Inhibitory transmission, activity-dependent ionic changes and neuronal network oscillations

Almost all theoretical and experimental studies of the mechanisms underlying learning and memory focus on synaptic efficacy and make the implicit assumption that changes in synaptic efficacy are both necessary and sufficient to account for learning and memory. However, network dynamics depends on the complex interaction between intrinsic membrane properties and synaptic strengths and time courses. Furthermore, neuronal activity itself modifies not only synaptic efficacy but also the intrinsic membrane properties of neurons. This paper presents examples demonstrating that neurons with complex temporal dynamics can provide short-term "memory" mechanisms that rely solely on intrinsic neuronal properties. Additionally, we discuss the potential role that activity may play in long-term modification of intrinsic neuronal properties. While not replacing synaptic plasticity as a powerful learning mechanism, these examples suggest that memory in networks results from an ongoing interplay between changes in synaptic efficacy and intrinsic membrane properties.

Neurons utilize bursts of action potentials as an efficient and reliable way to encode information. It is likely that the intrinsic membrane properties of neurons involved in burst generation may also participate in preserving its temporal features. Here we examined the contribution of the persistent and resurgent components of voltage-gated Na+ currents in modulating the burst discharge in sensory neurons. Using mathematical modeling, theory and dynamic-clamp electrophysiology, we show that, distinct from the persistent Na+ component which is important for membrane resonance and burst generation, the resurgent Na+ can help stabilize burst timing features including the duration and intervals. Moreover, such a physiological role for the resurgent Na+ offered noise tolerance and preserved the regularity of burst patterns. Model analysis further predicted a negative feedback loop between the persistent and resurgent gating variables which mediate such gain in burst stability. These results highlight a novel role for the voltage-gated resurgent Na+ component in moderating the entropy of burst-encoded neural information.

central nervous system and sensory inputs are essential for coordinated movement. Studies of central pattern generators have influenced profoundly the way we think about neurons, neuronal networks and their functional properties. It is clear, for example, that neuronal circuits can be reconfigured through the action of neuromodulatory neurons to produce a variety of outputs, and that intrinsic membrane properties of neurons are subject to homeostatic regulation. In this special issue, Marder and colleagues describe the effects of temperature on motor patterns generated by the stomatogastric nervous system of the crab, Cancer borealis, and consider how neuronal networks and the output they generate remain stable in the face of extreme temperature fluctuations. Temperature is a central focus also of the contribution from Xu and colleagues who consider the sophisticated mechanisms that have evolved to enable animals to sense and adapt to changes in temperature. In their review, these authors present a strongly comparative viewpoint, and their discussion offers fascinating insights into the effects of temperature on aging and longevity. Homeostasis, as an overarching theme, is central also to the contribution by Keene and colleagues, who discuss how the brain of the fruit fly modulates sleep and how sleep in this insect, and in other animals, is influenced by metabolic state. Insects have a long history in the study of sleep. Cockroaches, for example, were used to provide the first demonstration that animals show compensatory mechanisms after sleep loss (Campbell and Tobler, Neurosci Biobehav Rev 8:269–300, 1984), and the genetic mechanisms that underlie sleep and sleep disorders are now being investigated extensively using the fruit fly, Drosophila. Callaerts and colleagues use Drosophila to provide insights into the importance of glia in normal brain function. They explore what is, and what is not, known about This special issue celebrates excellent examples of invertebrate neuroscience. It has its origins in the Cold Spring Harbor Asia (CSHA) Conferences on invertebrate neurobiology held recently in Suzhou, China, and is designed to provide a ‘taster’ of some of the exciting works presented at these meetings. There are of course very many aspects of invertebrate neurobiology that have seen remarkable advances in recent years. This issue highlights a small number of interesting examples. The topics are as diverse as they are interesting, and illustrate well the excitement that exists in current invertebrate neuroscience. For many years, there has been intense interest in the neuronal circuits (central pattern generators, CPGs) that produce rhythmic motor patterns supporting activities such as feeding, walking, swimming, and breathing. Sakurai and Katz discuss the unique perspective that the study of gastropod CPGs brings to this field. One important emerging concept is that different and independently evolved circuits using the same set of neurons can generate the same behavior. Their contribution to this special issue illustrates beautifully the power of a comparative approach. This theme is expanded upon by Ayali and colleagues who discuss recent work on an important model of legged locomotion, the cockroach, Periplaneta americana. In their review, they emphasize that motor system activity is modulated by sensory information and that dynamic interactions between the

