell patch clamp recording under current clamp conditions was performed on visually identified pyramidal neurons in hippocampal slice preparations obtained from amygdala-kindled rats and the rats receiving LFS. ResultsKindling of the right basolateral amygdala profoundly affected spontaneous firing behavior and repetitive discharge characteristics of pyramidal neuronal electrophysiological properties. Application of LFS at the kindling site almost completely prevented the development of epilepsy and the disruptive effects of kindling on neuronal electrical activity through restoration of the normal electrophysiological characteristics. ConclusionsThe results of this study implied that application of LFS during kindling acquisition prevents the kindling induced changes in functional electrical properties of CA1 pyramidal neurons, suggesting that this action may be involved in the antiepileptogenic mechanism of LFS.

Performance limitations of relay neurons.

Relay cells are prevalent throughout sensory systems and receive two types of inputs: driving and modulating. The driving input contains receptive field properties that must be transmitted while the modulating input alters the specifics of transmission. For example, the visual thalamus contains relay neurons that receive driving inputs from the retina that encode a visual image, and modulating inputs from reticular activating system and layer 6 of visual cortex that control what aspects of the image will be relayed back to visual cortex for perception. What gets relayed depends on several factors such as attentional demands and a subject's goals. In this paper, we analyze a biophysical based model of a relay cell and use systems theoretic tools to construct analytic bounds on how well the cell transmits a driving input as a function of the neuron's electrophysiological properties, the modulating input, and the driving signal parameters. We assume that the modulating input belongs to a class of sinusoidal signals and that the driving input is an irregular train of pulses with inter-pulse intervals obeying an exponential distribution. Our analysis applies to any order model as long as the neuron does not spike without a driving input pulse and exhibits a refractory period. Our bounds on relay reliability contain performance obtained through simulation of a second and third order model, and suggest, for instance, that if the frequency of the modulating input increases or the DC offset decreases, then relay increases. Our analysis also shows, for the first time, how the biophysical properties of the neuron (e.g. ion channel dynamics) define the oscillatory patterns needed in the modulating input for appropriately timed relay of sensory information. In our discussion, we describe how our bounds predict experimentally observed neural activity in the basal ganglia in (i) health, (ii) in Parkinson's disease (PD), and (iii) in PD during therapeutic deep brain stimulation. Our bounds also predict different rhythms that emerge in the lateral geniculate nucleus in the thalamus during different attentional states.

Does too much sugar make for lost memories?

Does too much sugar make for lost memories?

The excitability of dorsal horn neurons is affected by cerebrospinal fluid from humans with osteoarthritis

Changes in central neural processing are thought to contribute to the development of chronic osteoarthritis pain. This may be reflected as the presence of inflammatory mediators in the cerebral spinal fluid (CSF). We therefore exposed organotypically cultured slices of rat spinal cord to CSF from human subjects with osteoarthritis (OACSF) at a ratio of 1 part CSF in 9 parts culture medium for 5-6 days, and measured changes in neuronal electrophysiological properties by means of whole-cell recording. Although OACSF had no effect on the membrane properties and excitability of neurons in the substantia gelatinosa, synaptic transmission was clearly altered. The frequency of spontaneous excitatory postsynaptic currents (sEPSC) in delay-firing putative excitatory neurons was increased, as was sEPSC amplitude and frequency in tonic-firing inhibitory neurons. These changes could affect sensory processing in the dorsal horn, and may affect the transfer of nociceptive information. Although OACSF also affected inhibitory synaptic transmission (frequency of spontaneous inhibitory synaptic currents; sIPSC), this may have little bearing on sensory processing by substantia gelatinosa neurons, as sEPSC frequency is >3× greater than sIPSC frequency in this predominantly excitatory network. These results support the clinical notion that changes in nociceptive processing at the spinal level contribute to the generation of chronic osteoarthritis pain.

