Excitatory Inhibitory Neurons Research Articles

Progressive myoclonus epilepsy caused by a gain-of-function KCNA2 mutation

Progressive myoclonus epilepsy caused by a gain-of-function KCNA2 mutation

0200 DIRECT ACTIVATION OF G-PROTEIN-COUPLED INWARD RECTIFYING K+ CHANNELS PROMOTE SLEEP IN RODENTS

The most common type of sleep disorder is insomnia which is characterized by difficulty falling asleep and/or maintaining sleep. Chronic insomniacs respond poorly to current treatments including benzodiazepines and non-benzodiazepines. Activation of G-protein-gated inward rectifying K channels (GIRKs) by GABAB agonists baclofen or γ-hydroxybutyric acid (GHB) predominantly promote non-rapid eye movement (NREM) sleep in rodents and humans. GHB especially reduces sleep fragmentation in narcoleptic patients. The present study explored the link between direct GIRK activation and sleep regulation in rodents using our potent and selective GIRK channel activator ML297. Whole-cell patch clamp recordings from hypocretin/orexin-EGFP neurons and extracellular recordings of mouse hippocampal CA1 area in mouse brain slices were made to study cellular and synaptic actions of ML297. Wake activity and locomotion were measured using the noninvasive behavior monitoring system SmartCageTM. Furthermore, wakefulness, REM and NREM sleep were determined using the electroencephalogram/electromyogram (EEG/EMG) in wild type mice (C57BL/C) implanted with electrodes. Bath-application of ML297 (5µM) hyperpolarized resting potential, decreased membrane input resistance and blocked spontaneous firing of action potentials in hypocretin/orexin neurons. These actions were reversed after prolonged washout. ML297 (5–50µM) produced no significant effects on normal synaptic activity measured by input-output of field postsynaptic excitatory potentials and an evoked single population of spikes in the hippocampal CA1 area, suggesting ML297 principally causes long-lasting postsynaptic inhibition. Using our noninvasive SmartCageTM system we observed that ML297 (30mg/kg, i.p.) caused a prolonged inhibition of wake activity and locomotion in mice. The EEG/EMG recordings confirmed that ML297 (30mg/kg, i.p.) significantly decreased wakefulness and revealed an increase in NREM sleep without affecting REM sleep in mice. The present study for the first time has demonstrated that direct action of GIRK produces similar sleep regulation to GABAB receptor-mediated modulation. Since GIRKs channels are predominantly expressed in principal excitatory neurons, inhibition of neuronal excitability and depression of the arousal system may powerfully modulate sleep. Direct GIRK activators may present an innovative approach for treatment of chronic insomnia as well as other sleep disorders. This work was supported by NIH grants: R42 HL084990, R44 AG043203, and R44 NS086343.

Activity-induced spontaneous spikes in GABAergic neurons suppress seizure discharges: an implication of computational modeling.

BackgroundEpilepsy, a prevalent neurological disorder, appears self-termination. The endogenous mechanism for seizure self-termination remains to be addressed in order to develop new strategies for epilepsy treatment. We aim to examine the role of activity-induced spontaneous spikes at GABAergic neurons as an endogenous mechanism in the seizure self-termination.Methods and ResultsNeuronal spikes were induced by depolarization pulses at cortical GABAergic neurons from temporal lobe epilepsy patients and mice, in which some of these neurons fired activity-induced spontaneous spikes. Neural networks including excitatory and inhibitory neurons were computationally constructed, and their functional properties were based on our studies from whole-cell recordings. With the changes in the portion and excitability of inhibitory neurons that generated activity-induced spontaneous spike, the efficacies to suppress synchronous seizure activity were analyzed, such as its onset time, decay slope and spike frequency. The increases in the proportion and excitability of inhibitory neurons that generated activity-induced spontaneous spikes effectively suppressed seizure activity in neural networks. These factors synergistically strengthened the efficacy of seizure activity suppression.ConclusionOur study supports a notion that activity-induced spontaneous spikes in GABAergic neurons may be an endogenous mechanism for seizure self-termination. A potential therapeutic strategy for epilepsy is to upregulate the cortical inhibitory neurons that generate activity-induced spontaneous spikes.

