Generation Of Dendritic Spikes Research Articles

Impaired dendritic spike generation in the Fragile X prefrontal cortex is due to loss of dendritic sodium channels.

Patients with Fragile X syndrome, the leading monogenetic cause of autism, suffer from impairments related to the prefrontal cortex, including working memory and attention. Synaptic inputs to the distal dendrites of layer 5 pyramidal neurons in the prefrontal cortex have a weak influence on the somatic membrane potential. To overcome this filtering, distal inputs are transformed into local dendritic Na+ spikes, which propagate to the soma and trigger action potential output. Layer 5 extratelencephalic (ET) prefrontal cortex (PFC) neurons project to the brainstem and various thalamic nuclei and are therefore well positioned to integrate task-relevant sensory signals and guide motor actions. We used current clamp and outside-out patch clamp recording to investigate dendritic spike generation in ET neurons from male wild-type and Fmr1 knockout (FX) mice. The threshold for dendritic spikes was more depolarized in FX neurons compared to wild-type. Analysis of voltage responses to simulated in vivo 'noisy' current injections showed that a larger dendritic input stimulus was required to elicit dendritic spikes in FX ET dendrites compared to wild-type. Patch clamp recordings revealed that the dendritic Na+ conductance was significantly smaller in FX ET dendrites. Taken together, our results suggest that the generation of Na+ -dependent dendritic spikes is impaired in ET neurons of the PFC in FX mice. Considering our prior findings that somatic D-type K+ and dendritic hyperpolarization-activated cyclic nucleotide-gated-channel function is reduced in ET neurons, we suggest that dendritic integration by PFC circuits is fundamentally altered in Fragile X syndrome. KEY POINTS: Dendritic spike threshold is depolarized in layer 5 prefrontal cortex neurons in Fmr1 knockout (FX) mice. Simultaneous somatic and dendritic recording with white noise current injections revealed that larger dendritic stimuli were required to elicit dendritic spikes in FX extratelencephalic (ET) neurons. Outside-out patch clamp recording revealed that dendritic sodium conductance density was lower in FX ET neurons.

High-fidelity dendritic sodium spike generation in human layer 2/3 neocortical pyramidal neurons.

Dendritic spikes function as cardinal components of rodent neocortical circuit computations. Recently, the biophysical properties of human pyramidal neurons (PNs) have been reported to be divergent, raising the question of whether dendritic spikes have homologous roles in the human neocortex. To directly address this, we made electrical recordings from the soma and apical dendrites of human and rat layer 2/3 PNs of the temporal cortex. In both species, dendritic excitatory input led to the initiation of sodium-channel-mediated dendritic spikes. Dendritic sodium spikes could be generated across a wide input range, exhibited a similar frequency range of activation, and forward-propagated with high-fidelity to implement stereotyped computations in human and rat PNs. However, the physical expansion and complexification of the apical dendritic trees of human PNs allowed the enriched expression of dendritic spike generation. The computational capacity of human PNs is therefore enhanced by the widespread implementation of a conserved dendritic integration mechanism.

Light-evoked dendritic spikes in sustained but not transient rabbit retinal ganglion cells

Dendritic computations have a central role in neuronal function, but it is unknown how cell-class heterogeneity of dendritic electrical excitability shapes physiologically engaged neuronal and circuit computations. To address this, we examined dendritic integration in closely related classes of retinal ganglion cells (GCs) using simultaneous somato-dendritic electrical recording techniques in a functionally intact circuit. Simultaneous recordings revealed sustained OFF-GCs generated powerful dendritic spikes in response to visual input that drove action potential firing. In contrast, the dendrites of transient OFF-GCs were passive and did not generate dendritic spikes. Dendritic spike generation allowed sustained, but not transient, OFF-GCs to signal into action potential output the local motion of visual stimuli to produce a continuous wave of action potential firing in adjacent cells as images moved across the retina. Conversely, this representation was highly fragmented in transient OFF-GCs. Thus, a heterogeneity of dendritic excitability defines the computations executed by classes of GCs.

