Search

One of the major contributors to the response profile of neurons in the auditory pathways is the I h current. Its properties such as magnitude, activation, and kinetics not only vary among different types of neurons (Banks et al., J Neurophysiol 70:1420-1432, 1993; Fu et al., J Neurophysiol 78:2235-2245, 1997; Bal and Oertel, J Neurophysiol 84:806-817, 2000; Cao and Oertel, J Neurophysiol 94:821-832, 2005; Rodrigues and Oertel, J Neurophysiol 95:76-87, 2006; Yi et al., J Neurophysiol 103:2532-2543, 2010), but they also display notable diversity in a single population of spiral ganglion neurons (Mo and Davis, J Neurophysiol 78:3019-3027, 1997), the first neural element in the auditory periphery. In this study, we found from somatic recordings that part of the heterogeneity can be attributed to variation along the tonotopic axis because I h in the apical neurons have more positive half-activation voltage levels than basal neurons. Even within a single cochlear region, however, I h current properties are not uniform. To account for this heterogeneity, we provide immunocytochemical evidence for variance in the intracellular density of the hyperpolarization-activated cyclic nucleotide-gated channel α-subunit 1 (HCN1), which mediates I h current. We also observed different combinations of HCN1 and HCN4 α-subunits from cell to cell. Lastly, based on the physiological data, we performed kinetic analysis for the I h current and generated a mathematical model to better understand varied I h on spiral ganglion function. Regardless of whether I h currents are recorded at the nerve terminals (Yi et al., J Neurophysiol 103:2532-2543, 2010) or at the somata of spiral ganglion neurons, they have comparable mean half-activation voltage and induce similar resting membrane potential changes, and thus our model may also provide insights into the impact of I h on synaptic physiology.

Pharmacological interventions for neurodevelopmental disorders are increasingly tractable. Autism is a neurodevelopmental disorder that affects approximately 1% of the population. Currently, the standard of care is early behavioral therapy. No approved medical treatments for the diagnostic symptoms are available. Strong evidence for genetic causes of autism implicates proteins that mediate synaptic transmission and structure. Mouse models with targeted mutations in these synaptic genes display behavioral symptoms relevant to the social communication abnormalities and repetitive behaviors that define autism spectrum disorder (ASD), along with biological abnormalities in synaptic physiology and morphology. As we discuss here, promising pharmacological targets, emerging from the mouse model studies, are now being pursued in early clinical trials. Thus, a high-prevalence disorder that was previously considered to be medically untreatable is now moving into the therapeutic arena.

Regulation of activity in neuronal circuits is poorly understood. Alterations in regulatory mechanisms may underlie the transition from interictal to ictal activity. Epileptogenesis is thought to arise from hyperexcitability in populations of neurons, resulting from alterations in connectivity and synaptic physiology. Recent studies suggest that excitability in local circuits of neurons also can be changed by short-term plasticity induced by repetitive stimulation and actions of neuromodulators. It is suggested that these factors could be elements underlying excitability changes that contribute to the periodic nature of seizures.

Fly and vertebrate nervous systems share many organizational features, such as layers, columns and glomeruli, and utilize similar synaptic components, such as ion channels and receptors. Both also exhibit similar network features. Recent technological advances, especially in electron microscopy, now allow us to determine synaptic circuits and identify pathways cell-by-cell, as part of the fly's connectome. Genetic tools provide the means to identify synaptic components, as well as to record and manipulate neuronal activity, adding function to the connectome. This review discusses technical advances in these emerging areas of functional connectomics, offering prognoses in each and identifying the challenges in bridging structural connectomics to molecular biology and synaptic physiology, thereby determining fundamental mechanisms of neural computation that underlie behavior.

Current concepts of cortical information processing and most cortical network models largely rest on the assumption that well-studied properties of local synaptic connectivity are sufficient to understand the generic properties of cortical networks. This view seems to be justified by the observation that the vertical connectivity within local volumes is strong, whereas horizontally, the connection probability between pairs of neurons drops sharply with distance. Recent neuroanatomical studies, however, have emphasized that a substantial fraction of synapses onto neocortical pyramidal neurons stems from cells outside the local volume. Here, we discuss recent findings on the signal integration from horizontal inputs, showing that they could serve as a substrate for reliable and temporally precise signal propagation. Quantification of connection probabilities and parameters of synaptic physiology as a function of lateral distance indicates that horizontal projections constitute a considerable fraction, if not the majority, of inputs from within the cortical network. Taking these non-local horizontal inputs into account may dramatically change our current view on cortical information processing.