Even when deprived of sensory stimulation, neurons hum continuously. That is, their membrane potential fluctuates constantly and the depolarizing phase of these oscillations sometimes gives rise to action potentials. Interestingly, this spontaneous activity is not random. Correlated neuronal events, occurring in a pulsatile or oscillatory manner, can be measured in the extracellular space as currents. These events result from non-linear interactions between the intrinsic membrane properties of neurons and the particular properties of the synaptic network of which they are a part (Llinás, 1988). Oscillations in various frequency ranges are observed in different brain regions; these rhythms vary depending on the behavioural state (Buzsáki et al., 1983; Steriade, 1997a).

Information flow in neocortical circuits is regulated by two key parameters: intrinsic neuronal properties and the short-term activity-dependent plasticity of synaptic transmission. Using multineuronal whole-cell voltage recordings, we characterized the postnatal maturation of the electrophysiological properties and short-term plasticity of excitatory synaptic transmission between pairs of layer 5 (L5) pyramidal neurons (n = 158) in acute slices of rat visual cortex over the first postnatal month. We found that the intrinsic and synaptic properties of L5 pyramidal neurons develop in parallel. Before postnatal day 15 (P15), intrinsic electrophysiological properties were tuned to low-frequency operation, characterized by high apparent input resistance, a long membrane time constant, and prolonged somatic action potentials. Unitary excitatory synaptic potentials were of large amplitude (P11-P15; median, 514 μV), but showed pronounced use-dependent depression during prolonged regular and physiologically relevant presynaptic action potential firing patterns. In contrast, in mature animals we observed a developmental decline of the peak amplitude of unitary EPSPs (P25-P29; median, 175 μV) paralleled by a decrease in apparent input resistance, membrane time constant, and somatic action potential duration. Notably, synaptic signaling of complex action potential firing patterns was also transformed, with P25-P29 connections faithfully signaling action potential trains at frequencies up to 40 Hz (1st to 50th action potential ratio, 0.91 ± 0.12). Postnatal refinement of intrinsic properties and short-term plasticity therefore transforms the capacity of the L5 excitatory neural network of the visual cortex to generate and process patterns of action potential firing and contribute to network activity.

BackgroundThe molecular mechanisms leading to Alzheimer's disease (AD) are poorly known. This is due to the lack of human tissue samples for research representing early changes of AD pathology, raising a need for development of novel human‐based preclinical models for AD. Idiopathic normal pressure hydrocephalus (iNPH) is an neurodegenerative disease characterized by an impaired cerebrospinal fluid (CSF) clearance. iNPH is treated by a shunt surger to drain the excess CSF into the abdominal cavity. During the surgery, 10‐20mm3 Broadman area 8 biopsy can be excised by minimally invasive methods for preclinical studies. Due to the early AD‐related pathology present in a subpopulation of iNPH patients, the brains of these patients offer a unique window to evaluate cellular events taking place during the course of AD pathology progression.MethodWe have set up a pipeline to evaluate, in a layer and cell‐type dependent manner, the intrinsic neuronal operational properties in the iNPH biopsies. Our patch clamp and multi electrode array (MEA) studies show that these biopsies are viable and retain the required microcircuit to study network and synaptic function in human cortex. We have carried out integrative analysis of human neuronal electrophysiology at single neuron and network level followed by subsequent cellular morphological reconstructions to register the primary pathological changes in neuronal functions in correlation with existing AD‐related pathology.ResultThe presence of Aβ deposits induced a decrease in the L1‐induced inhibition and led to hyperexcitability in response to application of NMDA in MEA recordings. Interestingly, the global spine density of supraganular pyramidal neurons was increased in biopsies with AD‐related pathology. Pyramidal neurons in cases with both Aβ and tau exhibited more consistent deficits in the intrinsic neuronal properties with increase in sodium and potassium currents and a strong propensity to bursting under NMDA stimulation.ConclusionThis is the first study to show that the accumulation of Aβ and tau alters synaptic transmission and consolidation of a hyperexcitable supragranular cortical network. The iNPH biopsies provide a unique opportunity to unravel how AD‐related pathology alters neuronal network functionality in humans.

