Spike Timing and Reliability in Cortical Pyramidal Neurons: Effects of EPSC Kinetics, Input Synchronization and Background Noise on Spike Timing

In vivo studies have shown that neurons in the neocortex can generate action potentials at high temporal precision. The mechanisms controlling timing and reliability of action potential generation in neocortical neurons, however, are still poorly understood. Here we investigated the temporal precision and reliability of spike firing in cortical layer V pyramidal cells at near-threshold membrane potentials. Timing and reliability of spike responses were a function of EPSC kinetics, temporal jitter of population excitatory inputs, and of background synaptic noise. We used somatic current injection to mimic population synaptic input events and measured spike probability and spike time precision (STP), the latter defined as the time window (Δt) holding 80% of response spikes. EPSC rise and decay times were varied over the known physiological spectrum. At spike threshold level, EPSC decay time had a stronger influence on STP than rise time. Generally, STP was highest (≤2.45 ms) in response to synchronous compounds of EPSCs with fast rise and decay kinetics. Compounds with slow EPSC kinetics (decay time constants>6 ms) triggered spikes at lower temporal precision (≥6.58 ms). We found an overall linear relationship between STP and spike delay. The difference in STP between fast and slow compound EPSCs could be reduced by incrementing the amplitude of slow compound EPSCs. The introduction of a temporal jitter to compound EPSCs had a comparatively small effect on STP, with a tenfold increase in jitter resulting in only a five fold decrease in STP. In the presence of simulated synaptic background activity, precisely timed spikes could still be induced by fast EPSCs, but not by slow EPSCs

A Selective Interplay between Aberrant EPSPKA and INaP Reduces Spike Timing Precision in Dentate Granule Cells of Epileptic Rats

Spike timing precision is a fundamental aspect of neuronal information processing in the brain. Here we examined the temporal precision of input–output operation of dentate granule cells (DGCs) in an animal model of temporal lobe epilepsy (TLE). In TLE, mossy fibers sprout and establish recurrent synapses on DGCs that generate aberrant slow kainate receptor–mediated excitatory postsynaptic potentials (EPSPKA) not observed in controls. We report that, in contrast to time-locked spikes generated by EPSPAMPA in control DGCs, aberrant EPSPKA are associated with long-lasting plateaus and jittered spikes during single-spike mode firing. This is mediated by a selective voltage-dependent amplification of EPSPKA through persistent sodium current (INaP) activation. In control DGCs, a current injection of a waveform mimicking the slow shape of EPSPKA activates INaP and generates jittered spikes. Conversely in epileptic rats, blockade of EPSPKA or INaP restores the temporal precision of EPSP–spike coupling. Importantly, EPSPKA not only decrease spike timing precision at recurrent mossy fiber synapses but also at perforant path synapses during synaptic integration through INaP activation. We conclude that a selective interplay between aberrant EPSPKA and INaP severely alters the temporal precision of EPSP–spike coupling in DGCs of chronic epileptic rats

The Effect of synchronized inputs at the single neuron level

It is commonly assumed that temporal synchronization of excitatory synaptic inputs onto a single neuron increases its firing rate. We investigate here the role of synaptic synchronization for the leaky integrate-and-fire neuron as well as for a biophysically and anatomically detailed compartmental model of a cortical pyramidal cell. We find that if the number of excitatory inputs, N, is on the same order as the number of fully synchronized inputs necessary to trigger a single action potential, N_t, synchronization always increases the firing rate (for both constant and Poisson-distributed input). However, for large values of N compared to N_t, ''overcrowding'' occurs and temporal synchronization is detrimental to firing frequency. This behavior is caused by the conflicting influence of the low-pass nature of the passive dendritic membrane on the one hand and the refractory period on the other. If both temporal synchronization as well as the fraction of synchronized inputs (Murthy and Fetz 1993) is varied, synchronization is only advantageous if either N or the average input frequency, ƒ(in), are small enough