Effects of Millimeter-Wave Electromagnetic Radiation on the Experimental Model of Migraine.

Effects of millimeter-wave electromagnetic radiation (40 GHz frequency, 0.01 mW power) on the spontaneous fi ring of convergent neurons of the spinal trigeminal nucleus and their responses to electrical stimulation of the dura mater were studied in neurophysiological experiments on rats. Irradiation of the area of cutaneous receptive fields of spinal trigeminal nucleus reversibly inhibited both spontaneous discharges and activity induced by electrical stimulation of the dura mater. The second and third exposures to electromagnetic radiation with an interval of 10 min were ineffective. These results suggest that suppression of neuronal excitability in the spinal trigeminal ganglion can be a mechanism of the anti-migraine effects of electromagnetic radiation observed in clinical practice.

In vitro refolding and functional analysis of polyhistidine-tagged Buthus martensii Karsch antitumor-analgesic peptide produced in Escherichia coli.

To identify an efficient in vitro refolding method to generate highly active His6-tagged scorpion toxin antitumor-analgesic peptide (AGAP) isolated from Escherichia coli inclusion bodies. N- and C-Terminal His6-tagged recombinant (r) AGAP (NHis6-rAGAP and CHis6-rAGAP, respectively) were expressed in E. coli; the purification and refolding conditions were optimized. CHis6-rAGAP, but not NHis6-rAGAP, exhibited significant in vitro antihepatoma activity that was much greater than that of rAGAP produced using SUMO fusion technology (IC50, 0.4±0.08 vs. 1.8±0.3μM). CHis6-rAGAP also showed significant inhibition of tumor growth in a mouse xenograft model of human hepatoma and inhibition of neuronal excitability, demonstrated by blockage of voltage-sensitive tetrodotoxin-resistant (TTX-R) sodium currents in acute isolated dorsal root ganglion neurons. This refolding protocol optimized for C-terminal His6-tagged scorpion rAGAP is potentially applicable to similar long-chain and cysteine-rich toxins.

Pyramidal cells make specific connections onto smooth (GABAergic) neurons in mouse visual cortex.

Author SummaryThe mammalian visual cortex, which is part of the cerebral cortex, contains 50 to 100 thousands of neurons per cubic millimetre, most of which are excitatory (85%) and the minority, inhibitory (15%). Unlike neurons in the retina, neurons in the visual cortex are preferentially activated by lines or edges of a particular orientation. This is termed a neuron's “orientation preference.” In the visual cortex of higher mammals like cats and monkeys, neurons that share an orientation preference are clustered in functional columns. However, in rodents like mice, orientation preferences are randomly distributed. In this study, we investigate whether the differences between columnar and non-columnar cortex is correlated with differences in the connectivity patterns between excitatory and inhibitory neurons. Using light and electron microscopy, we mapped the connectivity of pyramidal neurons—the primary excitatory neurons—in the superficial layers of the primary visual cortex (V1) of mice. Our results show that the ratio of excitatory-inhibitory neurons in mouse V1 is similar to that of cat or monkey V1, but in mouse V1 local pyramidal neurons target proportionately many more inhibitory neurons compared to what other studies found in cat or monkey. This difference may indicate the significance of inhibition in maintaining orientation selectivity in the non-columnar visual cortex of rodents like mice and is a distinct difference in the architecture of V1 between mice and higher mammals.

