Kv3.3 subunits control presynaptic action potential waveform and neurotransmitter release at a central excitatory synapse.

Kv3 potassium currents mediate rapid repolarisation of action potentials (APs), supporting fast spikes and high repetition rates. Of the four Kv3 gene family members, Kv3.1 and Kv3.

Glucose and lactate as metabolic constraints on presynaptic transmission at an excitatory synapse.

Key Points: Synapses have high energy demands which increase during intense activity. We show that presynaptic terminals can utilise extracellular glucose or lactate to generate energy to maintain synaptic transmission. Reducing energy substrates induces a metabolic stress: presynaptic ATP depletion impaired synaptic transmission through a reduction in the number of functional synaptic vesicle release sites and a slowing of vesicle pool replenishment, without a consistent change in release probability.

Phase changes in neuronal postsynaptic spiking due to short term plasticity.

In the brain, the postsynaptic response of a neuron to time-varying inputs is determined by the interaction of presynaptic spike times with the short-term dynamics of each synapse. For a neuron driven by stochastic synapses, synaptic depression results in a quite different postsynaptic response to a large population input depending on how correlated in time the spikes across individual synapses are. Here we show using both simulations and mathematical analysis that not only the rate but the phase of the postsynaptic response to a rhythmic population input varies as a function of synaptic dynamics and synaptic configuration.

Identification and modelling of fast and slow Ih current components in vestibular ganglion neurons.

Previous experimental data indicates the hyperpolarization-activated cation (Ih) current, in the inner ear, consists of two components [different hyperpolarization-activated cyclic nucleotide-gated (HCN) subunits] which are impossible to pharmacologically isolate. To confirm the presence of these two components in vestibular ganglion neurons we have applied a parameter identification algorithm which is able to discriminate the parameters of the two components from experimental data. Using simulated data we have shown that this algorithm is able to identify the parameters of two populations of non-inactivated ionic channels more accurately than a classical method.

Inhibitory control of site-specific synaptic plasticity in a model CA1 pyramidal neuron.

A computational model of a biochemical network underlying synaptic plasticity is combined with simulated on-going electrical activity in a model of a hippocampal pyramidal neuron to study the impact of synapse location and inhibition on synaptic plasticity. The simulated pyramidal neuron is activated by the realistic stimulation protocol of causal and anticausal spike pairings of presynaptic and postsynaptic action potentials in the presence and absence of spatially targeted inhibition provided by basket, bistratified and oriens-lacunosum moleculare (OLM) interneurons. The resulting Spike-timing-dependent plasticity (STDP) curves depend strongly on the number of pairing repetitions, the synapse location and the timing and strength of inhibition.

A computational study on plasticity during theta cycles at Schaffer collateral synapses on CA1 pyramidal cells in the hippocampus.

Cellular activity in the CA1 area of the hippocampus waxes and wanes at theta frequency (4-8 Hz) during exploratory behavior of rats. Perisomatic inhibition onto pyramidal cells tends to be strongest out of phase with pyramidal cell activity, whereas dendritic inhibition is strongest in phase with pyramidal cell activity. Synaptic plasticity also varies across the theta cycle, from strong long-term potentiation (LTP) to long-term depression (LTD), putatively corresponding to encoding and retrieval phases for information patterns encoded by pyramidal cell activity (Hasselmo et al.

Spine head calcium as a measure of summed postsynaptic activity for driving synaptic plasticity.

We use a computational model of a hippocampal CA1 pyramidal cell to demonstrate that spine head calcium provides an instantaneous readout at each synapse of the postsynaptic weighted sum of all presynaptic activity impinging on the cell. The form of the readout is equivalent to the functions of weighted, summed inputs used in neural network learning rules. Within a dendritic layer, peak spine head calcium levels are either a linear or sigmoidal function of the number of coactive synapses, with nonlinearity depending on the ability of voltage spread in the dendrites to reach calcium spike threshold.

On phasic inhibition during hippocampal theta.

Two computational models are used to explore the possible implications of recent experimental data (Royer et al. 2012) on phasic inhibition during theta frequency (4-10 Hz) oscillations in the hippocampi of actively behaving rodents. A working hypothesis from previous experimental and modelling studies is that a theta cycle is divided into encoding (when synaptic plasticity is enhanced) and recall (when plasticity is suppressed) half cycles.

Encoding and retrieval in a model of the hippocampal CA1 microcircuit.

It has been proposed that the hippocampal theta rhythm (4-7 Hz) can contribute to memory formation by separating encoding (storage) and retrieval of memories into different functional half-cycles (Hasselmo et al. (2002) Neural Comput 14:793-817). We investigate, via computer simulations, the biophysical mechanisms by which storage and recall of spatio-temporal input patterns are achieved by the CA1 microcircuitry.

Nitric oxide is a volume transmitter regulating postsynaptic excitability at a glutamatergic synapse.

