Zinc modulates a-type potassium currents and neuronal excitability in snail neurons

Summary 1. Zinc-induced actions were studied on the A-current and neuronal activity in identified and unidentified nerve cells of the snail,Helix pomatia L., under voltage and current clamp conditions.2. Extracellularly applied Zn²⁺ attenuated the peak amplitude of the A-current in a potential- and dose-dependent way (K _i=1.8 mM at –30 mV,n _H=0.6).3. Attenuation of the A-currents was initiated as Zn²⁺ shifted the potential dependence of both activation and inactivation of the currents toward more positive potential values.4. Zinc concomitantly prolonged the time to peak and decay time constant of the A-currents (K _d=1.7 mM,n _H=1.4) as well.5. Zn²⁺ decreased the resting membrane potential and the spike amplitude and increased the action potential duration and the input resistance of the cells in current clamp experiments.6. A complex action of zinc increased the neuronal excitability, indicating spontaneous and synaptically evoked spike discharges.7. Common and specific zinc binding sites are supposed on vertebrate and invertebrate A-type potassium channel proteins, where binding Zn²⁺ can modulate the gating properties and kinetics of the fast outward potassium currents.     

glide/gcm: at the crossroads between neurons and glia

Neurons and glia are generated by multipotent precursors. Recent studies indicate that the choice between the two fates depends on the combined activity of extracellular influences and factors that respond to precise spatial and temporal cues. Drosophila provides a simple genetic model to study the cellular and molecular mechanisms controlling fate choice, mode of precursor division and generation of cell diversity. Moreover, all glial precursors and glial-promoting activities have been identified in Drosophila, which provides us with a unique opportunity to dissect regulatory pathways controlling glial differentiation and specification.     

Signaling between glia and neurons: focus on synaptic plasticity

Glial cells are now emerging from the shadows cast by their more excitable CNS counterparts. Within the developing nervous system, astrocytes and Schwann cells actively help to promote synapse formation and function, and have even been implicated in synapse elimination. In the adult brain, astrocytes respond to synaptic activity by releasing transmitters that modulate synaptic activity. Thus, glia are active participants in brain function. Many questions remain about the identity of glial-neuronal signals and their significance.     

Dye-filling of the amphid sheath glia: implications for the functional relationship between sensory neurons and glia in Caenorhabditis elegans

The nervous system is composed of cells including neurons and glia. It has been believed that the former cells play central roles in various neural functions while the latter ones have only supportive functions for neurons. However, recent findings suggest that glial cells actively participate in neural activities, and the cooperation between neurons and glia is important for nervous system functions. In Caenorhabditis elegans, amphid sensory organs in the head also consist of sensory neurons and glia-like support cells (amphid socket and amphid sheath cells). Ciliary endings of some sensory neurons exposed to the environment detect various chemicals, molecules and signals, and the cilia of some neurons can also take up fluorescent dyes such as DiI. Here, we show that the amphid sheath glia are also stained with DiI and that its uptake by the amphid sheath cells correlates with DiI-filling of sensory neurons, suggesting that the amphid sheath glia might interact with sensory neurons. Furthermore, the localization of the amphid sheath cell reporter F52E1.2SP::YFP is abnormal in che-2 mutants, which have defective cilia. These findings imply that sensory neurons might affect amphid sheath glia functions in the amphid sensory organ of C. elegans.     

Chemokine CCL2 modulation of neuronal excitability and synaptic transmission in rat hippocampal slices

In addition to its well-characterized effects in immune system, chemokine CC motif ligand 2 (CCL2, formerly known as monocyte chemoattractant protein-1) is believed to play an important role in brain physiological and pathological processes. It has been shown that CCL2 and its cognate receptor chemokine CC motif receptor 2 are constitutively expressed in several brain regions including the hippocampus, and the expression is up-regulated under pathological conditions. Whereas most investigations have so far focused on its involvement in CNS pathology, few studies have examined the effects of CCL2 on neuronal and synaptic physiology. In this study, we tested the effects of CCL2 on neuronal excitability and excitatory synaptic transmission in the CA1 region of rat hippocampal slices using whole-cell patch clamp techniques. Bath application of CCL2 depolarized membrane potential and increased spike firing in CA1 neuronal cells. Bath application of CCL2 also produced an increase of excitatory post-synaptic currents recorded in Schaffer-collateral fibers to CA1 synapses. Quantal analysis revealed that CCL2 increased the frequency of spontaneous excitatory post-synaptic current occurrence and mean quantal content. Taken together, our data indicate that CCL2 enhances neuronal excitability and synaptic transmission via pre-synaptic mechanisms. These results support the emerging concept that chemokines function as neuromodulators in the CNS.     

Gap-like junctions between neurons and glia in the superior colliculus of mammals

The neuron cell bodies and glia cells are separated by a narrow intercellular cleft of 200 A. We present here evidence that perikarya neuronal and perineuronal glia of the superior colliculus of the Oryctolagus Cuniculus communicate through gap-like junctions according to ultrastructural parameters. These junctions would mean some degree of electronic coupling between neuron cell bodies and perineuronal glia cells.     