Somatic Depolarization Enhances Hippocampal CA1 Dendritic Spike Propagation and Distal Input-Driven Synaptic Plasticity

Synaptic inputs that target distal regions of neuronal dendrites can often generate local dendritic spikes that can amplify synaptic depolarization, induce synaptic plasticity, and enhance neuronal output. However, distal dendritic spikes are subject to significant attenuation by dendritic cable properties, and often produce only a weak subthreshold depolarization of the soma. Nonetheless, such spikes have been implicated in memory storage, sensory perception and place field formation. How can such a weak somatic response produce such powerful behavioral effects? Here, we use dual dendritic and somatic recordings in acute hippocampal slices of male mice to reveal that dendritic spike propagation, but not spike initiation, is strongly enhanced when the somatic resting potential is depolarized, likely as a result of increased inactivation of A-type K+ channels. Somatic depolarization also facilitates the induction of a form of dendritic spike driven heterosynaptic plasticity that enhances memory specificity. Thus, the effect of somatic membrane depolarization to enhance dendritic spike propagation and long-term synaptic plasticity is likely to play an important role in hippocampal-dependent spatial representations as well as learning and memory.SIGNIFICANCE STATEMENT Neurons receive synaptic input along their dendrites but produce action potential (AP) output at their soma. Signals arriving at the distal dendrites of pyramidal neurons (PNs) have little impact on the soma unless they combine to initiate a dendritic spike, which needs to propagate to the soma to trigger an AP. This study shows that small subthreshold depolarization of the soma powerfully enhances the propagation of dendritic spikes, through inactivation of dendritic A-type potassium channels. Enhanced dendritic spike propagation also markedly facilitates the induction of a form of plasticity driven by the distal synaptic inputs. Thus, small changes in somatic membrane potential, similar to those observed in vivo, act as a powerful gate of neuronal information transfer.

Acetylcholine Boosts Dendritic NMDA Spikes in a CA3 Pyramidal Neuron Model

Acetylcholine has been proposed to facilitate the formation of memory ensembles within the hippocampal CA3 network, by enhancing plasticity at CA3-CA3 recurrent synapses. Regenerative NMDA receptor (NMDAR) activation in CA3 neuron dendrites (NMDA spikes) increase synaptic Ca2+ influx and can trigger this synaptic plasticity. Acetylcholine inhibits potassium channels which enhances dendritic excitability and therefore could facilitate NMDA spike generation. Here, we investigate NMDAR-mediated nonlinear synaptic integration in stratum radiatum (SR) and stratum lacunosum moleculare (SLM) dendrites in a reconstructed CA3 neuron computational model and study the effect of cholinergic inhibition of potassium conductances on this nonlinearity. We found that distal SLM dendrites, with a higher input resistance, had a lower threshold for NMDA spike generation compared to SR dendrites. Simulating acetylcholine by blocking potassium channels (M-type, A-type, Ca2+-activated, and inwardly-rectifying) increased dendritic excitability and reduced the number of synapses required to generate NMDA spikes, particularly in the SR dendrites. The magnitude of this effect was heterogeneous across different dendritic branches within the same neuron. These results predict that acetylcholine facilitates dendritic integration and NMDA spike generation in selected CA3 dendrites which could strengthen connections between specific CA3 neurons to form memory ensembles.

General practice during COVID-19: an FY2's perspective.

<h3>ABSTRACT</h3> Patients with Fragile X syndrome, the leading monogenetic cause of autism, suffer from impairments related to the prefrontal cortex including working memory and attention. Synaptic inputs to the distal dendrites of layer 5 pyramidal neurons in the prefrontal cortex have a weak influence on the somatic membrane potential. To overcome this filtering, distal inputs are transformed into local dendritic Na⁺ spikes, which propagate to the soma and trigger action potential output. Layer 5 extratelencephalic (ET) PFC neurons project to the brainstem and various thalamic nuclei and are therefore well positioned to integrate task-relevant sensory signals and guide motor actions. We used current clamp and outside-out patch clamp recording to investigate dendritic spike generation in ET neurons from male wild type and <i>Fmr1</i> knockout (FX) mice. The threshold for dendritic spikes was more depolarized in FX neurons compared to wild type. Analysis of voltage responses to simulated in vivo “noisy” current injections showed that a larger dendritic input stimulus was required to elicit dendritic spikes in FX ET dendrites compared wild type. Patch clamp recordings revealed that the dendritic Na⁺ conductance was significantly smaller in FX ET dendrites. Taken together, our results suggest that input-output transformation is impaired in ET neurons of the PFC in FX mice. Considering our prior findings that somatic D-type K⁺ and dendritic HCN-channel function is reduced in ET neurons, we suggest that the integration of information by PFC circuits is fundamentally altered in Fragile X syndrome. <h3>KEY POINTS</h3> Dendritic spike threshold is depolarized in Layer 5 PFC neurons in FX mice Simultaneous somatic and dendritic recording with white noise current injections revealed that larger dendritic stimuli were required to elicit dendritic spikes in FX ET neurons Outside-out patch clamp recording revealed that dendritic sodium conductance density was lower in FX ET neurons