Electrophysiological insights into the enduring effects of early life stress on the brain

Increasing evidence links exposure to stress early in life to long-term alterations in brain function, which in turn have been linked to a range of psychiatric and neurological disorders in humans. Electrophysiological approaches to studying these causal pathways have been relatively underexploited. Effects of early life stress on neuronal electrophysiological properties offer a set of potential mechanisms for these susceptibilities, notably in the case of epilepsy. Thus, we review experimental evidence for altered cellular and circuit electrophysiology resulting from exposure to early life stress. Much of this work focuses on limbic long-term potentiation, but other studies address alterations in electrophysiological properties of ion channels, neurotransmitter systems, and the autonomic nervous system. We discuss mechanisms which may mediate these effects, including influences of early life stress on key components of brain synaptic transmission, particularly glutamate, GABA and 5-HT receptors, and influences on neuroplasticity (primarily neurogenesis and synaptic density) and on neuronal network activity. The existing literature, although small, provides strong evidence that early life stress induces enduring, often robust effects on a range of electrophysiological properties, suggesting further study of enduring effects of early life stress employing electrophysiological methods and concepts will be productive in illuminating disease pathophysiology.

Morphological and electrophysiological characteristics of neurons within identified subnuclei of the lateral habenula in rat brain slices

Based on the specificity of its inputs and targets, the lateral habenular complex (LHb) constitutes a pivotal motor-limbic interface implicated in various cerebral functions particularly in regulating monoamine transmission. Despite its functional significance, cellular characteristics underlying LHb functionality have not been examined systematically. The present study aimed to correlate morphological and electrophysiological properties of neurons within the different subnuclei of the LHb using whole-cell recording and neurobiotin labeling in rat slice preparations. Morphological analysis revealed a heterogeneous population of projection neurons randomly distributed throughout the LHb. According to somatodendritic characteristics four main categories were classified including spherical, fusiform, polymorphic and vertical cells. Electrophysiological characterization of neurons within the different categories demonstrated homologous profiles and no significant differences between groups. Typically, LHb neurons possessed high input resistances and long membrane time constants. They also displayed time-dependent inward rectification and distinct afterhyperpolarization. A salient electrophysiological feature of LHb neurons was their ability to generate rebound bursts of action potentials in response to membrane hyperpolarization. Based on the pattern of spontaneous activity, neurons were classified as silent, tonic or bursting. The occurrence of distinctive firing modes was not related to topographic allocation. The patterns of spontaneous firing and evoked discharge were highly sensitive to alterations in membrane potential and merged upon de- and hyperpolarizing current injection and synaptic stimulation. Besides projection neurons, recordings revealed the existence of a subpopulation of cells possessing morphological and physiological properties of neocortical neurogliaform cells. They were considered to be interneurons. Our data suggest that neurons within the different LHb subnuclei behave electrophysiologically more similar than expected, considering their morphological heterogeneity. We conclude that the formation of functional neuronal entities within the LHb may be achieved through defined synaptic inputs to particular neurons, rather than by individual neuronal morphologies and intrinsic membrane properties.

Electrophysiological properties of neurons in the robust nucleus of the arcopallium of adult male zebra finches

Nucleus robust arcopallium (RA) of the songbird is a distinct forebrain region that is essential for song production. To explore the electrophysiological properties, whole cell recordings were made from adult zebra finch RA neurons in slice preparations. Based on the electrophysiological properties, neurons in RA were classified into two distinct classes. Type I neurons were spontaneously active. They had larger input resistance, longer time constant, larger time-peak of an afterhyperpolarization (AHP), and broader action potentials than those of the other class. A slow, time-dependent inward rectification was induced by hyperpolarizing current pulses in this type of neuron, and was blocked by external CsCl (2 mM). Type II neurons had a more negative resting membrane potential than that of type I neurons. They were characterized by a steeper slope of the recovery from the peak of the AHP and frequency–current relationships, a higher firing threshold, and irregular spiking in response to depolarizing current injection.

Sexual dimorphism of the electrophysiological properties of the projection neurons in the robust nucleus of the arcopallium in adult zebra finches

To observe the sexual differences in electrophysiological properties of neurons in the robust nucleus of the arcopallium (RA) in adult zebra finches, and to provide the direct electrophysiological evidence for the sexual dimorphism of birdsong. Whole-cell recording was used to record the spontaneous action potential firing rates from RA projection neurons in acute brain slices. The projection neurons of RA in male birds fired spontaneously at 10 Hz or above, while in female birds, the frequency was significantly lower, and even no firings could be detected. There is a sexual difference in electrophysiological properties of projection neurons in RA, which may result from the difference in the levels of steroid hormones in birds.

