Cian O'Donnell

Tuning of Synaptic Integration in the Medial Entorhinal Cortex to the Organization of Grid Cell Firing Fields

Neurons important for cognitive function are often classified by their morphology and integrative properties. However, it is unclear if within a single class of neuron these properties tune synaptic responses to the salient features of the information that each neuron represents. We demonstrate that for stellate neurons in layer II of the medial entorhinal cortex, the waveform of postsynaptic potentials, the time window for detection of coincident inputs, and responsiveness to gamma frequency inputs follow a dorsal-ventral gradient similar to the topographical organization of grid-like spatial firing fields of neurons in this area. We provide evidence that these differences are due to a membrane conductance gradient mediated by HCN and leak potassium channels. These findings suggest key roles for synaptic integration in computations carried out within the medial entorhinal cortex and imply that tuning of neural information processing by membrane ion channels is important for normal cognitive function.

Stochastic Ion Channel Gating in Dendritic Neurons: Morphology Dependence and Probabilistic Synaptic Activation of Dendritic Spikes

Neuronal activity is mediated through changes in the probability of stochastic transitions between open and closed states of ion channels. While differences in morphology define neuronal cell types and may underlie neurological disorders, very little is known about influences of stochastic ion channel gating in neurons with complex morphology. We introduce and validate new computational tools that enable efficient generation and simulation of models containing stochastic ion channels distributed across dendritic and axonal membranes. Comparison of five morphologically distinct neuronal cell types reveals that when all simulated neurons contain identical densities of stochastic ion channels, the amplitude of stochastic membrane potential fluctuations differs between cell types and depends on sub-cellular location. For typical neurons, the amplitude of membrane potential fluctuations depends on channel kinetics as well as open probability. Using a detailed model of a hippocampal CA1 pyramidal neuron, we show that when intrinsic ion channels gate stochastically, the probability of initiation of dendritic or somatic spikes by dendritic synaptic input varies continuously between zero and one, whereas when ion channels gate deterministically, the probability is either zero or one. At physiological firing rates, stochastic gating of dendritic ion channels almost completely accounts for probabilistic somatic and dendritic spikes generated by the fully stochastic model. These results suggest that the consequences of stochastic ion channel gating differ globally between neuronal cell-types and locally between neuronal compartments. Whereas dendritic neurons are often assumed to behave deterministically, our simulations suggest that a direct consequence of stochastic gating of intrinsic ion channels is that spike output may instead be a probabilistic function of patterns of synaptic input to dendrites.

Dendritic Spine Dynamics Regulate the Long-Term Stability of Synaptic Plasticity

Long-term synaptic plasticity requires postsynaptic influx of Ca2+ and is accompanied by changes in dendritic spine size. Unless Ca2+ influx mechanisms and spine volume scale proportionally, changes in spine size will modify spine Ca2+ concentrations during subsequent synaptic activation. We show that the relationship between Ca2+ influx and spine volume is a fundamental determinant of synaptic stability. If Ca2+ influx is undercompensated for increases in spine size, then strong synapses are stabilized and synaptic strength distributions have a single peak. In contrast, overcompensation of Ca2+ influx leads to binary, persistent synaptic strengths with double-peaked distributions. Biophysical simulations predict that CA1 pyramidal neuron spines are undercompensating. This unifies experimental findings that weak synapses are more plastic than strong synapses, that synaptic strengths are unimodally distributed, and that potentiation saturates for a given stimulus strength. We conclude that structural plasticity provides a simple, local, and general mechanism that allows dendritic spines to foster both rapid memory formation and persistent memory storage.

Tuning of synaptic responses: an organizing principle for optimization of neural circuits

Neuron types are classically defined by anatomical and physiological properties that determine how synaptic inputs are integrated. Here, we provide an overview of the evidence that, among neurons of a single type, integration of synaptic responses is further tuned according to the particular function that individual neurons carry out. Recent data suggest that tuning of synaptic responses is not restricted to sensory pathways, but extends to cognitive and motor circuits. We propose that tuning of synaptic integration results from general cellular mechanisms for optimization of information processing that are distinct from, but complementary to, homeostasis and memory storage. These cellular tuning mechanisms might be crucial for distributed computations underlying sensory, motor and cognitive functions.

Beyond excitation/inhibition imbalance in multidimensional models of neural circuit changes in brain disorders

A leading theory holds that neurodevelopmental brain disorders arise from imbalances in excitatory and inhibitory (E/I) brain circuitry. However, it is unclear whether this one-dimensional model is rich enough to capture the multiple neural circuit alterations underlying brain disorders. Here, we combined computational simulations with analysis of in vivo two-photon Ca2+ imaging data from somatosensory cortex of Fmr1 knock-out (KO) mice, a model of Fragile-X Syndrome, to test the E/I imbalance theory. We found that: (1) The E/I imbalance model cannot account for joint alterations in the observed neural firing rates and correlations; (2) Neural circuit function is vastly more sensitive to changes in some cellular components over others; (3) The direction of circuit alterations in Fmr1 KO mice changes across development. These findings suggest that the basic E/I imbalance model should be updated to higher dimensional models that can better capture the multidimensional computational functions of neural circuits.