Chemokine Co-Receptor CCR5/CXCR4-Dependent Modulation of Kv2.1 Channel Confers Acute Neuroprotection to HIV-1 Glycoprotein gp120 Exposure

Infection with human immunodeficiency virus-1 (HIV-1) within the brain has long been known to be associated with neurodegeneration and neurocognitive disorder (referred as HAND), a condition characterized in its early stages by declining cognitive function and behavioral disturbances. Mechanistically, the HIV-1 coat glycoprotein 120 (gp120) has been suggested to be a critical factor inducing apoptotic cell death in neurons via the activation of p38 mitogen-activated protein kinase (MAPK), upon chronic exposure to the virus. Here we show that acute exposure of neurons to HIV-1 gp120 elicits a homeostatic response, which provides protection against non-apoptotic cell death, involving the major somatodendritic voltage-gated K+ (Kv) channel Kv2.1 as the key mediator. The Kv2.1 channel has recently been shown to provide homeostatic control of neuronal excitability under conditions of seizures, ischemia and neuromodulation/neuroinflammation. Following acute exposure to gp120, cultured rat hippocampal neurons show rapid dephosphorylation of the Kv2.1 protein, which ultimately leads to changes in specific sub-cellular localization and voltage-dependent channel activation properties of Kv2.1. Such modifications in Kv2.1 are dependent on the activation of the chemokine co-receptors CCR5 and CXCR4, and subsequent activation of the protein phosphatase calcineurin. This leads to the overall suppression of neuronal excitability and provides neurons with a homeostatic protective mechanism. Specific blockade of calcineurin and Kv2.1 channel activity led to significant enhancement of non-apoptotic neuronal death upon acute gp120 treatment. These observations shed new light on the intrinsic homeostatic mechanisms of neuronal resilience during the acute stages of neuro-HIV infections.

Circuits That Innervate Excitatory-Inhibitory Cells in the Inferior Colliculus Obtained with In Vivo Whole Cell Recordings

Neurons excited by stimulation of one ear and suppressed by the other, called excitatory/inhibitory (EI) neurons, are sensitive to interaural intensity disparities, the cues animals use to localize high frequencies. EI neurons are first formed in lateral superior olive, which then sends excitatory projections to the dorsal nucleus of the lateral lemniscus and the inferior colliculus (IC), both of which contain large populations of EI cells. We evaluate herein the inputs that innervate EI cells in the IC of Mexican free-tailed bats (Tadarida brasilensis mexicana) with in vivo whole-cell recordings from which we derived excitatory and inhibitory conductances. We show that the basic EI property in the majority of IC cells is inherited from lateral superior olive, but that each type of EI cell is also innervated by the ipsilateral or contralateral dorsal nucleus of the lateral lemniscus, as well as additional excitatory and inhibitory inputs from monaural nuclei. We identify three EI types, each of which receives a set of projections that is different from the other types. To evaluate the role that the various projections played in generating binaural responses, we used modeling to compute a predicted response from the conductances. We then omitted one of the conductances from the computation to evaluate the degree to which that input contributed to the binaural response. We show that the formation of the EI property in the various types is complex, and that some projections exert such subtle influences that they could not have been detected with extracellular recordings or even from intracellular recordings of postsynaptic potentials.