The ultrastructural basis of light-induced transmission and light scattering changes of thalli of Ulva and Porphyra were investigated by high resolution electron microscopy and microdensitometry. The results show that upon illumination of dark thalli (a) a reduction in thickness of thylakoid membranes (conformational change), (b) a more regular ordering, and (c) flattening of the thylakoids (configurational changes) have occurred. An explanation for the observed conformational and configurational changes was proposed in terms of correlated changes in ionic environment and osmotic properties of chloroplasts in vivo which are initiated by photosynthetic reactions.

1. Effects of changes in ionic environment on the receptor potential were studied in isolated frog spindle. Particular attention was focused on the action of potassium removal on the early adaptive decline of the response.2. Removal of potassium caused a reduction and final disappearance of the dynamic overshoot of the receptor potential. The static phase of the response was also reduced although to less extent. The repolarization phase of the response following release of phasic or maintained stretch was greatly prolonged.3. Increased potassium concentration caused a reduction of the response, but did not change its general time course. The amount of reduction was related to the potassium concentration.4. Removal of sodium caused a marked diminution of the response, the static phase being in general more affected than the dynamic phase.5. It is suggested that the effects of potassium removal are caused by a delay in sodium inactivation and a partial depolarization of the endings. It is concluded that the greater part of the early adaptation of the spindle proper may be attributed to ionic mechanisms in the transducer membrane.