Outside and in: development of neuronal excitability

Investigation of the development of excitability has revealed that cells are often specialized at early stages to generate Ca(2+) transients. Studies of excitability have converged on the central role of Ca(2+) and K(+) channels in the plasmalemma that regulate Ca(2+) influx and have identified critical functions for receptor-activated channels in the endoplasmic reticulum that allow efflux of Ca(2+) from intracellular stores. The parallels between excitability in these two locations motivate future work, because comparison of their properties identifies shared attributes.     

Calretinin: Modulator of neuronal excitability

Calretinin is a member of the calcium-binding protein EF-hand family first identified in the retina. As with the other 200-plus calcium-binding proteins, calretinin serves a range of cellular functions including intracellular calcium buffering, messenger targeting, and is involved in processes such as cell cycle arrest, and apoptosis. Calcium-binding proteins including calretinin are expressed differentially in neuronal subpopulations throughout the vertebrate and invertebrate nervous system and their expression has been used to selectively target specific cell types and isolate neuronal networks. More recent experiments have revealed that calretinin plays a crucial role in the modulation of intrinsic neuronal excitability and the induction of long-term potentiation (LTP). Furthermore, selective knockout of calretinin in mice produces disturbances of motor coordination and suggests a putative role for calretinin in the maintenance of calcium dynamics underlying motor adaptation.     

Decreased neuronal excitability in hippocampal neurons of mice exposed to cyclic hypoxia.

To study the physiological effects of chronic intermittent hypoxia on neuronal excitability and function in mice, we exposed animals to cyclic hypoxia for 8 h daily (12 cycles/h) for approximately 4 wk, starting at 2-3 days of age, and examined the properties of freshly dissociated hippocampal neurons in vitro. Compared with control (Con) hippocampal CA1 neurons, exposed (Cyc) neurons showed action potentials (AP) with a smaller amplitude and a longer duration and a more depolarized resting membrane potential. They also have a lower rate of spontaneous firing of AP and a higher rheobase. Furthermore, there was downregulation of the Na(+) current density in Cyc compared with Con neurons (356.09 +/- 54.03 pA/pF in Cyc neurons vs. 508.48 +/- 67.30 pA/pF in Con, P < 0.04). Na(+) channel characteristics, including activation, steady-state inactivation, and recovery from inactivation, were similar in both groups. The deactivation rate, however, was much larger in Cyc than in Con (at -100 mV, time constant for deactivation = 0.37 +/- 0.04 ms in Cyc neurons and 0.18 +/- 0.01 ms in Con neurons). We conclude that the decreased neuronal excitability in mice neurons treated with cyclic hypoxia is due, at least in part, to differences in passive properties (e.g., resting membrane potential) and in Na(+) channel expression and/or regulation. We hypothesize that this decreased excitability is an adaptive response that attempts to decrease the energy expenditure that is used for adjusting disturbances in ionic homeostasis in low-O(2) conditions.     

Carnosine-related dipeptides in neurons and glia

Carnosine-related dipeptides have been demonstrated to occur in the nervous tissue of many vertebrates, including humans. Although several hypotheses have been formulated, to date their precise physiological role in the nervous system remains unknown. This article will review the studies on the presence and distribution of these dipeptides in the nervous system of different classes of vertebrates. It will focus on the most recent data on their cellular localization and potential functions in mammals. The studies on localization of carnosine-related dipeptides show a complex pattern of expression that involves both neuronal and glial cell types. The glial localization, widely distributed throughout the whole brain and spinal cord, includes a subset of both mature astrocytes and oligodendrocytes, whereas the neuronal localization is restricted to a particular type of neurons (the olfactory receptor neurons), and to restricted populations of putative migrating neurons and neuroblasts. There is no definitive demonstration of the function of these dipeptides in the various cell types. However, a wide array of evidence suggests that carnosine-related dipeptides could act as natural protective agents. Moreover, recent studies have suggested that, as previously postulated for the olfactory receptor neurons, in mature functional glial cells as well, carnosine-related dipeptides could be implicated in a neuromodulatory functional mechanism.     

