Effects Of Synaptic Activity Research Articles

Potassium channel Kv2.1 is regulated through protein phosphatase-1 in response to increases in synaptic activity

The functional stability of neurons in the face of large variations in both activity and efficacy of synaptic connections suggests that neurons possess intrinsic negative feedback mechanisms to balance and tune excitability. While NMDA receptors have been established to play an important role in glutamate receptor-dependent plasticity through protein dephosphorylation, the effects of synaptic activation on intrinsic excitability are less well characterized. We show that increases in synaptic activity result in dephosphorylation of the potassium channel subunit Kv2.1. This dephosphorylation is induced through NMDA receptors and is executed through protein phosphatase-1 (PP1), an enzyme previously established to play a key role in regulating ligand gated ion channels in synaptic plasticity. Dephosphorylation of Kv2.1 by PP1 in response to synaptic activity results in substantial shifts in the inactivation curve of IK, resulting in a reduction in intrinsic excitability, facilitating negative feedback to neuronal excitability.

Neurons and Glia Talk Amongst Themselves

Voutsinos-Porche et al. used mutant mice lacking glial glutamate transporters to study the effects of synaptic activity on glucose utilization by astrocytes and discovered evidence for metabolic crosstalk between neurons and astrocytes through a mechanism involving glial glutamate uptake and the ensuing changes in glial intracellular Na + concentration [Na + ] i . Astrocytes have long been suspected of contributing to the metabolic support of neurons, but there has been little direct evidence. Mutant mice lacking one or the other of the glial glutamate transporters GLAST or GLT-1 showed reduced 2-deoxyglucose (2-DG) accumulation (a measure of glycolytic activity) in somatosensory cortex after whisker stimulation. In primary cultures, cortical astrocytes from GLAST − mice showed reduced uptake of the nonmetabolized glutamate analog aspartate, as well as reduced stimulation of 2-DG uptake and of lactate release after exposure to glutamate. A glutamate-dependent increase in [Na + ] i secondary to Na + cotransport with glutamate was also attenuated. The increase in 2-DG uptake and lactate release in response to glutamate were restored by pharmacological manipulation with cyclothiazide to stimulate glutamate-dependent Na + influx through the L-α-amino-3-hydroxy-5-methylisoxazole-4-propionate (AMPA) receptor. The effect of cyclothiazide was abolished in medium in which lithium, which cannot replace Na + on the Na + ,K + -ATPase, was substituted for Na + . The authors proposed a model in which activation of glial Na + ,K + -ATPase by increased [Na + ] i promotes enhanced glycolysis and lactate output. The lactate is then available as an additional energy source for the firing neurons that released the glutamate. B. Voutsinos-Porche, G. Bonvento, K. Tanaka, P. Steiner, E. Walker, J.-Y. Chatton, P. J. Magistretti, L. Pellerin, Glial glutamate transporters mediate a functional metabolic crosstalk between neurons and astrocytes in the mouse developing cortex. Neuron 37 , 275-286 (2003). [Online Journal]

Synaptic activation of slow depolarization in rat supraoptic nucleus neurones in vitro.

1. The effects of synaptic activation on rat supraoptic nucleus (s.o.n.) neurones were studied in the hypothalamic slice preparation. Intracellular recordings were obtained from forty-one probable magnocellular neuroendocrine cells using microelectrodes filled with 3 M-potassium acetate. Responses to single and repetitive stimulation of the area dorsolateral to the s.o.n., which would be expected to activate a cholinergic pathway (Hatton, Ho & Mason, 1983), were analysed. 2. In forty of forty-one cells, responses to single stimuli consisted of a short-latency excitatory post-synaptic potential (e.p.s.p.), which was often followed by a brief burst of fast depolarizing events which resembled spontaneous e.p.s.p.s. When the membrane was depolarized, single stimuli could consistently produce a burst of action potentials. 3. Brief trains of orthodromic stimuli produced three effects in most cells. Spontaneous fast depolarizing events, which appeared to be primarily e.p.s.p.s. significantly increased in frequency after the train. A slow membrane depolarization, which lasted up to 1-2 min, was observed in twenty-eight of forty-one cells. In several cells the slow depolarization was accompanied by an increase in input resistance (Ri). In some cells an after-discharge occurred during the slow depolarization. Slow depolarizations were observed in each of eleven phasic neurones, and in a smaller percentage of non-phasic and silent cells. 4. All components of the response to dorsolateral stimulation could be reduced or blocked in low-Ca2+, high-Mg2+ bathing medium. 5. Slow depolarizations were observed when action potentials were not elicited by the stimulus train. The slow depolarization was still present after manipulations that blocked discharge during the stimulus train, including injection of hyperpolarizing current and diffusion of the quaternary ammonium compound QX314. These data argue that the slow depolarization can occur independent of spike depolarizing after-potentials (d.a.p.s). 6. In some cells antidromic stimulation at an intensity just suprathreshold for the recorded cell did not produce comparable bursts of fast depolarizing events or slow depolarizations; similar periods of depolarizing current injection, which produced repetitive discharge, also did not mimic the effects of orthodromic stimulation. 7. The fast depolarizing events appear to reflect spontaneous e.p.s.p.s; increases in the frequency of these events may reflect the after-discharge of nearby neurones that are presynaptic to the recorded neurone.(ABSTRACT TRUNCATED AT 400 WORDS)

Effects of synaptic activity on the metabolism and release of purines in the rat superior cervical ganglion.