Neurons in the sensory system exhibit changes in excitability that unfold over many time scales. These fluctuations produce noise and could potentially lead to perceptual errors. However, to prevent such errors, postsynaptic neurons and synapses can adapt and counteract changes in the excitability of presynaptic neurons. Here we ask how neurons could optimally adapt to minimize the influence of changing presynaptic neural properties on their outputs. The resulting model, based on Bayesian inference, explains a range of physiological results from experiments which have measured the overall properties and detailed time-course of sensory tuning curve adaptation in the early visual cortex. We show how several experimentally measured short term plasticity phenomena can be understood as near-optimal solutions to this adaptation problem. This framework provides a link between high level computational problems, the properties of cortical neurons, and synaptic physiology., National Eye Institute (EY01362), Chicago Community Trust, National Institutes of Health (U.S.) (1R01NS063399 ), National Institutes of Health (U.S.) (2P01NS044393)

The nematode C.elegans, with its 302 neurons and abundance of genetic, laser ablation, electrophysiological and imaging tools, is a compact and attractive system for neural circuit analysis. An understanding of the functional dynamics of neural computation requires physiological analyses. We undertook the first characterization of transfer at central synapses in C.elegans. To achieve this we employed optical stimulation techniques using channelrhodopsin-2, and combined this with whole-cell patch clamp electrophysiological recording techniques. We show that the synapse between AFD and AIY, the first stage in the thermotactic circuit, exhibits excitatory, tonic and graded release. The gain at the synapse was low (

Publisher Summary Computer models of epilepsy and seizures require simulation of large networks in order to produce emergent phenomenology, but also require inclusion of details of cellular and synaptic physiology to retain connection with pharmacological effectors for therapeutic intervention. The former constraint suggests the use of simplifying approaches: integrate-and fire models or meanfield approximations. The latter constraint pushes one towards multi-compartment models. Compromise is required. Highly-simplified event-driven complex artificial-cell models that utilize a series of rules to emulate critical underlying phenomena likely important for seizure generation and patterning, have been developed. These include depolarization blockade, voltage-dependent NMDA activation, and after hyperpolarization. Using these units, one can readily run simulations of 1–2 million units on a single processor. This chapter presents results of data-mining 138,240 simulations of a 3,500-unit network. Parameter explorations can then relate single-unit dynamical “structure” to network function. It is found that the networks are prone to latch-up, reminiscent of a seizure tonic phase. This can alternate with a slow repetitive clonic-like activity. Parameter dependence of epileptiform features was typically complex. This consequence of network complexity fits with the multi-site activity of endogenous neuroeffectors and may help explain why “dirty” drugs, those acting at multiple sites, might be particularly effective for seizure control.

1. 1.|The effects of temperature on crustacean motor nerve, muscle and synaptic physiology have been reviewed in terms of passive properties, threshold potentials and response characteristics. 2. 2.|The generation of additional spikes in the peripheral branches of certain axons has been discussed. 3. 3.|Temperature effects on behaviour have been reviewed.

Neurons in plastic regions of the brain undergo fundamental changes in the number of cells connecting to them as a result of development, plasticity and disease. Across these same time periods, functional changes in cellular and synaptic physiology are known to occur and are often characterized as developmental features of these periods. However, it remains possible that many such changes are direct consequences of the modified degree of partnering, and that neurons intrinsically scale their physiological parameters with network size. To systematically vary a recurrent network's number of neurons while measuring its synaptic properties, we used microfabricated extracellular matrix adhesive islands created with soft lithography to culture neuronal clusters of precise sizes, and assessed their intrinsic connectivity using intracellular recordings and confocal microscopy. Both large and small clusters supported constant densities of excitatory and inhibitory neurons. However, neurons that were provided with more potential partners (larger clusters) formed more connections per cell via an expanded dendritic surface than cocultured smaller clusters. Electrophysiologically, firing rate was preserved across clusters even as size and synapse number increased, due in part to synapses in larger networks having reduced unitary strengths, and sparser paired connectivity. Larger networks also featured a particular increase in the number of excitatory connections onto inhibitory dendrites. We suggest that these specific homeostatic mechanisms, which match the number, strength, and architecture of connections to the number of total available cellular partners in the network, could account for several known phenomena implicated in the formation, organization and degeneration of neuronal circuits.

Research on the functional anatomy of visual cortical circuits has recently zoomed in from the macroscopic level to the microscopic. High-resolution functional imaging has revealed that the functional architecture of orientation maps in higher mammals is built with single-cell precision. By contrast, orientation selectivity in rodents is dispersed on visual cortex in a salt-and-pepper fashion, despite highly tuned visual responses. Recent studies of synaptic physiology indicate that there are disjoint subnetworks of interconnected cells in the rodent visual cortex. These intermingled subnetworks, described in vitro, may relate to the intermingled ensembles of cells tuned to different orientations, described in vivo. This hypothesis may soon be tested with new anatomic techniques that promise to reveal the detailed wiring diagram of cortical circuits.