Neuronal nitric oxide synthase (nNOS) is broadly expressed in the brain and associated with synaptic plasticity through NMDAR-mediated calcium influx. However, its physiological activation and the mechanisms by which nitric oxide (NO) influences synaptic transmission have proved elusive. Here, we exploit the unique input-specificity of the calyx of Held to characterize NO modulation at this glutamatergic synapse in the auditory pathway.

Wide-band information transmission at the calyx of Held.

We use a mathematical model of the calyx of Held to explore information transmission at this giant glutamatergic synapse. The significant depression of the postsynaptic response to repeated stimulation in vitro is a result of various activity-dependent processes in multiple timescales, which can be reproduced by multiexponential functions in this model. When the postsynaptic current is stimulated by Poisson-distributed spike trains, its amplitude varies considerably with the preceding interspike intervals.

Interactions between multiple sources of short-term plasticity during evoked and spontaneous activity at the rat calyx of Held.

Sustained activity at most central synapses is accompanied by a number of short-term changes in synaptic strength which act over a range of time scales. Here we examine experimental data and develop a model of synaptic depression at the calyx of Held synaptic terminal that combines many of these mechanisms (acting at differing sites and across a range of time scales). This new model incorporates vesicle recycling, facilitation, activity-dependent vesicle retrieval and multiple mechanisms affecting calcium channel activity and release probability.

Implications of noise and neural heterogeneity for vestibulo-ocular reflex fidelity.

The vestibulo-ocular reflex (VOR) is characterized by a short-latency, high-fidelity eye movement response to head rotations at frequencies up to 20 Hz. Electrophysiological studies of medial vestibular nucleus (MVN) neurons, however, show that their response to sinusoidal currents above 10 to 12 Hz is highly nonlinear and distorted by aliasing for all but very small current amplitudes. How can this system function in vivo when single cell response cannot explain its operation? Here we show that the necessary wide VOR frequency response may be achieved not by firing rate encoding of head velocity in single neurons, but in the integrated population response of asynchronously firing, intrinsically active neurons.

Mathematical modelling and numerical simulation of the morphological development of neurons.

Background: The morphological development of neurons is a very complex process involving both genetic and environmental components. Mathematical modelling and numerical simulation are valuable tools in helping us unravel particular aspects of how individual neurons grow their characteristic morphologies and eventually form appropriate networks with each other.

Methods: A variety of mathematical models that consider (1) neurite initiation (2) neurite elongation (3) axon pathfinding, and (4) neurite branching and dendritic shape formation are reviewed.

Stability in a mathematical model of neurite elongation.

We have developed a continuum partial differential equation model of tubulin-driven neurite elongation and solved the steady problem. For non-zero values of the decay coefficient, the authors identified three different regimes of steady neurite growth, small, moderate and large, dependent on the strength of the tubulin flux into the neurite at the soma. Solution of the fully time-dependent moving boundary problem is, however, hampered by its analytical intractibility.

Dynamics of outgrowth in a continuum model of neurite elongation.

Neurite outgrowth (dendrites and axons) should be a stable, but easily regulated process to enable a neuron to make its appropriate network connections during development. We explore the dynamics of outgrowth in a mathematical continuum model of neurite elongation. The model describes the construction of the internal microtubule cytoskeleton, which results from the production and transport of tubulin dimers and their assembly into microtubules at the growing neurite tip.

Unmasking group III metabotropic glutamate autoreceptor function at excitatory synapses in the rat CNS.

Presynaptic group III metabotropic glutamate receptor (mGluR) activation by exogenous agonists (such as L-2-amino-4-phosphonobutyrate (L-AP4)) potently inhibit transmitter release, but their autoreceptor function has been questioned because endogenous activation during high-frequency stimulation appears to have little impact on synaptic amplitude. We resolve this ambiguity by studying endogenous activation of mGluRs during trains of high-frequency synaptic stimuli at the calyx of Held. In vitro whole-cell patch recordings were made from medial nucleus of the trapezoid body (MNTB) neurones during 1 s excitatory postsynaptic current (EPSC) trains delivered at 200 Hz and at 37 degrees C.

Transport limited effects in a model of dendritic branching.

A variety of stochastic models of dendritic growth in developing neurons have been formulated previously. Such models indicate that the probability of a new branch forming in a growing tree may be modulated by factors such as the number of terminals in the tree and their centrifugal order. However, these models cannot identify any underlying biophysical mechanisms that may cause such dependencies.

Distinguishing between presynaptic and postsynaptic mechanisms of short-term depression during action potential trains.

Short-term facilitation and depression have a profound influence on transmission at many glutamatergic synapses, particularly during trains of stimuli. A major component of these processes is postsynaptic receptor desensitization. Both presynaptic and postsynaptic mechanisms can contribute to synaptic efficacy, but it is often difficult to define their respective contributions.