Maturation of neuronal excitability in hippocampal neurons of mice chronically exposed to cyclic hypoxia

To examine the effects of chronic cyclichypoxia on neuronal excitability and function in mice, we exposed miceto cyclic hypoxia for 8 h daily (9 cycles/h) for ~2 wk (startingat 2-3 days of age) and examined the properties of freshlydissociated hippocampal neurons obtained from slices. Compared withcontrol (Con) hippocampal CA1 neurons, exposed neurons (CYC) hadsimilar resting membrane potentials (V_m) andaction potentials (AP). CYC neurons, however, had a lower rheobase thanCon neurons. There was also an upregulation of the Na⁺current density (333 ± 84 pA/pF, n = 18) in CYCcompared with that of Con neurons (193 ± 20 pA/pF,n = 27, P < 0.03). Na⁺channel characteristics were significantly altered by hypoxia. Forexample, the steady-state inactivation curve was significantly morepositive in CYC than in Con (60 ± 6 mV, n = 8, for CYC and 71 ± 3 mV, n = 14, for Con,P < 0.04). The time constant for deactivation(_d) was much shorter in CYC than in Con (at 100 mV,_d=0.83 ± 0.23 ms in CYC neurons and 2.29 ± 0.38 ms in Con neurons, P = 0.004). We conclude thatthe increased neuronal excitability in mice neurons treated with cyclichypoxia is due to alterations in Na⁺ channelcharacteristics and/or Na⁺ channel expression. Wehypothesize from these and previous data from our laboratory (Gu XQ andHaddad GG. J Appl Physiol 91: 1245-1250, 2001) that thisincreased excitability is a reflection of an enhanced central nervoussystem maturation when exposed to low O₂ conditions inearly postnatal life.

     

The Kv4.2 mediates excitatory activity-dependent regulation of neuronal excitability in rat cortical neurons

Neuronal excitability can cooperate with synaptic transmission to control the information storage. This regulation of neuronal plasticity can be affected by alterations in neuronal inputs and accomplished by modulation of voltage-dependent ion channels. In this study, we report that enhanced excitatory input negatively regulated neuronal excitability. Enhanced excitatory input by glutamate, electric field stimulation or high K⁺ increased transient outward K⁺ current, whereas did not affect the delayed rectifier K⁺ current in rat cultured cortical neurons. Both the voltage-dependent K⁺ channel 4.2 and 4.3 subunits contributed to the increase. The increase in the K⁺ current density by Kv4.2 was ascribed to its cytoplasmic membrane translocation, which was mediated by NMDA type of glutamate receptor. Furthermore, enhanced excitatory input inhibited neuronal excitability. Taken together, our results suggest that excitatory neurotransmission affects neuronal excitability via the regulation of the K⁺ channel membrane translocation.     

Carboxylation and anaplerosis in neurons and glia

Anaplerosis, or de novo formation of intermediates of the tricarboxylic acid (TCA) cycle, compensates for losses of TCA cycle intermediates, especially α-ketoglutarate, from brain cells. Loss of α-ketoglutarate occurs through release of glutamate and GABA from neurons and through export of glutamine from glia, because these amino acids are α-ketoglutarate derivatives. Anaplerosis in the brain may involve four different carboxylating enzymes: malic enzyme, phosphoenopyruvate carboxykinase (PEPCK), propionyl-CoA carboxylase, and pyruvate carboxylase. Anaplerotic carboxylation was for many years thought to occur only in glia through pyruvate carboxylase; therefore, loss of transmitter glutamate and GABA from neurons was thought to be compensated by uptake of glutamine from glia. Recently, however, anaplerotic pyruvate carboxylation was demonstrated in glutamatergic neurons, meaning that these neurons to some extent can maintain transmitter synthesis independently of glutamine. Malic enzyme, which may carboxylate pyruvate, was recently detected in neurons. The available data suggest that neuronal and glial pyruvate carboxylation could operate at as much as 30% and 40–60% of the TCA cycle rate, respectively. Cerebral carboxylation reactions are probably balanced by decarboxylation reactions, because cerebral CO₂ formation equals O₂ consumption. The finding of pyruvate carboxylation in neurons entails a major revision of the concept of the glutamine cycle.     

Regulation of intrinsic excitability in hippocampal neurons by activity-dependent modulation of the KV2.1 potassium channel

K_V2.1 is the prominent somatodendritic sustained or delayed rectifier voltage-gated potassium (Kv) channel in mammalian central neurons, and is a target for activity-dependent modulation via calcineurin-dependent dephosphorylation. Using hanatoxin-mediated block of K_V2.1 we show that, in cultured rat hippocampal neurons, glutamate stimulation leads to significant hyperpolarizing shifts in the voltage-dependent activation and inactivation gating properties of the K_V2.1-component of delayed rectifier K⁺ (IK) currents. In computer models of hippocampal neurons, these glutamate-stimulated shifts in the gating of the K_V2.1-component of IK lead to a dramatic suppression of action potential firing frequency. Current-clamp experiments in cultured rat hippocampal neurons showed glutamate-stimulation induced a similar suppression of neuronal firing frequency. Membrane depolarization also resulted in similar hyperpolarizing shifts in the voltage-dependent gating properties of neuronal IK currents, and suppression of neuronal firing. The glutamate-induced effects on neuronal firing were eliminated by hanatoxin, but not by dendrotoxin-K, a blocker of K_V1.1-containing channels. These studies together demonstrate a specific contribution of modulation of K_V2.1 channels in the activity-dependent regulation of intrinsic neuronal excitability.