Resolution of ITD detection: stochastic vs. exquisite system

Differences in arrival times of a sound at the two ears (Interaural Time Differences, ITDs) are utilized by mammals to determine the location of low-frequency sound source in the horizontal dimension [4]. Simple calculation shows that to achieve psychophysically revealed accuracy of sound localization, binaural auditory system have to detect ITDs in the order of just a few tens of microseconds. It has long been assumed that such remarkable temporal resolution is the result of ITD encoding by systematically organized arrays of fast neurons - “coincidence detectors” that receive inputs from the two ears via axons of variable length - “delay lines” and create a neural “map” of physiological ITDs. However, despite its wide acceptance, an increasing number of recent morphological and physiological studies in mammals report findings that can not be interpreted in the framework of this classical coincidence detector concept (reviewed in [2]). Therefore, neural mechanisms of the mammalian auditory system underlying high-resolution ITD detection are still not fully understood. Here, we continue to consider an alternative ITD detection mechanism based on a population coding strategy [5], according to which ITDs are encoded by the relative “activity” levels within bilaterally located populations of binaural sluggish (slow) neurons. To implement studied ITD detection mechanism we employ biologically inspired computational model that simulates the behavior of two symmetric neural populations of the auditory system. Every single neuron model of each population has membrane time constant of >1 ms and receives the balanced excitatory-inhibitory (EI) synaptic inputs carrying ITD. The parameters of neuron [3] and synapse [1] models are turned to mimic pure trough-type activity of EI neurons, i.e., no (or minimal) responses occur when “ipsilateral” excitation and “contralateral” inhibition are near coincidence. Our previous theoretical and modeling studies have shown that precise distribution (oppositely directed linear gradients) of the conductance value of excitatory and inhibitory synapses within each population allows the proposed model to detect ITD with submillisecond precision. It was also revealed that presence of jitter (related to the dynamic travel time deviation of ipsi- and contralateral signals) or neuronal noise from the physiological range does not have dramatic influence on ITD detection accuracy. In this work, we focus on the further analysis of stochastic and noise processes in the auditory system and present a computational evidence indicating the necessity to reassess the role of stochasticity in ITD processing. We demonstrate that microsecond order resolution of ITD detection, based on the population coding mechanism, can be accomplished by the auditory system without exquisite tunings of synapses or/and axon lengths. It is also shown that biologically relevant levels of both intrinsic neuronal noise and random time jitter in the synaptic input underlie ITD detection acuity similar to that observed in the model with a precise as well as a random balance of excitatory and inhibitory synaptic inputs. Thus, the results suggest that the considered stochastic processes can play crucial role as complementary/replaceable sources of “perturbation” for the sluggish neuron based populations; that is needed for high-resolution ITD detection.

Bioassay-Guided Evaluation of Antinociceptive Effect ofN-Salicyloyltryptamine: A Behavioral and Electrophysiological Approach

We investigated the antinociceptive and nerve excitability effects of the N-salicyloyltryptamine (NST) NST-treated mice exhibited a significant decrease in the number of writhes when 100 and 200 mg/kg (i.p.) were administered (i.p.). This effect was not antagonized by naloxone (1.5 mg/kg, i.p.). NST inhibited the licking response of the injected paw when 100 and 200 mg/kg were administered (i.p.) to mice in the first and second phases of the formalin test. Because the antinociceptive effects could be associated with neuronal excitability inhibition, we performed the single sucrose gap technique and showed that NST (3.57 mM) significantly reduced (29.2%) amplitude of the compound action potential (CAP) suggesting a sodium channel effect induced by NST. Our results demonstrated an antinociceptive activity of the NST that could be, at least in part, associated to the reduction of the action potential amplitude. NST might represent an important tool for pain management.

Suppression of neuronal excitability by the secretion of the lamprey (Lampetra japonica) provides a mechanism for its evolutionary stability

Lampreys are one of the most primitive vertebrates still living today. They attach themselves to the body surface of the host fish through their sucker-like mouths and suck blood of the host for days. Recent fossil evidence has indicated that morphology of lampreys in the late Devonian period, over 360 million years ago, already possessed the present day major characteristics, suggesting the evolutionary stability of a highly specialized parasitic feeding habit. Obviously, nociceptive responses and hemostasis of the host are two major barriers to long-term feeding of the parasitic lamprey. It has been found, to counteract hemostasis of the host, that paired buccal glands of lampreys secrete antihemostatic compounds to prevent blood of the host from coagulation. However, it is not known how lampreys make the host lose nociceptive responses. Here, we prepared components of the crude extract from the buccal glands of the lampreys (Lampetra japonica). Then, we show that crude extract and one of its purified components reduce the firing frequency of neuronal action potentials probably through inhibiting the voltage-dependent Na(+) channels. As the voltage-gated Na(+) channels are highly conserved throughout evolution, we argue that the secretion of the lampreys could exert the similar effect on the Na(+) channels of their host fish as well. Therefore, together with its antihemostatic effect, the secretion due to its inhibitory effect on neuronal excitability might provide a mechanism for the parasitic lampreys to keep their evolutionary stability.