Vertebrate Hair Cells: Modern and Historic Perspectives.- The Development of Hair Cells in the Inner Ear.- The Structure and Composition of the Stereociliary Bundle of Vertebrate Hair Cells.- Mechanoelectrical Transduction in Auditory Hair Cells.- Contribution of Ionic Currents to Tuning in Auditory Hair Cells.- The Synaptic Physiology of Hair Cells.- The Piezoelectric Outer Hair Cell.- Mammalian Vestibular Hair Cells.

A number of genetically encoded reporters of neuronal activity are being developed to assay synaptic activity with single synapse resolution. A recently engineered probe allows imaging of glutamatergic transmission with high sensitivity, and similar probes may help pave the way for optical imaging of excitatory synaptic function in vivo.

When given orally to a transgenic mouse model of Alzheimer disease, cyclohexanehexol stereoisomers inhibit aggregation of amyloid beta peptide (Abeta) into high-molecular-weight oligomers in the brain and ameliorate several Alzheimer disease-like phenotypes in these mice, including impaired cognition, altered synaptic physiology, cerebral Abeta pathology and accelerated mortality. These therapeutic effects, which occur regardless of whether the compounds are given before or well after the onset of the Alzheimer disease-like phenotype, support the idea that the accumulation of Abeta oligomers has a central role in the pathogenesis of Alzheimer disease.

After many years backstage, lipids have made a come back in the limelight of neuroscience. This renewed excitement was sparked by a series of convergent discoveries in the fields of neural development, synaptic physiology and receptor pharmacology, which have begun to reveal the roles played by lipid messengers and their receptors in brain function. Such roles extend from the development of the neocortex to the processing of complex behaviors, encompassing a territory as vast as those traditionally assigned to growth factors, neurotransmitters and neuropeptides. Along with these basic discoveries, technical advances have simplified the identification and quantification of neural lipids, achieving a degree of sensitivity and selectivity that was unthinkable only 10 years ago. Thanks to this progress, we can now resolve complex mixtures of lipid molecules and quantify each of their components, which are often present in tissues at vanishingly low concentrations. In this review, I outline several key features of brain lipid signaling and discuss the opportunities and challenges that such features impose on future lipidomic approaches. © 2004 Elsevier Inc. All rights reserved.

The study of pain development has come into its own. Reaping the rewards of years of developmental and molecular biology, it has now become possible to translate fundamental knowledge of signalling pathways and synaptic physiology into a better understanding of infant pain. Research has cast new light on the physiological and pharmacological processes that shape the newborn pain response, which will help us to understand early pain behaviour and to design better treatments. Furthermore, it has shown how developing pain circuitry depends on non-noxious sensory activity in the healthy newborn, and how early injury can permanently alter pain processing.

Recent studies suggest that endogenous neurotrophins play a central role in the patterning of cortical connections and in cortical synaptic physiology. Do these effects of neurotrophins reflect independent cellular events, or are they manifestations of a single cellular mechanism central to developmental plasticity?

Nguyen, Peter V., Leo Marin, and Harold L. Atwood. Synaptic physiology and mitochondrial function in crayfish tonic and phasic motor neurons. J. Neurophysiol. 78: 281–294, 1997. Phasic and tonic motor neurons of crustaceans differ strikingly in their junctional synaptic physiology. Tonic neurons generally produce small excitatory postsynaptic potentials (EPSPs) that facilitate strongly as stimulation frequency is increased, and normally show no synaptic depression. In contrast, phasic neurons produce relatively large EPSPs with weak frequency facilitation and pronounced depression. We addressed the hypothesis that mitochondrial function is an important determinant of the features of synaptic transmission in these neurons. Mitochondrial fluorescence was measured with confocal microscopy in phasic and tonic axons and terminals of abdominal and leg muscles after exposure to supravital mitochondrial fluorochromes, rhodamine-123 (Rh123) and 4-diethylaminostyryl-N-methylpyridinium iodide (4-Di-2-Asp). Mitochondria of tonic axons and neuromuscular junctions had significantly higher mean Rh123 and 4-Di-2-Asp fluorescence than in phasic neurons, indicating more accumulation of the fluorochromes. Mitochondrial membrane potential, which is responsible for Rh123 uptake and is related to mitochondrial oxidative activity (the production of ATP by oxidation of metabolic substrates), is likely higher in tonic axons. Electron microscopy showed that tonic axons contain approximately fivefold more mitochondria per μm2cross-sectional area than phasic axons. Neuromuscular junctions of tonic axons also have a much higher mitochondrial content than those of phasic axons. We tested the hypothesis that synaptic fatigue resistance is dependent on mitochondrial function in crayfish motor axons. Impairment of mitochondrial function by uncouplers of oxidative phosphorylation, dinitrophenol or carbonyl cyanide m-chlorophenylhydrazone, or by the electron transport inhibitor sodium azide, led to marked synaptic depression of a tonic axon and accelerated depression of a phasic axon during maintained stimulation. Iodoacetate, an inhibitor of glycolysis, and chloramphenicol, a mitochondrial protein synthesis inhibitor, had no significant effects on either mitochondrial fluorescence or synaptic depression in tonic or phasic axons. Collectively, the results provide evidence that mitochondrial oxidative metabolism is important for sustaining synaptic transmission during maintained stimulation of tonic and phasic motor neurons. Tonic neurons have a higher mitochondrial content and greater oxidative activity; these features are correlated with their greater resistance to synaptic depression. Conversely, phasic neurons have a lower mitochondrial content, less oxidative activity, and greater synaptic fatigability.

