Bruce P. Graham

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. NO is generated in an activity-dependent manner by MNTB principal neurons receiving a calyceal synaptic input. It acts in the target neuron and adjacent inactive neurons to modulate excitability and synaptic efficacy, inhibiting postsynaptic Kv3 potassium currents (via phosphorylation), reducing EPSCs and so increasing action potential duration and reducing transmission fidelity. We conclude that NO serves as a volume transmitter and slow dynamic modulator, integrating spontaneous and evoked neuronal firing, thereby providing an index of global activity and regulating information transmission across a population of active and inactive neurons.

Fuzzy adaptive control of a first-order process

Fuzzy adaptive control of a first-order process with a varying gain and time constant is demonstrated. The fuzzy adaptive controller is based on a fuzzy model-based controller that uses an explicit fuzzy model of the process. Adaptation is achieved by the addition of on-line identification of the fuzzy process model. Starting with a crude initial model the adaptive controller matches the model to the process to self-tune the controller. The model is further modified when the operating point is changed to adapt the controller to the new process conditions. Two different fuzzy identification algorithms are both shown to provide a successful fuzzy adaptive controller. The robustness of the algorithms in the presence of process noise is investigated and improved by the addition of weighting factors.

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. A model of the CA1 microcircuit is presented that uses biophysical representations of the major cell types, including pyramidal (P) cells and four types of inhibitory interneurons: basket (B) cells, axo‐axonic (AA) cells, bistratified (BS) cells and oriens lacunosum‐moleculare (OLM) cells. Inputs to the network come from the entorhinal cortex (EC), the CA3 Schaffer collaterals and medial septum. The EC input provides the sensory information, whereas all other inputs provide context and timing information. Septal input provides timing information for phasing storage and recall. Storage is accomplished via a local STDP mediated hetero‐association of the EC input pattern and the incoming CA3 input pattern on the CA1 pyramidal cell target synapses. The model simulates the timing of firing of different hippocampal cell types relative to the theta rhythm in anesthetized animals and proposes experimentally confirmed functional roles for the different classes of inhibitory interneurons in the storage and recall cycles (Klausberger et al., ( 2003 , 2004 ) Nature 421:844–848, Nat Neurosci 7:41–47). Measures of recall performance of new and previously stored input patterns in the presence or absence of various inhibitory interneurons are employed to quantitatively test the performance of our model. Finally, the mean recall quality of the CA1 microcircuit is tested as the number of stored patterns is increased.

Fuzzy identification and control of a liquid level rig

The most difficult problem in fuzzy control is the development of a control rule set that is both complete and correct. We describe a fuzzy adaptive controller that can learn a control algorithm on-line and adapt it to changing process conditions. The controller makes use of fuzzy identification techniques for learning and adaption. Its control algorithm is based not on an explicit control rule set, but on predictions obtained from a fuzzy model of the process. The learning properties of the controller are demonstrated by its application to the control of a laboratory liquid level rig. Experimental results are given, and a comparison is made with traditional PI/feedforward control techniques.

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°C. The group III mGluR antagonist (R,S)‐cyclopropyl‐4‐phosphonophenylglycine (CPPG, 300 μm) had no effect on EPSC short‐term depression, but accelerated subsequent recovery time course (τ: 4.6 ± 0.8 s to 2.4 ± 0.4 s, P= 0.02), and decreased paired pulse ratio from 1.18 ± 0.06 to 0.97 ± 0.03 (P= 0.01), indicating that mGluR activation reduced release probability (P). Modelling autoreceptor activation during repetitive stimulation revealed that as P declines, the readily releasable pool size (N) increases so that the net EPSC (NP) is unchanged and short‐term depression proceeds with the same overall time course as in the absence of autoreceptor activation. Thus, autoreceptor action on the synaptic response is masked but the synapse is now in a different state (lower P, higher N). While vesicle replenishment clearly underlies much of the recovery from short‐term depression, our results show that the recovery time course of P also contributes to the reduced response amplitude for 1–2 s. The results show that passive equilibration between N and P masks autoreceptor modulation of the EPSC and suggests that mGluR autoreceptors function to change the synaptic state and distribute metabolic demand, rather than to depress synaptic amplitude.