Neural correlates of spatial short-term memory in the rodent frontal orienting field

Event Abstract Back to Event Neural correlates of spatial short-term memory in the rodent frontal orienting field Jeffrey C. Erlich1*, Max Bialek1 and Carlos D. Brody1 1 HHMI and Princeton University, United States We have trained rats on a memory-guided delayed orienting task, inspired by delayed saccade tasks performed by human and non-human primates. The delayed orienting task requires rats to ’fixate’ by holding their nose in a central nose port while a light is on in the port. During the fixation, a brief sound (the "target stimulus") indicates to the rat whether it should orient to the right or to the left after the end of fixation in order to obtain a reward. The end of fixation is indicated by the offset of the center light. We randomly interleave two types of trials: memory and non-memory. In memory trials, the target stimulus is presented shortly after the beginning of fixation and 700 ms before its end. In these trials, the rat must inhibit the impulse to respond immediately and must also remember the reward location (either as a retrospective memory of the stimulus or a prospective motor plan/prediction of reward location). These two elements, inhibition and planning, make the delayed-orienting task suitable for understanding the neural basis of cognitive control. In non-memory trials, the target stimulus is presented at the end of the fixation period, and no memory is required for correct performance. The two types of trials allow us to distinguish activity associated with spatial memory from activity associated with fixation only. The electrophysiological properties of neurons in the rodent orientation system remain largely unexplored. One cortical area of potential interest is the Frontal Orienting Field (FOF, +2 AP, ±1.3 ML [mm from Bregma]). Previous anatomical data has suggested that the FOF is homologous to primate frontal eye fields: in particular, the FOF connects strongly to both prefrontal cortex and the superior colliculus. Nevertheless, almost no electrophysiological recordings from the FOF exist. To our knowledge, no previous studies have recorded from FOF using repeated, identically prepared trials requiring an orientation movement, whether memory or non-memory-based. We have now recorded from over 500 single-units from the FOF while rats performed the delayed orienting task. We found that a significant portion of neurons in this region (approx 30%) show spatial working memory: after the offset of the stimulus, and before the onset of the movement, firing rates are selective for the rat’s upcoming choice. We have preliminary lesion and pharmacological evidence indicating that unilateral disruption of activity in the FOF creates a contralateral impairment. For example, rats with left FOF lesions are impaired at making rightward responses. Thus, we have both correlational physiological evidence and causal evidence that the FOF is an important element of the rat’s neural circuit for spatial orientation and spatial short-term memory. Conference: Computational and Systems Neuroscience 2010, Salt Lake City, UT, United States, 25 Feb - 2 Mar, 2010. Presentation Type: Poster Presentation Topic: Poster session I Citation: Erlich JC, Bialek M and Brody CD (2010). Neural correlates of spatial short-term memory in the rodent frontal orienting field. Front. Neurosci. Conference Abstract: Computational and Systems Neuroscience 2010. doi: 10.3389/conf.fnins.2010.03.00019 Copyright: The abstracts in this collection have not been subject to any Frontiers peer review or checks, and are not endorsed by Frontiers. They are made available through the Frontiers publishing platform as a service to conference organizers and presenters. The copyright in the individual abstracts is owned by the author of each abstract or his/her employer unless otherwise stated. Each abstract, as well as the collection of abstracts, are published under a Creative Commons CC-BY 4.0 (attribution) licence (https://creativecommons.org/licenses/by/4.0/) and may thus be reproduced, translated, adapted and be the subject of derivative works provided the authors and Frontiers are attributed. For Frontiers’ terms and conditions please see https://www.frontiersin.org/legal/terms-and-conditions. Received: 17 Feb 2010; Published Online: 17 Feb 2010. * Correspondence: Jeffrey C Erlich, HHMI and Princeton University, Princeton, United States, jerlich@princeton.edu Login Required This action requires you to be registered with Frontiers and logged in. To register or login click here. Abstract Info Abstract The Authors in Frontiers Jeffrey C Erlich Max Bialek Carlos D Brody Google Jeffrey C Erlich Max Bialek Carlos D Brody Google Scholar Jeffrey C Erlich Max Bialek Carlos D Brody PubMed Jeffrey C Erlich Max Bialek Carlos D Brody Related Article in Frontiers Google Scholar PubMed Abstract Close Back to top Javascript is disabled. Please enable Javascript in your browser settings in order to see all the content on this page.

