Memory from the dynamics of intrinsic membrane currents.

Changes in membrane properties of CA1 pyramidal neurons after transient forebrain ischemia in vivo

Oscillatory network activity arises from interactions between synaptic and intrinsic membrane properties of neurons. In this review, we summarize general mechanisms of synchronous neuronal oscillations. In addition, we focus on recent experimental and computational studies which suggest that activity-dependent changes of ionic environment can affect both the synaptic and intrinsic neuronal properties and influence the network behavior. GABA(A) receptor (GABA(A)R)-mediated signaling, that is based on Cl(-) and HCO(3)(-) permeability, is thought to be important for the oscillogenesis and synchronization in cortical networks. A remarkable feature of GABAergic synapses is that prolonged GABA(A)R activation may lead to switching from a hyperpolarizing to a depolarizing response. This is partly due to a positive shift of the GABA(A) R reversal potential (E(GABA)) that is generated by GABA-induced Cl(-) accumulation in neurons. Recent studies suggest that activity-dependent E(GABA) changes may have important implications for the mechanisms of gamma oscillations and seizure-like discharges. Thus, a better understanding of the impact of intracellular Cl(-) dynamics on network behavior may provide insights into the mechanisms of physiological and pathological brain rhythms. Combination of experiments and simulations is a promising approach for elucidating which properties of the time-varying ionic environment can shape the dynamics of a given circuit.

Neuromuscular Junction (NMJ): Presynaptic Short-Term Plasticity of Neuromuscular Transmission

We investigated the effects of repeated early-life seizures induced by flurothyl inhalation on intrinsic membrane properties of hippocampal pyramidal neurons from young rats (postnatal day 15-20). Intracellular recordings of CA1 and CA3 pyramidal neurons from flurothyl-treated and control rats revealed no significant differences in resting membrane potential, input resistance, membrane time constant, and action potential characteristics. In CA1 pyramidal cells from flurothyl-treated rats, the spike frequency adaptation and afterhyperpolarizing potential following a spike train were markedly reduced when compared with controls. In contrast, no significant alterations in the firing properties of CA3 pyramidal neurons were found. It is concluded that neonatal seizures lead to persistent changes in intrinsic membrane properties of CA1 pyramidal neurons. These alterations are consistent with an increase in neuronal excitability and may contribute to the behavioral deficit and epileptogenic predisposition observed in rats that experienced repeated neonatal seizures.

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).

The normal process of excitation of the heart involves propagation of action potentials through cardiac regions of different anatomy and different intrinsic membrane properties. Although our understanding of these properties is still incomplete, it is well accepted that the parameters measured from a single cell penetration in an electrical syncytium (e.g., action potential duration, rate of rise, and velocity) reflect not only the properties of that cell but also the electrotonic interactions with other cells to which the recorded cell is electrically coupled. We have used simulation techniques to predict the spatial distribution of action potential parameters resulting from discretely localized alterations in the intrinsic membrane properties of some of the cells of an electrical syncytium. We have shown that the resulting spatial distribution is markedly different for alterations in plateau and pacemaker currents vs. rising phase currents, and that other factors, such as the site of stimulation and the underlying spatial pattern of cell-cell coupling resistance, also modify the spatial distribution of action potential properties resulting from a discrete regional change in intrinsic membrane properties.