Progress toward an understanding of cortical computation

The additional data, perspectives, questions, and criticisms contributed by the commentaries strengthen our view that local cortical processors coordinate their activity with the context in which it occurs using contextual fields and synchronized population codes. We therefore predict that whereas the specialization of function has been the keynote of this century the coordination of function will be the keynote of the next

Short-Term Synaptic Plasticity Orchestrates the Response of Pyramidal Cells and Interneurons to Population Bursts

The synaptic drive from neuronal populations varies considerably over short time scales. Such changes in the pre-synaptic rate trigger many temporal processes absent under steady-state conditions. This paper examines the differential impact of pyramidal cell population bursts on post-synaptic pyramidal cells receiving depressing synapses, and on a class of interneuron that receives facilitating synapses. In experiment a significant shift of the order of one hundred milliseconds is seen between the response of these two cell classes to the same population burst. It is demonstrated here that such a temporal differentiation of the response can be explained by the synaptic and membrane properties without recourse to elaborate cortical wiring schemes. Experimental data is first used to construct models of the two types of dynamic synaptic response. A population-based approach is then followed to examine analytically the temporal synaptic filtering effects of the population burst for the two post-synaptic targets. The peak-to-peak delays seen in experiment can be captured by the model for experimentally realistic parameter ranges. It is further shown that the temporal separation of the response is communicated in the outgoing action potentials of the two post-synaptic cells: pyramidal cells fire at the beginning of the burst and the class of interneuron receiving facilitating synapses fires at the end of the burst. The functional role of such delays in the temporal organisation of activity in the cortical microcircuit is discusse

Monosynaptic connections between pairs of spiny stellate cells in layer 4 and pyramidal cells in layer 5A indicate that lemniscal and paralemniscal afferent pathways converge in the infragranular somatosensory cortex.

Monosynaptic interlaminar connections between spiny stellate cells in layer 4 (L4), the main cortical recipient layer for thalamic projections, and pyramidal cells in layer 5A (L5A), one of the main cortical output layers, were examined anatomically and functionally by paired recordings in acute brain slices. The somata of pairs forming interlaminar L4-to-L5A connections were located predominantly close to or directly under the barrel-septum wall in layer 4. Superposition of spiny stellate axon arbors and L5A pyramidal cell dendritic arbors suggested an innervation domain underneath an L4 barrel wall. Functionally, the L4-to-L5A connections were of high reliability and relatively low efficacy, with a unitary EPSP amplitude of 0.6 mV, and the connectivity was moderately high (one in seven pairs tested was connected). The EPSP amplitude was weakly depressing (paired-pulse ratio of approximately 0.8) during repetitive presynaptic action potentials at 10 Hz. The existence of Monosynaptic L4-to-L5A connections indicates that the specific 'lemniscal' thalamic input from the ventro-basal nucleus of the thalamus to the cortex and the more unspecific 'paralemniscal' afferent thalamic projections from the posterior medial nucleus of the thalamus merge already at an initial stage of cortical signal processing. These Monosynaptic connections establish a Monosynaptic coupling of the input to the cortex and its output, thereby effectively bypassing the supragranular layers

Near-Perfect Synaptic Integration by Na(v)1.7 in Hypothalamic Neurons Regulates Body Weight

Neurons are well suited for computations on millisecond timescales, but some neuronal circuits set behavioral states over long time periods, such as those involved in energy homeostasis. We found that multiple types of hypothalamic neurons, including those that oppositely regulate body weight, are specialized as near-perfect synaptic integrators that summate inputs over extended timescales. Excitatory postsynaptic potentials (EPSPs) are greatly prolonged, outlasting the neuronal membrane time-constant up to 10-fold. This is due to the voltage-gated sodium channel Nav1.7 (Scn9a), previously associated with pain-sensation but not synaptic integration. Scn9a deletion in AGRP, POMC, or paraventricular hypothalamic neurons reduced EPSP duration, synaptic integration, and altered body weight in mice. In vivo whole-cell recordings in the hypothalamus confirmed near-perfect synaptic integration. These experiments show that integration of synaptic inputs over time by Nav1.7 is critical for body weight regulation and reveal a mechanism for synaptic control of circuits regulating long term homeostatic functions