Insights into medio‐lateral signalling in the developing mouse hindbrain: properties of midline drivers of network activity

The ability to generate primitive patterns of spontaneous activity is a well preserved feature of immature central nervous system (CNS) networks. From the retina to the hindbrain or the spinal cord, synchronized episodes of activity take place primarily or exclusively during restricted windows of time and are globally similar among different structures during intense synaptogenesis or growth (O’Donovan, 1999; Ben-Ari, 2001; Moody & Bosma, 2005). Recurrent activity often propagates allowing contiguous structures to perform as an ensemble (Feller, 1999). The slow propagation of this activity usually follows a precise spatial distribution that changes over the course of development (Ben-Ari, 2001; Gust et al. 2003). Although the roles of this activity during ontogenesis remain mostly unresolved, one traditional view is that it contributes to the activity-dependent developmental organization of neuronal circuits with specific functions (Feller, 1999; Ben-Ari, 2001; Moody & Bosma, 2005). In the mouse embryonic hindbrain, endogenous neuronal domains have been suggested to lead spontaneous activity underlying intracellular calcium transients, since these episodes are recorded in whole hindbrain or slice preparations, deprived of influences from other CNS regions (Gust et al. 2003). Synchronized activity originates from midline neurons and propagates laterally (Gust et al. 2003; Moruzzi et al. 2009), and such a spontaneous activity eventually disappears at later stages of CNS development. It has been suggested that a differential expression of peculiar intrinsic properties consistently, yet only transiently, confer to midline neurons the ability to initiate episodes of activity. Certainly to appreciate how spontaneous activity shapes hindbrain embryonic circuits requires an understanding of the mechanisms which confer to primitive events certain spatial correlations. Such mechanisms may rely on single neuronal electrophysiological properties. Do midline neurons possess intrinsic features or voltage-dependent conductances that would endow them with the ability to drive activity in the developing hindbrain? In this issue of The Journal of Physiology, Moruzzi et al. (2009) provide evidence supporting the hypothesis that a combination of low gap-junctional coupling, T-type calcium channels and high input resistance underpins the ability of midline neurons to drive primitive episodes of activity in the immature hindbrain rostral circuits. In accordance with previous studies, the authors confirmed the correlation between spontaneous electrical events and calcium events within the isolated embryonic hindbrain. Electrical events consist of slow graded depolarisations that, as assessed by dual patch clamp recordings, originate near the midline and propagate towards lateral regions. Using pipettes filled with neurobiotin (a widely used tracer in neurobiology) they marked cell positions, and the electrophysiological properties recorded from each neuron were plotted on a functional map relative to the midline region. The shape of the depolarizing events varies by region, in particular in the peak amplitude and duration of both initial spike and plateau components of the biphasic event. Lateral events are usually slower and smaller. Investigating the extent of dye coupling after recordings performed with neurobiotin-filled electrodes reveals the presence of a differential gap junction coupling. Confocal microscopy assessment of clusters of neurobiotin-coupled neurons shows a medio-lateral distribution of coupling. Lateral tissue, displaying lower and slower depolarizing events, is significantly more coupled via neurobiotin-permeant gap junctions. The direct consequence of the higher coupling is that lateral cells are more ‘leaky’, less excitable, an evidence supported by the medio-lateral spatial variation in resting leak conductance. The medial tissue lower gap junctional coupling is reflected in larger and faster electrical events, more prone to initiate spontaneous activity. In addition, medial cells possess inward T-type currents that correlate with the ability to express the rapid spike component of the spontaneous events, absent in lateral neurons. The driving of spontaneous activity at the midline is transient and may reinforce the ability of differentiating or migrating cells to sense medio-lateral position, playing a role in decision-making near the midline. It will be important in future studies to identify other ion channels responsible for the changes, during subsequent developmental stages, of the medial and lateral neuron activity profile and how this influences the behaviour of hindbrain networks.