ARTICLESInfluence of sodium and calcium on norepinephrine uptake by isolated perfused rat heartsWD Horst, IJ Kopin, and ER RameyWD Horst, IJ Kopin, and ER RameyPublished Online:01 Oct 1968https://doi.org/10.1152/ajplegacy.1968.215.4.817MoreSectionsPDF (1 MB)Download PDF ToolsExport citationAdd to favoritesGet permissionsTrack citations ShareShare onFacebookTwitterLinkedInWeChat Previous Back to Top Next Download PDF FiguresReferencesRelatedInformation Cited ByAlkali Metal Ion Transport and Biochemical Activity9 March 2007The Transport of Amines Across the Axonal Membranes of Noradrenergic and Dopaminergic NeuronesLithium Pharmacology and PhysiologyContribution of the sympathetic nervous system to the hypertensive effect of a high sodium diet in stroke-prone spontaneously hypertensive rats.Hypertension, Vol. 4, No. 6HypertonieStimulation recording of uptake and secretion of14C-noradrenalin by rat brain synaptosomesBulletin of Experimental Biology and Medicine, Vol. 91, No. 3The inhibitory effect of some monovalent cations on the stimulation by Na+ of the neuronal uptake of noradrenalineNaunyn-Schmiedeberg's Archives of Pharmacology, Vol. 309, No. 2Kinetic analysis of the interaction between noradrenaline and Na+ in neuronal uptake: Kinetic evidence for CO-transportNaunyn-Schmiedeberg's Archives of Pharmacology, Vol. 309, No. 2Noradrenaline transport by rat heart sympathetic nerves: A re-examination of the role of sodium ionsNaunyn-Schmiedeberg's Archives of Pharmacology, Vol. 302, No. 3On the brain ascorbic acid and its importance in metabolism of biogenic aminesLife Sciences, Vol. 20, No. 9False Transmitters as Antihypertensive AgentsINFLUENCE OF COCAINE AND SODIUM ON BRETYLIUM UPTAKE BY RESERPINE-TREATED GUINEA-PIG LEFT ATRIUM19 July 2012 | British Journal of Pharmacology, Vol. 53, No. 2Regulation Mechanisms of Central and Peripheral Sympathetic NeuronsInfluence of lithium chloride on adrenergic mechanisms in ventricle of frog heart and guinea-pig left atriumExperientia, Vol. 31, No. 1Ascorbic acid: Effect of high doses on brain and heart catecholamine levels in guinea-pigs and ratsExperientia, Vol. 29, No. 7The effects of changes in ionic environment and modification of adrenergic function on the vascular responses to sympathomimetic amines12 April 2011 | Journal of Pharmacy and Pharmacology, Vol. 25, No. 7Uptake kinetics and ion requirements for extraneuronal uptake of noradrenaline by arterial smooth muscle and collagen19 July 2012 | British Journal of Pharmacology, Vol. 47, No. 3Pharmacology—Lithium Absorption, Distribution, Renal Handling, and Effect on Body ElectrolytesSome Factors Affecting the Neuron Blocking Action of Guanethidine, Xylocholine, Bretylium and DebrisoquinJapanese Journal of Pharmacology, Vol. 23, No. 6In vitro Studies on the Uptake of Biogenic Amines by Rat Mast CellsActa Physiologica Scandinavica, Vol. 86, No. 2Adrenocortical steroid hormones, electrolytes, and the disposition of the catecholamines with particular reference to depressive statesJournal of Psychiatric Research, Vol. 9, No. 3Potassium Deficiency and Cardiac Catecholamine Metabolism in the RatCirculation Research, Vol. 30, No. 5Influence of serotonin on adrenergic mechanismsBiochemical Pharmacology, Vol. 21, No. 3Contractile Responses of Isolated Rabbit Aortae to Transmural Stimulation as Affected by Calcium, Strontium, Sodium and OuabainJapanese Journal of Pharmacology, Vol. 22, No. 3Possible role of sodium and calcium ions in retention and physiological release of norepinephrine by adrenergic nerve endingsBiochemical Pharmacology, Vol. 20, No. 12The fate of [14C]l-3,4-dihydroxyphenylalanine in isolated perfused rat heartsBiochemical Pharmacology, Vol. 20, No. 10Factors affecting the action of guanethidine on adrenergic neurones19 July 2012 | British Journal of Pharmacology, Vol. 42, No. 3Interactions between Adrenocortical Steroid Hormones, Electrolytes, and the CatecholaminesAn investigation of α-methyl amino-acids and their derivatives on isolated tissue preparations19 July 2012 | British Journal of Pharmacology, Vol. 40, No. 4Mechanism of transport and storage of biogenic amines. III. Effects of sodium and potassium on kinetics of 5-hydroxytryptamine and norepinephrine transport by rabbit synaptosomesBiochimica et Biophysica Acta (BBA) - Biomembranes, Vol. 219, No. 1Influence of debrisoquin (Declinax) on adrenergic function and norepinephrine metabolismBiochemical Pharmacology, Vol. 19, No. 7Accumulation of debrisoquin-14C by the human plateletBiochemical Pharmacology, Vol. 19, No. 3Sodium-dependent accumulation of 5-hydroxytryptamine by rat blood platelets19 July 2012 | British Journal of Pharmacology, Vol. 37, No. 3 More from this issue > Volume 215Issue 4October 1968Pages 817-822 Copyright & PermissionsCopyright © 1968 by American Physiological Societyhttps://doi.org/10.1152/ajplegacy.1968.215.4.817PubMed5676382History Published online 1 October 1968 Published in print 1 October 1968 Metrics

The variation of individual synaptic transmission impacts the dynamics of complex neural circuits. We performed whole-cell recordings from monosynaptically connected hippocampal neurons in rat organotypic slice cultures using a synapse mapping method. The amplitude of unitary excitatory postsynaptic current (uEPSC) varied from trial to trial and was independent of the physical distance between cell pairs. To investigate the source of the transmission variability, we obtained patch-clamp recordings from intact axons. Axonal action potentials (APs) were reliably transmitted throughout the axonal arbour and showed modest changes in width. In contrast, calcium imaging from presynaptic boutons revealed that the amplitude of AP-evoked calcium transients exhibited large variations both among different boutons at a given trial and among trials in a given bouton. These results suggest that a factor contributing to the uEPSC fluctuations is the variability in calcium dynamics at presynaptic terminals. Finally, we acquired triple whole-cell recordings from divergent circuit motifs with one presynaptic neuron projecting to two postsynaptic neurons. Consistent with the independency of calcium dynamics among axonal boutons, a series of uEPSC fluctuations was not correlated between the two postsynaptic cells, indicating that different synapses even from the same neuron act independently.We conclude that the intra-bouton and inter-bouton variability in AP-induced calcium dynamics determine the heterogeneity and independency of uEPSCs.