Antinociceptive Activity of (-)-Carvone: Evidence of Association with Decreased Peripheral Nerve Excitability

(-)-Carvone is a monoterpene ketone that is the main active component of Mentha plant species like Mentha spicata. This study aimed to investigate the antinociceptive activity of (-)-carvone using different experimental models of pain and to investigate whether such effects might be involved in the nervous excitability elicited by others monoterpenes. In the acetic acid-induced writhing test, we observed that (-)-carvone-treated mice exhibited a significant decrease in the number of writhes when 100 and 200 mg/kg was administered. It was also demonstrated that (-)-carvone inhibited the licking response of the injected paw when 100 and 200 mg/kg was administered (i.p.) to mice in the first and second phases of the formalin test. Since naloxone (5 mg/kg, s.c.), an opioid antagonist, showed no influence on the antinociceptive action of (-)-carvone (100 mg/kg), this suggested nonparticipation of the opioid system in the modulation of pain induced by (-)-carvone. Such results were unlikely to be provoked by motor abnormality, since (-)-carvone-treated mice did not exhibit any performance alteration on the Rota-rod apparatus. Because the antinociceptive effects could be associated with neuronal excitability inhibition, we performed the single sucrose gap technique and observed that (-)-carvone (10 mM) was able to reduce the excitability of the isolated sciatic nerve through a diminution of the compound action potential amplitude by about 50% from control recordings. We conclude that (-)-carvone has antinociceptive activity associated with decreased peripheral nerve excitability.

Dissociated lateralization of transient and sustained blood oxygen level-dependent signal components in human primary auditory cortex

Among other auditory operations, the analysis of different sound levels received at both ears is fundamental for the localization of a sound source. These so-called interaural level differences, in animals, are coded by excitatory-inhibitory neurons yielding asymmetric hemispheric activity patterns with acoustic stimuli having maximal interaural level differences. In human auditory cortex, the temporal blood oxygen level-dependent (BOLD) response to auditory inputs, as measured by functional magnetic resonance imaging (fMRI), consists of at least two independent components: an initial transient and a subsequent sustained signal, which, on a different time scale, are consistent with electrophysiological human and animal response patterns. However, their specific functional role remains unclear. Animal studies suggest these temporal components being based on different neural networks and having specific roles in representing the external acoustic environment. Here we hypothesized that the transient and sustained response constituents are differentially involved in coding interaural level differences and therefore play different roles in spatial information processing. Healthy subjects underwent monaural and binaural acoustic stimulation and BOLD responses were measured using high signal-to-noise-ratio fMRI. In the anatomically segmented Heschl's gyrus the transient response was bilaterally balanced, independent of the side of stimulation, while in opposite the sustained response was contralateralized. This dissociation suggests a differential role at these two independent temporal response components, with an initial bilateral transient signal subserving rapid sound detection and a subsequent lateralized sustained signal subserving detailed sound characterization.

Sensory Neuroscience: From Skin to Object in the Somatosensory Cortex

Humans can perceive the shape of objects by touch alone, by extracting geometric features such as edges. Recently recorded responses of single neurons in the secondary somatosensory cortex of monkeys suggest how the brain integrates tactile shape information across different regions of skin and builds up a representation of tactile objects.

Graded Regulation of the Kv2.1 Potassium Channel by Variable Phosphorylation

Dynamic modulation of ion channels by phosphorylation underlies neuronal plasticity. The Kv2.1 potassium channel is highly phosphorylated in resting mammalian neurons. Activity-dependent Kv2.1 dephosphorylation by calcineurin induces graded hyperpolarizing shifts in voltage-dependent activation, causing suppression of neuronal excitability. Mass spectrometry-SILAC (stable isotope labeling with amino acids in cell culture) identified 16 Kv2.1 phosphorylation sites, of which 7 were dephosphorylated by calcineurin. Mutation of individual calcineurin-regulated sites to alanine produced incremental shifts mimicking dephosphorylation, whereas mutation to aspartate yielded equivalent resistance to calcineurin. Mutations at multiple sites were additive, showing that variable phosphorylation of Kv2.1 at a large number of sites allows graded activity-dependent regulation of channel gating and neuronal firing properties.