Image stability during self motion depends on the combined actions of the vestibuloocular and optokinetic reflexes (VOR and OKR, respectively). Neurons in the medial vestibular nucleus (MVN) participate in the VOR and OKR by firing in response to both head and image motion. Their intrinsic spike-generating properties enable MVN neurons to modulate firing rates linearly over a broad range of input amplitudes and frequencies such as those that occur during natural head and image motion. This study examines the postnatal development of the intrinsic spike-generating properties of rat MVN neurons with respect to maturation of peripheral vestibular and visual function. Spike generation was studied in a brain stem slice preparation by recording firing responses to current injected intracellularly through whole cell patch electrodes. MVN neurons fired spontaneously and modulated their firing rate in response to injected current at all postnatal ages. However, the input-output properties of the spike generator changed dramatically during the first two postnatal weeks. Neurons younger than postnatal day 10 could not fire faster than 80 spikes/s, modulated their firing rates over a limited range of input amplitudes, and tended to exhibit a nonlinear relationship between input current and mean evoked firing rate. In response to sustained depolarization, firing rates declined significantly in young neurons. Response gains tended to be highest in the first few postnatal days but varied widely across neurons and were not correlated with age. By about the beginning of the third postnatal week, MVN neurons could fire faster than 100 spikes/s in response to a broad range of input amplitudes, exhibited predominantly linear current-firing rate relationships, and adapted little in response to sustained depolarization. Concomitant decreases in action potential width and the time course of the afterhyperpolarization suggest that changes in potassium currents contribute to the maturation of the MVN neuronal spike generator. The results demonstrate that developmental changes in intrinsic membrane properties enable MVN neurons to fire linearly in response to a broad range of stimuli in time for the onset of visual function at the beginning of the third postnatal week.

The dorsal horn of the spinal cord is the first central relay where nociceptive inputs are processed. Based on the expression and modulation of intrinsic electrophysiological properties in in vitro slice preparations, dorsal horn neurones (DHNs) display different discharge patterns (tonic, plateau or rhythmic), which shape the neurone's response to sensory inputs. However, it is unclear whether intrinsic properties play any role in sensory processing in vivo. Using in vivo patch clamp recordings in the adult rat, we here examine whether these intrinsic properties are present, and to what extent they determine the DHN response to natural stimulation. We focused primarily on wide dynamic range neurones in deep laminae. These cells displayed a multicomponent peripheral receptive field, comprising an excitatory firing zone, a low-probability firing fringe, and adjacent inhibitory zones. Deep DHNs presented similar intrinsic properties to those observed in vitro, including plateau potentials. These plateaus, underlying high frequency accelerating discharges and after-discharges, were triggered by mechanical stimulation of the excitatory receptive field. Persistent activities induced by activation of plateau potentials were interrupted by stimulation of peripheral inhibitory zones. Moreover, we show that plateau activation is necessary for the expression of windup in response to repetitive, nociceptive stimulation. Finally, using the spinal nerve ligation model of neuropathy, we demonstrate a significant increase in the proportion of plateau neurones in deep dorsal laminae. Our data, therefore, establish that intrinsic amplification properties are expressed within intact spinal circuits and suggest their involvement in neuropathy-induced hyperexcitability of deep DHNs.

Synaptic plasticity in the central nervous system enables the encoding, storing, and integrating new information. AMPA-type glutamate receptors (AMPARs) are ligand-gated ion channels that mediate most fast excitatory synaptic transmission in the brain, and plasticity of AMPARs signaling underlies the long-lasting changes in synaptic efficacy and strength important for learning and memory.1,2 Recent work has indicated that the enigmatic N-terminal domain (NTD) of AMPARs may be a critical regulator of synaptic targeting and plasticity of AMPARs. However, few synaptic proteins have been identified that regulate AMPAR plasticity through interactions with AMPAR NTDs. Moreover, the scope of AMPAR NTD interactors that are important for synaptic plasticity remains unknown. Here, we present the dynamic, extracellular interactome for AMPARs during synaptic plasticity. Using surface-restricted proximity labeling and BioSITe-based proteomics, we identified 70 proteins that were differentially labeled by APEX2-tagged AMPARs after induction of chemical Long-term potentiation of synapses (cLTP) in cultured neurons. Included in this list, were four members of the IgLON family of GPI-anchored proteins (Ntm, OBCAM/Opcml, Negr1, Lsamp). We show OBCAM and NTM directly interact with the extracellular domains of AMPARs. Moreover, overexpression of NTM significantly attenuates the mobility of surface AMPARs in dendritic spines. These data represent a significant first step at uncovering the unexplored extracellular regulation of AMPARs, with broad implications for synapse function and synaptic plasticity.

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 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.

GENERAL COMMENTARY article Front. Neurol., 03 April 2012 | https://doi.org/10.3389/fneur.2012.00050

Neuromodulation of activity-dependent synaptic enhancement at crayfish neuromuscular junction