Intracellular recordings are routinely used to study the synaptic and intrinsic properties of neurons in vitro. A key requirement for these recordings is a mechanically very stable preparation; thus their use in vivo had been limited previously to head-restrained animals. We have recently demonstrated that anchoring the electrode rigidly in place with respect to the skull provides sufficient stabilization for long-lasting, high-quality whole-cell recordings in awake, freely moving rats. This protocol describes our procedure in detail, adds specific instructions for targeting hippocampal CA1 pyramidal neurons and updates it with changes that facilitate patching and improve the success rate. The changes involve combining a standard, nonhead-mounted micromanipulator with a gripper to firmly hold the recording pipette during the anchoring process then gently release it afterwards. The procedure from the beginning of surgery to the end of a recording takes approximately 5 h. This technique allows new studies of the mechanisms underlying neuronal integration and cellular/synaptic plasticity in identified cells during natural behaviors.

Altered intrinsic and synaptic properties of lumbosacral dorsal horn neurons in a mouse model of colitis

The periaqueductal gray (PAG) represents a key target of projection neurons residing in the spinal dorsal horn. In comparison to lamina I spinoparabrachial neurons, little is known about the intrinsic and synaptic properties governing the firing of spino-PAG neurons, or whether such activity is modulated by neonatal injury. In this study, this issue was addressed using ex vivo whole-cell patch clamp recordings from lamina I spino-PAG neurons in adult male and female FVB mice after hindpaw incision at postnatal day (P)3. Spino-PAG neurons were classified as high output, medium output, or low output based on their action potential discharge after dorsal root stimulation. The high-output subgroup exhibited prevalent spontaneous burst firing and displayed initial burst or tonic patterns of intrinsic firing, whereas low-output neurons showed little spontaneous activity. Interestingly, the level of dorsal root-evoked firing significantly correlated with the resting potential and membrane resistance but not with the strength of primary afferent-mediated glutamatergic drive. Neonatal incision failed to alter the pattern of monosynaptic sensory input, with most spino-PAG neurons receiving direct connections from low-threshold C-fibers. Furthermore, primary afferent-evoked glutamatergic input and action potential discharge in adult spino-PAG neurons were unaltered by neonatal surgical injury. Finally, Hebbian long-term potentiation at sensory synapses, which significantly increased afferent-evoked firing, was similar between P3-incised and naive littermates. Collectively, these data suggest that the functional response of lamina I spino-PAG neurons to sensory input is largely governed by their intrinsic membrane properties and appears resistant to the persistent influence of neonatal tissue damage.

The ability to assess and rapidly respond to predator threats in the environment is necessary for survival and requires dedicated neural circuits for threat detection, sensorimotor integration, and execution of ethologically appropriate behavioral responses. Although numerous brain circuits are involved in these processes, the midbrain periaqueductal gray (PAG) serves as an important central hub to generate ethologically appropriate passive and/or active defensive behaviors. Despite its central role in generating defensive behaviors, little is known about the intrinsic and synaptic properties of neurons across columns in the PAG. To address this knowledge gap, we made whole-cell voltage- and current-clamp recordings from unlabeled neurons in the vl- and dmPAG of mice. Consistent with in vivo work, our data highlights the relative importance of synaptic inhibition in both columns. Further, our results suggest that neurons in both the vl- and dmPAG prioritize frequency-invariant coding strategies, showing remarkably stable paired pulse ratios across interstimulus intervals. Despite this common theme, the underlying mechanism each column utilizes to achieve such frequency invariant coding is distinct, reflecting important differences in synaptic processing across columns. More specifically, while the vlPAG is relatively resistant to phasic short-term depression across stimulation frequencies, neurons in the dmPAG show a pronounced buildup of tonic/slow current during high frequency stimulation trains, which counteracts short-term depression of the phasic current amplitude observed during high frequency stimulation trains. This prolonged tonic current observed in the dmPAG prolongs the period of spike elevation, suggesting that high frequency stimulation may drive sustained activity in the dmPAG. Together, these results provide fundamental information of synaptic integration and network properties across columns in the PAG, which ultimately support their distinct roles in threat processing.

![Figure][1] Simulated neural circuits can generate similar output despite variability in the intrinsic properties of individual neurons and the connections among them (synaptic properties). But few studies have attempted to actually measure just how much a particular neural circuit varies