Changes of K +–Cl − cotransporter 2 (KCC2) and circuit activity in propofol-induced impairment of long-term potentiation in rat hippocampal slices

Enhancing inhibition via gamma-aminobutyric acid type A (GABA A) receptors contributes to anesthetic-induced impairment of long-term potentiation (LTP) of excitatory synaptic transmission, which may account for general anesthesia-associated memory impairment (amnesia). The neuron-specific K +–Cl − cotransporter 2 (KCC2) is necessary for fast synaptic inhibition via maintaining the low intracellular chloride concentration required for the hyperpolarizing actions of GABA via GABA A receptors. To explore a possible role of KCC2-dependent inhibition in anesthetic-induced impairment of LTP, we used field excitatory postsynaptic potentials (fEPSP) recording and immunoblotting to study the effect of propofol on LTP maintenance and KCC2 expression in CA1 region of rat hippocampal slices. We found that propofol (30 μM) not only impaired LTP expression but also prevented LTP-accompanied downregulation of KCC2 without affecting the basal transmission of glutamatergic synapses. Moreover, the recurrent inhibition in hippocampal slices was enhanced by propofol. These propofol-induced effects were completely abolished by picrotoxin, a specific GABA A receptor-chloride channel blocker. Thus, enhancement of GABAergic inhibition and suppression of neuronal excitability may account for the sustained expression of KCC2 and the impairment of LTP by propofol. Together, this study supports a novel role for KCC2 in LTP expression and gives hints to a molecular mechanism, by which anesthetics might cause impairment of LTP.

Opioids, the Enteric Nervous System, and Postoperative Ileus

Postoperative ileus, which is characterized by quiescence of the intestinal musculature, reflects the operation of a neural program in the enteric nervous system (ENS) in which the synapses that form the propulsive motor circuits are “locked” into an inactive state. In the inactive state, a component of the inhibitory motor innervation of the musculature remains active, and as a consequence, responsiveness of the muscle to electrical signals from pacemaker cells called interstitial cells of Cajal is suppressed. Physiological ileus is the normal absence of motility that occurs for varying lengths of time in different digestive states. Physiological motor quiescence becomes pathological when the synapses in the neural microcircuits for the motor programs in the ENS program library are rendered inoperative for abnormally long periods. In this state of paralytic ileus, the basic circuits are “locked” in an inactive state, while unremitting activity of inhibitory motor neurons continuously suppresses autogenic muscular activity. Release and actions of endogenous opioid peptides within the ENS inactivate the synaptic microcircuits and might account for the accompanying paralytic ileus. This hypothesis is based in part on the known actions of opioid peptides and opiates on the cellular neurophysiology of enteric neurons. The prototype opiate is morphine, which acts to delay gastric emptying and intestinal transit, to suppress intestinal secretion of water and electrolytes, and to suppress transport of bile into the duodenum—all of which are related to suppression of neuronal excitability and synaptic transmission in the ENS.

Furosemide and Mannitol Suppression of Epileptic Activity in the Human Brain

Most research on basic mechanisms of epilepsy and the design of new antiepileptic drugs has focused on synaptic transmission or action potential generation. However, a number of laboratory studies have suggested that nonsynaptic mechanisms, such as modulation of electric field interactions via the extracellular space (ECS), might also contribute to neuronal hypersynchrony and epileptogenicity. To date, a role for nonsynaptic modulation of epileptic activity in the human brain has not been investigated. Here we studied the effects of molecules that modulate the volume and water content of the ECS on epileptic activity in patients suffering from neocortical and mesial temporal lobe epilepsy. Electrophysiological and optical imaging data were acquired from the exposed cortices of anesthetized patients undergoing surgical treatment for intractable epilepsy. Patients were given a single intravenous injection containing either 20 mg furosemide (a cation-chloride cotransporter antagonist) or 50 g mannitol (an osmolyte). Furosemide and mannitol both significantly suppressed spontaneous epileptic spikes and electrical stimulation-evoked epileptiform discharges in all subjects, completely blocking all epileptic activity in some patients without suppressing normal electroencephalographic activity. Optical imaging suggested that the spread of electrical stimulation-evoked activity over the cortex was significantly reduced by these treatments, but the magnitude of neuronal activation near the stimulating electrode was not diminished. These results suggest that nonsynaptic mechanisms play a critical role in modulating the epileptogenicity of the human brain. Furosemide and other drugs that modulate the ECS might possess clinically useful antiepileptic properties, while avoiding the side effects associated with the suppression of neuronal excitability.