Acceleration of AMPA receptor kinetics underlies temperature-dependent changes in synaptic strength at the rat calyx of Held

It is well established that synaptic transmission declines at temperatures below physiological, but many in vitro studies are conducted at lower temperatures. Recent evidence suggests that temperature‐dependent changes in presynaptic mechanisms remain in overall equilibrium and have little effect on transmitter release at low transmission frequencies. Our objective was to examine the postsynaptic effects of temperature. Whole‐cell patch‐clamp recordings from principal neurons in the medial nucleus of the trapezoid body showed that a rise from 25°C to 35°C increased miniature EPSC (mEPSC) amplitude from −33 ± 2.3 to −46 ± 5.7 pA (n= 6) and accelerated mEPSC kinetics. Evoked EPSC amplitude increased from −3.14 ± 0.59 to −4.15 ± 0.73 nA with the fast decay time constant accelerating from 0.75 ± 0.09 ms at 25°C to 0.56 ± 0.08 ms at 35°C. Direct application of glutamate produced currents which similarly increased in amplitude from −0.76 ± 0.10 nA at 25°C to −1.11 ± 0.19 nA 35°C. Kinetic modelling of fast AMPA receptors showed that a temperature‐dependent scaling of all reaction rate constants by a single multiplicative factor (Q10= 2.4) drives AMPA channels with multiple subconductances into the higher‐conducting states at higher temperature. Furthermore, Monte Carlo simulation and deconvolution analysis of transmission at the calyx of Held showed that this acceleration of the receptor kinetics explained the temperature dependence of both the mEPSC and evoked EPSC. We propose that acceleration in postsynaptic AMPA receptor kinetics, rather than altered presynaptic release, is the primary mechanism by which temperature changes alter synaptic responses at low frequencies.

Mathematical modelling and numerical simulation of the morphological development of neurons

BackgroundThe 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.MethodsA 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. The different mathematical techniques employed are also described.ResultsSome comparison of modelling results with experimental data is made. A critique of different modelling techniques is given, leading to a proposal for a unified modelling environment for models of neuronal development.ConclusionA unified mathematical and numerical simulation framework should lead to an expansion of work on models of neuronal development, as has occurred with compartmental models of neuronal electrical activity.

Improving recall from an associative memory

The associative net as a model of biological associative memory is investigated. Calculating the output pattern retrieved from a partially connected associative net presented with noisy input cues involves several computations. This is complicated by variations in the dendritic sums of the output units due to errors in the cue and differences in input activity and unit usage. The possible implementation of these computations by biological neural machinery is unclear. We demonstrate that a relatively simple transformation can reduce variation in the dendritic sums. This leads to a winners-take-all type of strategy that produces increased recall performance which is equivalent to the more complicated optimal strategy proposed by others. We describe in detail the possible biological implications of our strategies, the novel feature of which ascribes a role to the NMDA and non-NMDA channels found in hippocampal pyramidal cells.

Competition for tubulin between growing neurites during development

Abstract At its tip—called growth cone—a neurite is elongated by the assembly of tubulin into microtubules. We present a model of elongation (extended from Van Veen and Van Pelt, Bull. Math. Biol. 56 (1994) 249–273) in which tubulin is produced in the soma and transported to the growth cone by diffusion and active transport. The model accounts for competition observed between growing neurites of the same neuron and for ‘dormant growth cones’, and shows that cessation of growth in one neurite—e.g., when it encounters a target—can trigger the growth of the other neurites. The model makes testable predictions for the time course of outgrowth and the concentration of tubulin during competition.

Unmasking group III metabotropic glutamate autoreceptor function at excitatory synapses

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°C. The group III mGluR antagonist (R,S)‐cyclopropyl‐4‐phosphonophenylglycine (CPPG, 300 μm) had no effect on EPSC short‐term depression, but accelerated subsequent recovery time course (τ: 4.6 ± 0.8 s to 2.4 ± 0.4 s, P= 0.02), and decreased paired pulse ratio from 1.18 ± 0.06 to 0.97 ± 0.03 (P= 0.01), indicating that mGluR activation reduced release probability (P). Modelling autoreceptor activation during repetitive stimulation revealed that as P declines, the readily releasable pool size (N) increases so that the net EPSC (NP) is unchanged and short‐term depression proceeds with the same overall time course as in the absence of autoreceptor activation. Thus, autoreceptor action on the synaptic response is masked but the synapse is now in a different state (lower P, higher N). While vesicle replenishment clearly underlies much of the recovery from short‐term depression, our results show that the recovery time course of P also contributes to the reduced response amplitude for 1–2 s. The results show that passive equilibration between N and P masks autoreceptor modulation of the EPSC and suggests that mGluR autoreceptors function to change the synaptic state and distribute metabolic demand, rather than to depress synaptic amplitude.