Dendritic Spikes Expand the Range of Well Tolerated Population Noise Structures.

The brain operates surprisingly well despite the noisy nature of individual neurons. The central mechanism for noise mitigation in the nervous system is thought to involve averaging over multiple noise-corrupted inputs. Subsequently, there has been considerable interest in identifying noise structures that can be integrated linearly in a way that preserves reliable signal encoding. By analyzing realistic synaptic integration in biophysically accurate neuronal models, I report a complementary denoising approach that is mediated by focal dendritic spikes. Dendritic spikes might seem to be unlikely candidates for noise reduction due to their miniscule integration compartments and poor averaging abilities. Nonetheless, the extra thresholding step introduced by dendritic spike generation increases neuronal tolerance for a broad category of noise structures, some of which cannot be resolved well with averaging. This property of active dendrites compensates for compartment size constraints and expands the repertoire of conditions that can be processed by neuronal populations.SIGNIFICANCE STATEMENT Noise, or random variability, is a prominent feature of the neuronal code and poses a fundamental challenge for information processing. To reconcile the surprisingly accurate output of the brain with the inherent noisiness of biological systems, previous work examined signal integration in idealized neurons. The notion that emerged from this body of work is that accurate signal representation relies largely on input averaging in neuronal dendrites. In contrast to the prevailing view, I show that denoising in simulated neurons with realistic morphology and biophysical properties follows a different strategy: dendritic spikes act as classifiers that assist in extracting information from a variety of noise structures that have been considered before to be particularly disruptive for reliable brain function.

Paradoxical Excitatory Impact of SK Channels on Dendritic Excitability.

Dendritic excitability regulates how neurons integrate synaptic inputs and thereby influences neuronal output. As active dendritic events are associated with significant calcium influx they are likely to be modulated by calcium-dependent processes, such as calcium-activated potassium channels. Here we investigate the impact of small conductance calcium-activated potassium channels (SK channels) on dendritic excitability in male and female rat cortical pyramidal neurons in vitro and in vivo Using local applications of the SK channel antagonist apamin in vitro, we show that blocking somatic SK channels enhances action potential output, whereas blocking dendritic SK channels paradoxically reduces the generation of dendritic calcium spikes and associated somatic burst firing. Opposite effects were observed using the SK channel enhancer NS309. The effect of apamin on dendritic SK channels was occluded when R-type calcium channels were blocked, indicating that the inhibitory impact of apamin on dendritic calcium spikes involved R-type calcium channels. Comparable effects were observed in vivo Intracellular application of apamin via the somatic whole-cell recording pipette reduced the medium afterhyperpolarization and increased action potential output during UP states. In contrast, extracellular application of apamin to the cortical surface to block dendritic SK channels shifted the distribution of action potentials within UP states from an initial burst to a more distributed firing pattern, while having no impact on overall action potential firing frequency or UP and DOWN states. These data indicate that somatic and dendritic SK channels have opposite effects on neuronal excitability, with dendritic SK channels counter-intuitively promoting rather than suppressing neuronal output.SIGNIFICANCE STATEMENT Neurons typically receive input from other neurons onto processes called dendrites, and use electrical events such as action potentials for signaling. As electrical events in neurons are usually associated with calcium influx they can be regulated by calcium-dependent processes. One such process is through the activation of calcium-dependent potassium channels, which usually act to reduce action potential signaling. Although this is the case for calcium-dependent potassium channels found at the cell body, we show here that calcium-dependent potassium channels in dendrites of cortical pyramidal neurons counter-intuitively promote rather than suppress action potential output.