Slow synaptic transmission in myenteric AH neurons from the inflamed guinea pig ileum

We investigated the effect of inflammation on slow synaptic transmission in myenteric neurons in the guinea pig ileum. Inflammation was induced by the intraluminal injection of trinitrobenzene sulfonate, and tissues were taken for in vitro investigation 6-7 days later. Brief tetanic stimulation of synaptic inputs (20 Hz, 1 s) induced slow excitatory postsynaptic potentials (EPSPs) in 49% and maintained postsynaptic excitation that lasted from 27 min to 3 h in 13% of neurons from the inflamed ileum. These neurons were classified electrophysiologically as AH neurons; 10 were morphological type II neurons, and one was type I. Such long-term hyperexcitability after a brief stimulus is not encountered in enteric neurons of normal intestine. Electrophysiological properties of neurons with maintained postsynaptic excitation were similar to those of neurons with slow EPSPs. Another form of prolonged excitation, sustained slow postsynaptic excitation (SSPE), induced by 1-Hz, 4-min stimulation, in type II neurons from the inflamed ileum reached its peak earlier but had lower amplitude than that in control. Unlike slow EPSPs and similar to SSPEs, maintained excitation was not inhibited by neurokinin-1 or neurokinin-3 receptor antagonists. Maintained postsynaptic excitation was not influenced by PKC inhibitors, but the PKA inhibitor, H-89, caused further increase in neuronal excitability. In conclusion, maintained excitation, observed only in neurons from the inflamed ileum, may contribute to the dysmotility, pain, and discomfort associated with intestinal inflammation.

The Influence of Stress Hormones on Fear Circuitry

Fear arousal, initiated by an environmental threat, leads to activation of the stress response, a state of alarm that promotes an array of autonomic and endocrine changes designed to aid self-preservation. The stress response includes the release of glucocorticoids from the adrenal cortex and catecholamines from the adrenal medulla and sympathetic nerves. These stress hormones, in turn, provide feedback to the brain and influence neural structures that control emotion and cognition. To illustrate this influence, we focus on how it impacts fear conditioning, a behavioral paradigm widely used to study the neural mechanisms underlying the acquisition, expression, consolidation, reconsolidation, and extinction of emotional memories. We also discuss how stress and the endocrine mediators of the stress response influence the morphological and electrophysiological properties of neurons in brain areas that are crucial for fear-conditioning processes, including the amygdala, hippocampus, and prefrontal cortex. The information in this review illuminates the behavioral and cellular events that underlie the feedforward and feedback networks that mediate states of fear and stress and their interaction in the brain.

Neural Activity Regulates Synaptic Properties and Dendritic Structure In Vivo through Calcineurin/NFAT Signaling

The calcium-regulated protein phosphatase Calcineurin (CaN) participates in synaptic plasticity and the regulation of transcription factors, including Nuclear Factor of Activated T cells (NFAT). To understand how CaN contributes to neuronal circuit development, whole-cell mEPSC recordings and multiphoton imaging were performed in the visual system of living Xenopus laevis tadpoles electroporated to express either a CaN phosphatase inhibitor or N-VIVIT, a nuclear localization sequence-tagged VIVIT peptide that blocks the binding of CaN to select substrates including NFAT. Both strategies increased mEPSC frequency and dendritic arbor complexity in tectal neurons over 3 days. Expression of either of two constitutively active Xenopus NFATs (CA-NFATs) restored normal synaptic properties in neurons expressing N-VIVIT. However, the morphological phenotype was only rescued by a CA-NFAT bearing an intact regulatory domain, implying that transcriptional control of morphological and electrophysiological properties of neurons is mediated by distinct NFAT interactions.

Neural Simulations on Multi-Core Architectures

Neuroscience is witnessing increasing knowledge about the anatomy and electrophysiological properties of neurons and their connectivity, leading to an ever increasing computational complexity of neural simulations. At the same time, a rather radical change in personal computer technology emerges with the establishment of multi-cores: high-density, explicitly parallel processor architectures for both high performance as well as standard desktop computers. This work introduces strategies for the parallelization of biophysically realistic neural simulations based on the compartmental modeling technique and results of such an implementation, with a strong focus on multi-core architectures and automation, i.e. user-transparent load balancing.

Regeneration and characterization of adult mouse hippocampal neurons in a defined in vitro system

Although the majority of human illnesses occur during adulthood, most of the available in vitro disease models are based upon cells obtained from embryonic/fetal tissues because of the difficulties involved with culturing adult cells. Development of adult mouse neuronal cultures has a special significance because of the abundance of transgenic disease models that use this species. In this study a novel cell culture method has been developed that supports the long-term survival and physiological regeneration of adult mouse hippocampal cells in a serum-free defined environment. In this well-defined, controlled system, adult mouse hippocampal cells survived for up to 21 days in culture. The cultured cells exhibited typical hippocampal neuronal morphology and electrophysiological properties after recovery from the trauma of dissociation, and stained positive for the expected neuronal markers. This system has great potential as an investigative tool for in vitro studies of adult diseases, the aging brain or transgenic models of age-associated disorders.