Inhibitory collaterals between striatal medium spiny neuron (MSN) subtypes have been shown to critically influence striatal output. However, the low rate of inhibitory collateral detection between striatal MSNs in conventional ex vivo slice recordings has made the study of these connections challenging. Furthermore, most studies on MSN collaterals have been conducted either blind or in models, in which only one MSN subtype can be distinguished. Here, we describe a dissociated culture system using striatal and cortical neurons harvested from genetically modified mice at postnatal day 0. These mice express tdTomato and enhanced green fluorescent protein (EGFP) downstream of the dopamine D1 and D2 receptor promoters, respectively, allowing for simultaneous distinction between the two major subtypes of MSNs. In vitro, these neurons develop spines, hyperpolarized resting membrane potentials and exhibit up-and-down states, while also maintaining expression of both fluorophores through time. Using paired whole-cell patch-clamp recordings from identified MSNs at 14 days in vitro, we are able to detect a much higher rate of inhibitory functional synapses than what has been previously reported in slice recordings. These collateral synapses release γ-Aminobutyric acid (GABA) and shape the firing patters of other MSNs. Although reduced in vitro models have a number of inherent limitations, the cultures described here provide a unique opportunity to study frequently observed functional collaterals between identifiable MSNs. Additionally, cultured neurons allow for control of the extracellular environment, with the potential to investigate pharmacological regulation of inhibitory MSNs collaterals.

Until recently, the mouse was rarely used to study the biology of learning and memory. With advancements in gene-targeting technology, which now allow the structure and expression of a specific protein to be controlled in the intact animal, the mouse provides a powerful new tool to explore cognitive function. In mice, in contrast to other organisms, it is now possible to regulate the expression of a protein in the same neurons that are electrophysiologically and biochemically manipulable and are in a circuit involved in a defined learned behavior. Mouse mutants have been described that alter synaptic physiology, neuroanatomy, neurochemistry, and behavior. The mutants provide the first opportunity to correlate these phenotypes within animals engineered with defined molecular alterations. This review will discuss a range of methodologies that are required to describe the phenotype of mice with synaptic and behavioral abnormalities and focus on the interpretative difficulties of integrating these techniques.

Do graded potential synapses work the same way as action potential synapses? Recent work emphasizes the differences and suggests that graded potential synapses are not all the same either.

The changes in synaptic physiology that accompany fragile X syndrome (FXS) and autism are poorly understood, but Baudouin et al. provide evidence that the synaptic protein neuroligin 3 (NLGN3) might be involved in both. Non-syndromic autism (in which autism is the primary disorder) can be associated with defects in NLGN3. The authors showed that cerebellar Purkinje cells of NLGN-null mice exhibited a loss of long-term depression mediated by metabotrophic glutamate receptors. This type of plasticity is also associated with FXS and suggests that NLGN3-related synaptic mechanisms may be involved in both FXS and autism.

Crustacean phasic motor neurons, recruited for rapid movements, are generally silent, release relatively large amounts of transmitter onto their target muscle fibers and exhibit rapid synaptic depression with repeated activation. Tonic motor neurons, recruited for postural activities or slow movements, are more continuously active, generally produce small, facilitating synaptic potentials in target muscle fibers, and resist synaptic depression. In adult crustaceans, imposition of a tonic pattern of activity on phasic neurons in vivo leads to adaptive alterations of their synaptic physiology and morphology; such neurons assume a more tonic phenotype. Short-lasting inhibition of protein synthesis by cycloheximide, when timed to occur before a period of imposed tonic activity, effectively prevents the activity-dependent adaptive modification of synaptic transmission.