Spatially dispersed synapses yield sharply-tuned place cell responses through dendritic spike initiation.

Key points The generation of dendritic spikes and the consequent sharp tuning of neuronal responses are together attainable even when iso‐feature synapses are randomly dispersed across the dendritic arbor.Disparate combinations of channel conductances with distinct configurations of randomly dispersed place field synapses concomitantly yield similar sharp tuning profiles and similar functional maps of several intrinsic properties.Targeted synaptic plasticity converts silent cells to place cells for specific place fields in models with disparate channel combinations that receive dispersed synaptic inputs from multiple place field locations.Dispersed localization of iso‐feature synapses is a strong candidate for achieving sharp feature selectivity in neurons across sensory‐perceptual systems, with several degrees of freedom in relation to synaptic locations.Quantitative evidence for the possibility that degeneracy (i.e. the ability of disparate structural components to yield similar functional outcomes) could act as a broad framework that effectively accomplishes the twin goals of input‐feature encoding and homeostasis of intrinsic properties without cross interferences. A prominent hypothesis spanning several sensory‐perceptual systems implicates spatially clustered synapses in the generation of dendritic spikes that mediate sharply‐tuned neuronal responses to input features. In this conductance‐based morphologically‐precise computational study, we tested this hypothesis by systematically analysing the impact of distinct synaptic and channel localization profiles on sharpness of spatial tuning in hippocampal pyramidal neurons. We found that the generation of dendritic spikes, the emergence of an excitatory ramp in somatic voltage responses, the expression of several intrinsic somatodendritic functional maps and sharp tuning of place‐cell responses were all attainable even when iso‐feature synapses are randomly dispersed across the dendritic arbor of models with disparate channel combinations. Strikingly, the generation and propagation of dendritic spikes, reliant on dendritic sodium channels and N‐methyl‐d‐asparate receptors, mediated the sharpness of spatial tuning achieved with dispersed synaptic localization. To ensure that our results were not artefacts of narrow parametric choices, we confirmed these conclusions with independent multiparametric stochastic search algorithms spanning thousands of unique models for each synaptic localization scenario. Next, employing virtual knockout models, we demonstrated a vital role for dendritically expressed voltage‐gated ion channels, especially the transient potassium channels, in maintaining sharpness of place‐cell tuning. Importantly, we established that synaptic potentiation targeted to afferents from one specific place field was sufficient to impart place field selectivity even when intrinsically disparate neurons received randomly dispersed afferents from multiple place field locations. Our results provide quantitative evidence for disparate combinations of channel and synaptic localization profiles to concomitantly yield similar tuning and similar intrinsic properties.

Adrenergic Modulation Regulates the Dendritic Excitability of Layer 5 Pyramidal Neurons In Vivo

The excitability of the apical tuft of layer 5 pyramidal neurons is thought to play a crucial role in behavioral performance and synaptic plasticity. We show that the excitability of the apical tuft is sensitive to adrenergic neuromodulation. Using two-photon dendritic Ca2+ imaging and invivo whole-cell and extracellular recordings in awake mice, we show that application of the α2A-adrenoceptor agonist guanfacine increases the probability of dendritic Ca2+ events in the tuft and lowers the threshold for dendritic Ca2+ spikes. We further show that these effects are likely to be mediated by the dendritic current Ih. Modulation of Ih in a realistic compartmental model controlled both the generation and magnitude of dendritic calcium spikes in the apical tuft. These findings suggest that adrenergic neuromodulation may affect cognitive processes such as sensory integration, attention, and working memory by regulating the sensitivity of layer 5 pyramidal neurons to top-down inputs.

Single excitatory axons form clustered synapses onto CA1 pyramidal cell dendrites.

CA1 pyramidal neurons are a major output of the hippocampus and encode features of experience that constitute episodic memories. Feature-selective firing of these neurons results from the dendritic integration of inputs from multiple brain regions. While it is known that synchronous activation of spatially clustered inputs can contribute to firing through the generation of dendritic spikes, there is no established mechanism for spatiotemporal synaptic clustering. Here we show that single presynaptic axons form multiple, spatially clustered inputs onto the distal, but not proximal, dendrites of CA1 pyramidal neurons. These compound connections exhibit ultrastructural features indicative of strong synapses and occur much more commonly in entorhinal than in thalamic afferents. Computational simulations revealed that compound connections depolarize dendrites in a biophysically efficient manner, owing to their inherent spatiotemporal clustering. Our results suggest that distinct afferent projections use different connectivity motifs that differentially contribute to dendritic integration.