Training improves the electrophysiological properties of lumbar neurons and locomotion after thoracic spinal cord injury in rats

The aim of the present study was to evaluate the effect of a stepping-based rehabilitation program in voluntary wheel cages on the functional recovery and electrophysiological properties of neurons in the rat lumbar spinal cord after compressive thoracic (T10) spinal cord injury (SCI). A significant decrease in stance/swing duration and the number of limbs simultaneously in the stance phase was seen in trained compared to sedentary rats at 28 days after SCI ( p < 0.05). These kinematic improvements were associated with a significant increase in the amplitude of extracellular recordings from the tibial motoneuron pool in response to descending neuronal drive as well as significant amelioration of electrophysiological properties assessed from intracellular recordings. In fact, electrophysiological properties were not significantly different between uninjured controls and SCI-trained rats. Brain-derived neurotrophic factor (BDNF) levels were significantly elevated in the lumbar spinal cord of SCI-trained rats compared to SCI-sedentary controls. The data support a therapeutic role of increased neuromuscular activity in promoting functional recovery and suggest that it might occur via the beneficial effects of neurotrophic factors on neuronal plasticity.

New Eph Receptor Ligand

A point mutation (P56S) in VAPB (VAMP-associated membrane protein B) is associated with certain forms of familial amyotrophic lateral sclerosis (ALS), which is characterized by progressive loss of motor neuron function. VAPB is a member of the VAP family of proteins, which are typically associated with the endoplasmic reticulum (ER) and thought to function in lipid metabolism. They have an N-terminal major sperm protein (MSP) domain, a coiled-coil motif, and a transmembrane domain. Tsuda et al . found with immunofluorescent analysis of either endogenous proteins or versions tagged on the N and C termini with different epitope tags that the Drosophila homolog of human VAPB, which they call dVAP, was localized both intracellularly and extracellularly in wing imaginal discs. Western blot analysis of fly extracts or human white blood cells suggested that a cleaved form of the protein was present in addition to the full-length protein, and detection of the short forms in human serum suggested that the cleavage product was secreted. Analysis of a version of dVAP in which the residue homologous to the one associated with ALS was mutated (P58S) showed that the protein was not present extracellularly but instead formed aggregates in the wing disc cells or neurons. These P58S aggregates also included wild-type dVAP and ER proteins and appeared to trigger the ER stress response in motor neurons. Antibodies against ubiquitin recognized the aggregated P58S protein on Western blots of immunoprecipitated P58S, and ubiquitin colocalized with the aggregates in Drosophila neurons. Although presynaptic overexpression of wild-type dVAP alters motor neuron morphology and electrophysiological properties and causes muscle defects, as well as impairs flight, overexpression of P58S did not cause such phenotypes. Furthermore, the P58S mutant rescued the lethality of null mutations in dVAP; thus, P58S retains some biological activity but not all properties of the wild-type protein. Because VAPs have a MSP domain and MSPs are ligands for Eph homologs in Caenorhabditis elegans , the authors performed genetic experiments that placed dVAP and Eph in common developmental pathways in flies and placed VPR-1, the C. elegans VAP homolog, and VAB-1, the C. elegans Eph receptor, in common pathways in worms. Fluorescein isothiocyanate (FITC)-conjugated versions of the MSP domain of human VAP, dVAP, or VPR-1 were incubated with isolated C. elegans gonads, and all three proteins bound in the same pattern as that of MSP-FITC. Additionally, the hVAP MSP domain competed with MSP-FITC, suggesting that they recognized the same binding sites. The MSP domain of hVAP also competed with EphrinB2 for binding to EphA4 in a dose-dependent manner, suggesting that VAPs may serve as Eph ligands in mammals as well. Ackerman and Cox provide insight into the importance of these results in understanding the mechanism underlying ALS. H. Tsuda, S. M. Han, Y. Yang, C. Tong, Y. Q. Lin, K. Mohan, C. Haueter, A. Zoghbi, Y. Harati, J. Kwan, M. A. Miller, H. J. Bellen, The amyotrophic lateral sclerosis 8 protein VAPB is cleaved, secreted, and acts as a ligand for Eph receptors. Cell 133 , 963-977 (2008). [PubMed]