The release of radioactive metabolites from isolated rat superior cervical ganglia was measured under various conditions following preloading with 3H-adenosine. The 3H label was recovered primarily in the adenosine metabolites, ATP, ADP, AMP, IMP, and inosine, rather than in adenosine itself. Increased release was evoked by preganglionic stimulation or by exposure to a high-K+ medium, whereas in a low-Ca2+-high-Mg2+ medium, both spontaneous release and evoked release of most metabolites were inhibited. Exposure of the ganglion to an atmosphere of N2 also increased the release of most labeled metabolites, but this release was not substantially affected by a low-Ca2+ medium. The fluorescent derivatives of the endogenous adenine-containing compounds present in the ganglion were prepared from homogenates and separated by high-performance liquid chromatography (HPLC). By the end of the testing period (6 hr), levels of ATP in the isolated ganglia had dropped to 10-20% of the initial values, while levels of ADP, AMP, and adenosine increased. There was little difference in these values between nonstimulated ganglia and those exposed to N2 or to a high-K+ medium.

Effects of synaptic activation and serotonin application on the calcium current inHelix lucorum neurons

Changes in inward calcium current observed on the background of postsynaptic currents have been studied in snail neurons under voltage clamp conditions. It is shown that when inhibitory or excitatory postsynaptic current developed, the calcium current reversibly decreased. Application of serotonin to the neuronal soma has also led to a reversible block of the calcium current. Possible cellular mechanisms involved in the changes under study and their putative physiological role are discussed.

Prolonged changes in excitability of pyramidal tract neurones in the cat: a post‐synaptic mechanism.

1. Prolonged changes in the excitability of cortical neurones can be produced by altering their firing rates for brief periods. In the anaesthetized cat, increased firing of pyramidal tract cells induced by trains of antidromic conditioning shocks led to increases in cell excitability, as measured by the size of the mass response at the medullary pyramid to test shocks applied to the cortical surface. We have shown in two ways that post-synaptic mechanisms could be responsible. 2. In one experimental design, MgCl2 solution (1 mole/l.) was applied to the cortical surface in order to block synaptic activity throughout the cortical depth. Following antidromic conditioning trains, cell excitability was increased; the size of the mass response was up to 30% larger than the control values. This persisted undiminished for up to 3 hr. 3. In the second experimental design, synaptic activity was not blocked, but we compared the effects of antidromic plus synaptic activation of pyramidal tract cells with the effects of synaptic activation alone. Antidromic plus synaptic activation was obtained by applying conditioning trains to the pyramidal tract at the medulla ipsilateral to the cortical test shock; prolonged increases in the ipsilateral response to the test shock were produced. Synaptic activation alone was obtained by the same conditioning trains, but in those cells whose axons projected into the contralateral pyramidal tract; prolonged increases in the contralateral response to the cortical test shock were never seen. In many instances prolonged decreases in excitability were found. 4. We conclude that prolonged increases in excitability of pyramidal tract cells can occur in the absence of any synaptic input, demonstrating that the underlying mechanism is post-synaptic; this does not preclude the action of synaptic mechanisms when synaptic transmission is not blocked.

The effect of synaptic activation on the extracellular potassium concentration in the hippocampal dentate area, in vitro

Excitatory synaptic inputs to the granule cells of the dentate area elicit first of all EPSPs and then action potentials in the cells, giving rise to the characteristic extracellular field potentials referred to as the synaptic wave and population spike 13. The excitability of the cell population is easily altered by prior conditioning shocks or trains of shocks 1-~,9,13, though the mechanisms of these alterations are not fully understood. It is possible that potassium (K +) etttux from the granule cells might account for some of the alterations in excitability. It is already known that large increases in extracellular potassium concentration can accompany states of abnormal cortical function such as spreading depression 7,1°,17 and epilepsy 6. In this study we have used K+-sensitive microelectrodes 18 to show that there are detectable changes in the K + concentration around the dentate granule cells of the guinea pig hippocampus after synaptic activation of a well defined afferent pathway. We are not at present able to say whether such changes in fact account for changes in excitability of the cell population. Slices from the ventral surface of the hippocampus of guinea-pig brains were cut approximately 500 #m thick and maintained at 20-23 °C in vitro, cut surface uppermost, at the surface of an oxygenated saline solution (NaC1 124 mM, NaHCO3 24 mM, NaH2POa 1.25 mM, KC1 6 mM, CaCI2 4 mM, MgSOa 2 mM, glucose 10 mM) under an atmosphere of moist 95 ~o 02-5 ~ COz. The bath K + concentration is approximately twice that of brain extracellular fluidS,n; this high level has been employed by previous workers using similar techniques 4,15,~9, and in our hands it favours the occurrence of synaptic activation comparable to that seen in the intact hippocampus. Some nerve fibres do, however, behave abnormally in 6 mM potassium in vitro and normally in 3 mM potassium s. In the present experiments the pO2 is higher than in vivo and the temperature lower: both these conditions favour the survival of relatively thick slices with the least damage to cells. In view of the various

The effect of spike activity versus synaptic activation on the metabolism of ribonucleic acid in a molluscan giant neurone.

Abstract—Previous experiments on a giant neurone (R2) from Aplysia californica have shown that a prolonged electrical stimulation of ganglionic nerves, strong enough to elicit post‐synaptic spikes in the giant neurone, caused a marked increase in the uptake of labelled nucleosides into the neuronal RNA. The results described in the present paper very strongly indicate that these effects of synaptic activation were not due to the discharge of spikes in the giant neurone itself. Spikes which were directly elicited in the giant neurone by current pulses injected into the cell through an intracellular microelectrode had no significant effect on RNA labelling. Weak stimulation of ganglionic nerves, eliciting post‐synaptic potentials but few spikes in the giant neurone, produced a small but significant increase of RNA labelling.