Dendro-dendritic cholinergic excitation controls dendritic spike initiation in retinal ganglion cells

The retina processes visual images to compute features such as the direction of image motion. Starburst amacrine cells (SACs), axonless feed-forward interneurons, are essential components of the retinal direction-selective circuitry. Recent work has highlighted that SAC-mediated dendro-dendritic inhibition controls the action potential output of direction-selective ganglion cells (DSGCs) by vetoing dendritic spike initiation. However, SACs co-release GABA and the excitatory neurotransmitter acetylcholine at dendritic sites. Here we use direct dendritic recordings to show that preferred direction light stimuli evoke SAC-mediated acetylcholine release, which powerfully controls the stimulus sensitivity, receptive field size and action potential output of ON-DSGCs by acting as an excitatory drive for the initiation of dendritic spikes. Consistent with this, paired recordings reveal that the activation of single ON-SACs drove dendritic spike generation, because of predominate cholinergic excitation received on the preferred side of ON-DSGCs. Thus, dendro-dendritic release of neurotransmitters from SACs bi-directionally gate dendritic spike initiation to control the directionally selective action potential output of retinal ganglion cells.

The ionic mechanism of the Purkinje cell dendritic spikes generation and propagation: a model exploration

Due to the lack of sodium channel expression in the Purkinje cell (PC) dendrite, the passively propagated sodium spikes can hardly be detected in the dendrite. However, the substantial expression of T type calcium channels (ICaT) and P type calcium channels (ICaP) can cause local regenerative spikes to occur in the dendrite after receiving a parallel fiber (PF) stimulus [1]. In this study, with the previously published PC dendrite model [2] from our group as the starting point, we have built a new PC dendrite model incorporating the low threshold A-type K+ current (IKA) [3], high threshold activated K+ current (IKV3) and hyperpolarization-activated cation current (Ih). In our model, in agreement with experimental observations [1], the EPSP amplitude increases nonlinearly with the strength of the PF synaptic input until it reaches the spike threshold. During this range, we find that ICaT amplifies the EPSP caused by PF synaptic input to boost the EPSP close to the spike threshold. Around the spike threshold there is an obvious spike delay due to the interactive role of IKA and ICaT. Above the spike threshold, high threshold activated ICaP takes over and depolarizes the dendrite rapidly, finally leading to the generation of dendritic spikes. The amplitude of dendritic spikes doesn't increase further with the stimulation intensity and is mainly determined by the struggle among ICaP, IKV3 and high conductance calcium activated K+ currents (IBK). Injecting a negative current can eliminate the PF input evoked dendritic spikes by lowering the membrane potential which implies less activation of the ICaT and subsequent less amplification of the EPSP. We also find that the simulated dendritic spikes can't propagate to the whole dendrite due to the regulating role of mainly IBK and IKV3. Surprisingly by partially blocking IKV3 and IBK parallel fiber evoked dendritic spikes can propagate to the whole dendrite because of the broadening of its width. The calcium influx by dendritic spikes is vital to a lot of calcium dependent processes like synaptic plasticity. Understanding the mechanism of generation of the local dendritic spikes evoked by PF stimulus and how their localized nature works will help us better explore how information is processed in the PC dendrite.

Contribution of extrasynaptic N-methyl-D-aspartate and adenosine A1 receptors in the generation of dendritic glutamate-mediated plateau potentials.