Dendritic trafficking faces physiologically critical speed-precision tradeoffs

Nervous system function requires intracellular transport of channels, receptors, mRNAs, and other cargo throughout complex neuronal morphologies. Local signals such as synaptic input can regulate cargo trafficking, motivating the leading conceptual model of neuron-wide transport, sometimes called the ‘sushi-belt model’ (Doyle and Kiebler, 2011). Current theories and experiments are based on this model, yet its predictions are not rigorously understood. We formalized the sushi belt model mathematically, and show that it can achieve arbitrarily complex spatial distributions of cargo in reconstructed morphologies. However, the model also predicts an unavoidable, morphology dependent tradeoff between speed, precision and metabolic efficiency of cargo transport. With experimental estimates of trafficking kinetics, the model predicts delays of many hours or days for modestly accurate and efficient cargo delivery throughout a dendritic tree. These findings challenge current understanding of the efficacy of nucleus-to-synapse trafficking and may explain the prevalence of local biosynthesis in neurons. DOI: http://dx.doi.org/10.7554/eLife.20556.001

Distance-dependent gradient in NMDAR-driven spine calcium signals along tapering dendrites

Significance Neurons in the brain extend long dendrites that are packed with small protrusions, or spines, responsible for receiving information from presynaptic axons. Although we know much about the workings of spines, we know little about the large-scale distribution of the properties of these compartments along dendritic trees. Here, we provide a map of the structure and function of spines along dendrites. We find that synapses are not randomly distributed, but show a gradual decrease in size with distance along a dendrite, which is matched by an increase in the amplitude of neurotransmitter-evoked calcium signals. This distance-dependent gradient in calcium signals will have important implications for neuronal integration of synaptic information and for the rules behind the calcium-driven plasticity of spines. Neurons receive a multitude of synaptic inputs along their dendritic arbor, but how this highly heterogeneous population of synaptic compartments is spatially organized remains unclear. By measuring N-methyl-d-aspartic acid receptor (NMDAR)-driven calcium responses in single spines, we provide a spatial map of synaptic calcium signals along dendritic arbors of hippocampal neurons and relate this to measures of synapse structure. We find that quantal NMDAR calcium signals increase in amplitude as they approach a thinning dendritic tip end. Based on a compartmental model of spine calcium dynamics, we propose that this biased distribution in calcium signals is governed by a gradual, distance-dependent decline in spine size, which we visualized using serial block-face scanning electron microscopy. Our data describe a cell-autonomous feature of principal neurons, where tapering dendrites show an inverse distribution of spine size and NMDAR-driven calcium signals along dendritic trees, with important implications for synaptic plasticity rules and spine function.

Dendritic trafficking faces fundamental speed-precision tradeoffs

Nervous system function requires intracellular transport of channels, receptors, mRNAs, and other cargo throughout complex neuronal morphologies. Local signals such as synaptic input can regulate cargo trafficking, motivating the leading conceptual model of neuron-wide transport, sometimes called the “sushi-belt model” (Doyle and Kiebler, 2011). Current theories and experiments are based on this model, yet its predictions are not rigorously understood. We formalized the sushi belt model mathematically, showing how it can achieve arbitrarily complex spatial distributions of cargo in reconstructed morphologies. However, the model also predicts an unavoidable, morphology dependent tradeoff between speed, precision and metabolic efficiency of cargo transport. With experimental estimates of trafficking kinetics, the model predicts delays of many hours or days for modestly accurate and efficient cargo delivery throughout a dendritic tree. These findings challenge current understanding of the efficacy of nucleus-to-synapse trafficking and may explain the prevalence of local biosynthesis in neurons.

Multidimensional imbalances in cortical circuit activity in Fragile-X Syndrome mice

A leading theory for multiple neurodevelopmental brain disorders holds that they arise from imbalances in excitatory and inhibitory (E/I) brain circuitry. However this theory has rarely been quantitatively tested. Here we combined computational modeling and analysis of in vivo 2-photon Ca2+ imaging data from cortex of wild-type and Fmr1 knock-out (KO) mice to test the E/I imbalance model. Our main findings were: 1) the E/I imbalance model was not rich enough to capture the alterations in neural activity statistics in Fmr1 KO mice; 2) greatly varying effects of synaptic and cellular properties on network activity; 3) opposite changes in circuit properties of Fmr1 KO mice at different stages of development; 4) a reduction in the entropy of circuit activity in young Fmr1 KO mice, but an opposite increase in adult Fmr1 KO mice. These findings suggest qualitatively new strategies for understanding circuit alterations in Fragile-X Syndrome and related disorders.A leading theory holds that neurodevelopmental brain disorders arise from imbalances in excitatory and inhibitory (E/I) brain circuitry. However, it is unclear whether this one-dimensional model is rich enough to capture the multiple neural circuit alterations underlying brain disorders. Here we combined computational simulations with analysis of in vivo 2-photon Ca2+ imaging data from somatosensory cortex of Fmr1 knock-out (KO) mice, a model of Fragile-X Syndrome, to test the E/I imbalance theory. We found that: 1) The E/I imbalance model cannot account for joint alterations in the observed neural firing rates and correlations; 2) Neural circuit function is vastly more sensitive to changes in some cellular components over others; 3) The direction of circuit alterations in Fmr1 KO mice changes across development. These findings suggest that the basic E/I imbalance model should be updated to higher-dimensional models that can better capture the multidimensional computational functions of neural circuits.

Spontaneous action potentials and neural coding in unmyelinated axons

The voltage-gated Na and K channels in neurons are responsible for action potential generation. Because ion channels open and close in a stochastic fashion, spontaneous (ectopic) action potentials can result even in the absence of stimulation. While spontaneous action potentials have been studied in detail in single-compartment models, studies on spatially extended processes have been limited. The simulations and analysis presented here show that spontaneous rate in unmyelinated axon depends nonmonotonically on the length of the axon, that the spontaneous activity has sub-Poisson statistics, and that neural coding can be hampered by the spontaneous spikes by reducing the probability of transmitting the first spike in a train.