Physiological types of substantia gelatinosa neurons in the rat spinal cord

Electrophysiological properties of neurons in the substantia gelatinosa (SG, or lamina II) were studied in vitro in spinal cord slices from 3-to 5-week-old rats. Based on the type of action potentials (APs) firing in response to long depolarization (0.5 to 0.8 sec), neurons were categorized into three types: tonic (APs were generated over the whole duration of the stimulus, n = 26, or 41.2%), adapting (a few APs occurred only at the beginning of stimulation, n = 8, 12.7%), and delayed-firing neurons, DFNs (APs occurred at the end of stimulation, n = 22, 35.1%); 11% of the cells had intermediate properties. Neurons of each type expressed distinct ion currents that were subthreshold for AP generation (< −40 mV). Tonic and adapting neurons either had no subthreshold currents (n = 21, or 61.3%) or expressed T-type calcium currents (n = 13, or 38.7%). All DFNs had outward A-type potassium currents. Statistical analysis confirmed this classification scheme: neurons of each type were differentially distributed in a 3-D parametric space of the main cellular properties. Distributions of tonic and adapting neurons partially overlapped, while that of DFNs differed significantly from both the above groups. It is suggested that DFNs perform a special function in the processing of sensory information; the functions of tonic and adapting neurons might be rather similar to each other.

Functional and molecular partitioning of the brain provides neuroprotection to cardiorespiratory nuclei in ground squirrels during hibernation

Torpor and hibernation are among the most extreme examples of energy conservation and CNS plasticity in endotherms. In torpor the respiratory rate of the 13‐lined ground squirrel (Spermophilus tridecemlineatus) decreases 98%, and heart rate drops to 1% of the aroused state. While dendrites of cortical neurons retract during torpor, corresponding to a cessation of neuronal activity, cardiorespiratory function is maintained. We are investigating molecular and electrophysiological properties of neurons in the cortex and brainstem of ground squirrels during the annual cycle that may underlie this partitioning. Data indicate that cortex is significantly remodeled upon entrance into and arousal from torpor, whereas the brainstem, which contains cardiorespiratory nuclei, remains static. qRT‐PCR showed significant increases in mRNA for several GABA‐A receptor subunits as well as synaptophysin in cortex during interbout arousals. No such changes were seen in brainstem. Ongoing experiments using intracellular recordings and dye injection will determine functional components of this partitioning at a cellular level. We speculate that cardiorespiratory nuclei remain active during torpor and are protected from the morphological and functional remodeling associated with hibernation by modulation of GABA receptors. DARPA W81XWH‐05‐02‐0016 (HC), NIH AG18760 (MB) and NIH T32 GM007507.

A multitarget basal ganglia dopaminergic and GABAergic transplantation strategy enhances behavioural recovery in parkinsonian rats

The current transplantation paradigm for Parkinson's disease that places foetal dopaminergic cells in the striatum neither normalizes neuronal activity in basal ganglia structures such as the substantia nigra (SN) and subthalamic nucleus (STN) nor leads to complete functional recovery. It was hypothesized that restoration of parkinsonian deficits requires inhibition of the pathological overactivity of the STN and SN in addition to restoration of dopaminergic activity in the striatum. To achieve inhibition, a multitargeted basal ganglia transplantation strategy using GABAergic cells derived from either foetal striatal primordia (FSP) cells or human neural precursor cells (hNPCs) expanded in suspension bioreactors was investigated. In hemiparkinsonian rats, transplantation of foetal rat dopaminergic cells in the striatum in conjunction with GABAergic grafts in the STN and/or SN promoted significant improvement in forelimb akinesia and motor function compared to transplantation of intrastriatal dopaminergic grafts alone or in conjunction with undifferentiated hNPCs. In culture, FSP cells exhibited neuronal electrophysiological properties. However, recordings from GABAergic hNPCs revealed limited ionic conductances and an inability to fire action potentials. Despite this, they were almost as efficacious as FSP cells in inducing functional recovery following transplantation, suggesting that such recovery may have been mediated by secretion of GABA rather than by functional integration into the host. Thus, restoration of dopaminergic activity to the striatum in concert with inhibition of the STN and SN by GABAergic grafts may be beneficial for improving clinical outcomes in patients with Parkinson's disease and potential clinical application of this strategy may be enhanced by the use of differentiated hNPCs.