Thin basal dendrites can strongly influence neuronal output via generation of dendritic spikes. It was recently postulated that glial processes actively support dendritic spikes by either ceasing glutamate uptake or by actively releasing glutamate and adenosine triphosphate (ATP). We used calcium imaging to study the role of NR2C/D-containing N-methyl-d-aspartate (NMDA) receptors and adenosine A1 receptors in the generation of dendritic NMDA spikes and plateau potentials in basal dendrites of layer 5 pyramidal neurons in the mouse prefrontal cortex. We found that NR2C/D glutamate receptor subunits contribute to the amplitude of synaptically evoked NMDA spikes. Dendritic calcium signals associated with glutamate-evoked dendritic plateau potentials were significantly shortened upon application of the NR2C/D receptor antagonist PPDA, suggesting that NR2C/D receptors prolong the duration of calcium influx during dendritic spiking. In contrast to NR2C/D receptors, adenosine A1 receptors act to abbreviate dendritic and somatic signals via the activation of dendritic K(+) current. This current is characterized as a slow-activating outward-rectifying voltage- and adenosine-gated current, insensitive to 4-aminopyridine but sensitive to TEA. Our data support the hypothesis that the release of glutamate and ATP from neurons or glia contribute to initiation, maintenance and termination of local dendritic glutamate-mediated regenerative potentials.

Weak sinusoidal electric fields entrain spontaneous Ca transients in the dendritic tufts of CA1 pyramidal cells in rat hippocampal slice preparations.

Neurons might interact via electric fields and this notion has been referred to as ephaptic interaction. It has been shown that various types of ion channels are distributed along the dendrites and are capable of supporting generation of dendritic spikes. We hypothesized that generation of dendritic spikes play important roles in the ephaptic interactions either by amplifying the impact of electric fields or by providing current source to generate electric fields. To test if dendritic activities can be modulated by electric fields, we developed a method to monitor local Ca-transients in the dendrites of a neuronal population in acute rat hippocampal slices by applying spinning-disk confocal microscopy and multi-cell dye loading technique. In a condition in which the dendrites of CA1 pyramidal neurons show spontaneous Ca-transients due to added 50 μM 4-aminopyridine to the bathing medium and adjusted extracellular potassium concentration, we examined the impact of sinusoidal electric fields on the Ca-transients. We have found that spontaneously occurring fast-Ca-transients in the tufts of the apical dendrites of CA1 pyramidal neurons can be blocked by applying 1 μM tetrodotoxin, and that the timing of the transients become entrained to sub-threshold 1-4 Hz electric fields with an intensity as weak as 0.84 mV/mm applied parallel to the somato-dendritic axis of the neurons. The extent of entrainment increases with intensity below 5 mV/mm, but does not increase further over the range of 5-20 mV/mm. These results suggest that population of pyramidal cells might be able to detect electric fields with biologically relevant intensity by modulating the timing of dendritic spikes.

A Quantitative Description of Dendritic Conductances and Its Application to Dendritic Excitation in Layer 5 Pyramidal Neurons

Postsynaptic integration is a complex function of passive membrane properties and nonlinear activation of voltage-gated channels. Some cortical neurons express many voltage-gated channels, with each displaying heterogeneous dendritic conductance gradients. This complexity has hindered the construction of experimentally based mechanistic models of cortical neurons. Here we show that it is possible to overcome this obstacle. We recorded the membrane potential from the soma and apical dendrite of layer 5 (L5) pyramidal neurons of the rat somatosensory cortex. A combined experimental and numerical parameter peeling procedure was implemented to optimize a detailed ionic mechanism for the generation and propagation of dendritic spikes in neocortical L5 pyramidal neurons. In the optimized model, the density of voltage-gated Ca(2+) channels decreased linearly from the soma, and leveled at the distal apical dendrite. The density of the small-conductance Ca(2+)-activated channel decreased along the apical dendrite, whereas the density of the large-conductance Ca(2+)-gated K(+) channel was uniform throughout the apical dendrite. The model predicted an ionic mechanism for the generation of a dendritic spike, the interaction of this spike with the backpropagating action potential, the mechanism responsible for the ability of the proximal apical dendrite to control the coupling between the axon and the dendrite, and the generation of NMDA spikes in the distal apical tuft. Moreover, in addition to faithfully predicting many experimental results recorded from the apical dendrite of L5 pyramidal neurons, the model validates a new methodology for mechanistic modeling of neurons in the CNS.