Chandelier cells control excessive cortical excitation: Characteristics of whisker-evoked synaptic responses of layer 2/3 nonpyramidal and pyramidal neurons

Chandelier cells form inhibitory axo-axonic synapses on pyramidal neurons with their characteristic candlestick-like axonal terminals. The functional role of chandelier cells is still unclear, although the preferential loss of this cell type at epileptic loci suggests a role in epilepsy. Here we report an examination of whisker-and spontaneous activity-evoked responses in chandelier cells and other fast-spiking nonpyramidal neurons and regular-spiking pyramidal neurons in layer 2/3 of the barrel cortex. Fast-spiking nonpyramidal neurons, including chandelier cells, basket cells, neurogliaform cells, double bouquet cells, net basket cells, bitufted cells, and regular-spiking pyramidal neurons all respond to stimulation of multiple whiskers on the contralateral face. Whisker stimulation, however, evokes small, delayed EPSPs preceded by an earlier IPSP and no action potentials in chandelier cells, different from other nonpyramidal and pyramidal neurons. In addition, chandelier cells display a larger receptive field with lower acuity than other fast-spiking nonpyramidal neurons and pyramidal neurons. Notably, simultaneous dual whole-cell in vivo recordings show that chandelier cells, which rarely fire action potentials spontaneously, fire more robustly than other types of cortical neurons when the overall cortical excitation increases. Thus, chandelier cells may not process fast ascending sensory information but instead may be reserved to prevent excessive excitatory activity in neuronal networks

Encoding and decoding of dendritic excitation during active states in pyramidal neurons

Neocortical neurons spontaneously fire action potentials during active network states; how are dendritic synaptic inputs integrated into the ongoing action potential output pattern of neurons? Here, the efficacy of barrages of simulated EPSPs generated at known dendritic sites on the rate and pattern of ongoing action potential firing is determined using multisite whole-cell recording techniques from rat layer 5 neocortical pyramidal neurons in vitro. Under quiescent conditions, the somatic impact of proximal (253 +/- 15 microm from soma; n = 28) dendritic barrages of simulated EPSPs was 4.7-fold greater than identical barrages of EPSPs generated from distal (572 +/- 13 microm from soma) sites. In contrast, barrages of proximal simulated EPSPs enhanced the rate of ongoing action potential firing, evoked by somatic simulated EPSPs, by only 1.6-fold more than distal simulated EPSPs. This relationship was apparent across a wide frequency range of action potential firing (6-22 Hz) and dendritic excitation (100-500 Hz). The efficacy of distal dendritic EPSPs was formed by the recruitment of active dendritic processes that transformed the ongoing action potential firing pattern, promoting action potential burst firing. Paired recordings (n = 42) revealed that patterns of action potential firing generated by concerted somatic and distal dendritic excitation reliably and powerfully drove postsynaptic excitation as a result of enhanced reliability of transmitter release during bursts of action potential firing. During active states, therefore, distal excitatory synaptic inputs decisively control the excitatory synaptic output of layer 5 neocortical pyramidal neurons and so powerfully influence network activity in the neocortex

Temporal Modulation of Spike-Timing-Dependent Plasticity

Spike-timing-dependent plasticity (STDP) has attracted considerable experimental and theoretical attention over the last decade. In the most basic formulation, STDP provides a fundamental unit – a spike pair – for quantifying the induction of long-term changes in synaptic strength. However, many factors, both pre- and postsynaptic, can affect synaptic transmission and integration, especially when multiple spikes are considered. Here we review the experimental evidence for multiple types of nonlinear temporal interactions in STDP, focusing on the contributions of individual spike pairs, overall spike rate, and precise spike timing for modification of cortical and hippocampal excitatory synapses. We discuss the underlying processes that determine the specific learning rules at different synapses, such as postsynaptic excitability and short-term depression. Finally, we describe the success of efforts toward building predictive, quantitative models of how complex and natural spike trains induce long-term synaptic modifications