Roles of inhibition for transforming binaural properties in the brainstem auditory system

This review is concerned with the operation of circuits in the central auditory system, how they transform response features and what functional significance may be attributed to those transformations. We focus on the role that GABAergic inhibition plays in processing interaural intensity disparities (IIDs), the principal cues for localizing high frequencies, and the transformations of IID coding that occur between the superior olivary complex and the inferior colliculus (IC). IIDs are coded by excitatory–inhibitory (EI) cells, so called because they are excited by one ear and inhibited by the other. EI neurons are first created in the lateral superior olive (LSO), but they also dominate the dorsal nucleus of the lateral lemniscus (DNLL) and regions of the IC. The three nuclei are intimately linked through a complex arrangement of excitatory and inhibitory connections. One of these is a crossed excitatory projection from the LSO to both the DNLL and IC. The binaural properties of EI neurons in LSO, DNLL and IC appear strikingly similar, suggesting that the EI properties created in the LSO are simply imposed on the DNLL and IC through the crossed excitatory projections. Recent studies support the idea that EI properties created in lower centers are imposed on some IC cells. However, other studies show that the circuitry linking LSO, DNLL and IC generates a number of response transformations in many IC cells. These transformations include marked changes in EI properties with stimulus duration, the generation of highly focused spatial receptive fields, shifts in sensitivity to IIDs, and the de novo creation of the EI response property. All of these transformations are produced by inhibitory innervation of the IC. An additional emergent property is also imposed on IC cells that receive GABAergic innervation from the DNLL. That property is a change in the binaural features of the IC cell, a change produced by the reception of an earlier sound whose IID is strongly excitatory to the IC cell. We illustrate each of these transformations, propose circuitry that could account for the observed properties and suggest some functional relevance for each. In the final section, we discuss some of the inherent uncertainties associated with attributing functional consequences to response features and then consider whether the transformations found in some mammals are species-specific or are universal features of all mammals.

2-Deoxy- d-glucose attenuates harmaline induced tremors in rats

Neuronal hyperactivity in essential tremor is accompanied by high energy demand in cerebellum, medulla and the thalamus. It has been suggested that brain regions that have increased metabolic demands are highly vulnerable to interruptions in glucose metabolism. In the present investigation attempt was made to study the effect of 2-deoxyglucose (2DG) a glycolytic pathway inhibitor on harmaline induced tremor in rats. Wistar rats of either sex weighing 100±3 g were given harmaline (10 mg/kg, i.p.) alone or along with 2DG (15 min before harmaline) in doses of 300, 600 and 900 mg/kg, respectively. The latency of onset, intensity and duration of tremor following harmaline administration were recorded. Neurobehavioral responses, electromyography (EMG) and levels of blood glucose and cerebellar serotonin (5HT) were determined after 40 min of harmaline administration. 2DG significantly and dose dependently attenuated severity of harmaline induced tremors and amplitude of EMG. Treatment of rats with 2DG alone reduced the locomotor activity, however, no significant change was observed in grip strength, landing foot splay, air righting reflex and response to tactile stimuli. Harmaline alone and along with 2DG had no effect on behavioral parameters except a decrease in landing foot splay. 2DG produced a dose-dependent hyperglycemia and attenuated harmaline induced increase in cerebellar 5HT levels. Our results clearly suggest the protective effect of 2DG in harmaline induced tremor. Further studies are warranted to assess the role of glucoprivation in the suppression of neuronal excitability in tremors.