Single-neuron criticality optimizes analog dendritic computation

Active dendritic branchlets enable the propagation of dendritic spikes, whose computational functions remain an open question. Here we propose a concrete function to the active channels in large dendritic trees. Modelling the input-output response of large active dendritic arbors subjected to complex spatio-temporal inputs and exhibiting non-stereotyped dendritic spikes, we find that the dendritic arbor can undergo a continuous phase transition from a quiescent to an active state, thereby exhibiting spontaneous and self-sustained localized activity as suggested by experiments. Analogously to the critical brain hypothesis, which states that neuronal networks self-organize near criticality to take advantage of its specific properties, here we propose that neurons with large dendritic arbors optimize their capacity to distinguish incoming stimuli at the critical state. We suggest that “computation at the edge of a phase transition” is more compatible with the view that dendritic arbors perform an analog rather than a digital dendritic computation.

The activity-dependent transcription factor NPAS4 regulates domain-specific inhibition

A heterogeneous population of inhibitory neurons controls the flow of information through a neural circuit. Inhibitory synapses that form on pyramidal neuron dendrites modulate the summation of excitatory synaptic potentials and prevent the generation of dendritic calcium spikes. Precisely timed somatic inhibition limits both the number of action potentials and the time window during which firing can occur. The activity-dependent transcription factor NPAS4 regulates inhibitory synapse number and function in cell culture, but how this transcription factor affects the inhibitory inputs that form on distinct domains of a neuron in vivo was unclear. Here we show that in the mouse hippocampus behaviourally driven expression of NPAS4 coordinates the redistribution of inhibitory synapses made onto a CA1 pyramidal neuron, simultaneously increasing inhibitory synapse number on the cell body while decreasing the number of inhibitory synapses on the apical dendrites. This rearrangement of inhibition is mediated in part by the NPAS4 target gene brain derived neurotrophic factor (Bdnf), which specifically regulates somatic, and not dendritic, inhibition. These findings indicate that sensory stimuli, by inducing NPAS4 and its target genes, differentially control spatial features of neuronal inhibition in a way that restricts the output of the neuron while creating a dendritic environment that is permissive for plasticity.

Direction selectivity is computed by active dendritic integration in retinal ganglion cells

Active dendritic integration is thought to enrich the computational power of central neurons. However, a direct role of active dendritic processing in the execution of defined neuronal computations in intact neural networks has not been established. Here we used multi-site electrophysiological recording techniques to demonstrate that active dendritic integration underlies the computation of direction selectivity in rabbit retinal ganglion cells. Direction-selective retinal ganglion cells fire action potentials in response to visual image movement in a preferred direction. Dendritic recordings revealed that preferred-direction moving-light stimuli led to dendritic spike generation in terminal dendrites, which were further integrated and amplified as they spread through the dendritic arbor to the axon to drive action potential output. In contrast, when light bars moved in a null direction, synaptic inhibition vetoed neuronal output by directly inhibiting terminal dendritic spike initiation. Active dendritic integration therefore underlies a physiologically engaged circuit-based computation in the retina.

Stochastic Calcium Mechanisms Cause Dendritic Calcium Spike Variability

Bursts of dendritic calcium spikes play an important role in excitability and synaptic plasticity in many types of neurons. In single Purkinje cells, spontaneous and synaptically evoked dendritic calcium bursts come in a variety of shapes with a variable number of spikes. The mechanisms causing this variability have never been investigated thoroughly. In this study, a detailed computational model using novel simulation routines is applied to identify the roles that stochastic ion channels, spatial arrangements of ion channels, and stochastic intracellular calcium have toward producing calcium burst variability. Consistent with experimental recordings from rats, strong variability in the burst shape is observed in simulations. This variability persists in large model sizes in contrast to models containing only voltage-gated channels, where variability reduces quickly with increase of system size. Phase plane analysis of Hodgkin-Huxley spikes and of calcium bursts identifies fluctuation in phase space around probabilistic phase boundaries as the mechanism determining the dependence of variability on model size. Stochastic calcium dynamics are the main cause of calcium burst fluctuations, specifically the calcium activation of mslo/BK-type and SK2 channels. Local variability of calcium concentration has a significant effect at larger model sizes. Simulations of both spontaneous and synaptically evoked calcium bursts in a reconstructed dendrite show, in addition, strong spatial and temporal variability of voltage and calcium, depending on morphological properties of the dendrite. Our findings suggest that stochastic intracellular calcium mechanisms play a crucial role in dendritic calcium spike generation and are therefore an essential consideration in studies of neuronal excitability and plasticity.