Conditioning by subthreshold synaptic input changes the intrinsic firing pattern of CA3 hippocampal neurons

Unlike synaptic strength, intrinsic excitability is assumed to be a stable property of neurons. For example, learning of somatic conductances is generally not incorporated into computational models, and the discharge pattern of neurons in response to test stimuli is frequently used as a basis for phenotypic classification. However, it is increasingly evident that signal processing properties of neurons are more generally plastic on the timescale of minutes. Here we demonstrate that the intrinsic firing patterns of CA3 neurons of the rat hippocampus in vitro undergo rapid long-term plasticity in response to a few minutes of only subthreshold synaptic conditioning. This plasticity on the spike timing could also be induced by intrasomatic injection of subthreshold depolarizing pulses and was blocked by kinase inhibitors, indicating that discharge dynamics are modulated locally. Cluster analysis of firing patterns before and after conditioning revealed systematic transitions toward adapting and intrinsic burst behaviors, irrespective of the patterns initially exhibited by the cells. We used a conductance-based model to decide appropriate pharmacological blockade and found that the observed transitions are likely due to recruitment of low-voltage calcium and Kv7 potassium conductances. We conclude that CA3 neurons adapt their conductance profile to the subthreshold activity of their input, so that their intrinsic firing pattern is not a static signature, but rather a reflection of their history of subthreshold activity. In this way, recurrent output from CA3 neurons may collectively shape the temporal dynamics of their embedding circuits. NEW & NOTEWORTHY Although firing patterns are widely conserved across the animal phyla, it is still a mystery why nerve cells present such diversity of discharge dynamics upon somatic step currents. Adding a new timing dimension to the intrinsic plasticity literature, here we show that CA3 neurons rapidly adapt through the space of known firing patterns in response to the subthreshold signals that they receive from their embedding circuit, potentially adjusting their network processing to the temporal statistics of their circuit.

Reconstruction of in-vivo subthreshold activity of single neurons from large-scale spiking recordings

SummaryCurrent developments in the manufacturing of silicon probes allow recording of spikes from large populations of neurons from several brain structures in freely moving animals. It is still, however, technically challenging to record the membrane potential from awake behaving animals. Routine access to the subthreshold activity of neurons would be of great value in order to understand the role of, for example, neuronal integration, oscillations, and excitability. Here we have developed a framework for reconstructing the subthreshold activity of single neurons using the spiking activity from large neuronal populations. The reconstruction accuracy and reliability have been evaluated with ground truth data provided from simultaneous patch clamp membrane potential recordings in-vivo. Given the abundance of large-scale spike recordings in the contemporary systems neuroscience society, this approach provides a general access to the subthreshold activity and hence could shed light on the intricate mechanisms of the genesis of spiking activity.

Mesoscale-duration activated states gate spiking in response to fast rises in membrane voltage in the awake brain

We analyzed subthreshold activity preceding spikes in hippocampus and barrel cortex of awake mice. Aperiodic voltage ramps extending over tens to hundreds of milliseconds consistently precede and facilitate spikes, in a manner dependent on both their amplitude and their duration. These voltage ramps represent a “mesoscale” activated state that gates spike production in vivo.

Conditioning by Subthreshold Synaptic Input Changes the Intrinsic Firing Pattern of CA3 Hippocampal Neurons

Unlike synaptic strength, intrinsic excitability is assumed to be a stable property of neurons. For example, learning of somatic conductances is generally not incorporated into computational models, and the discharge pattern of neurons in response to test stimuli is frequently used as a basis for phenotypic classification. However, it is increasingly evident that signal processing properties of neurons are more generally plastic on the timescale of minutes. Here we demonstrate that the intrinsic firing patterns of CA3 neurons of the rat hippocampus in vitro undergo rapid long-term plasticity in response to a few minutes of only subthreshold synaptic conditioning. This plasticity on the spike-timing could also be induced by intrasomatic injection of subthreshold depolarizing pulses and was blocked by kinase inhibitors, indicating that discharge dynamics are modulated locally. Cluster analysis of firing patterns before and after conditioning revealed systematic transitions towards adapting and intrinsic burst behaviours, irrespective of the patterns initially exhibited by the cells. We used a conductance-based model to decide appropriate pharmacological blockade, and found that the observed transitions are likely due to recruitment of calcium and M-type potassium conductances. We conclude that CA3 neurons adapt their conductance profile to the subthreshold activity of their input, so that their intrinsic firing pattern is not a static signature, but rather a reflection of their history of subthreshold activity. In this way, recurrent output from CA3 neurons may collectively shape the temporal dynamics of their embedding circuits.New & NoteworthyDespite being widely conserved across the animal phyla, it is still a mystery why nerve cells present diverse discharge dynamics upon somatic step currents. Adding a new timing dimension to the intrinsic plasticity literature, here we show that CA3 neurons rapidly adapt through the space of known firing patterns in response to the subthreshold signals that they receive from their embedding circuit. This result implies that CA3 neurons collectively adjust their network processing to the temporal statistics of their circuit.

Contrasting roles of Ih and the persistent sodium current at subthreshold voltages during naturalistic stimuli

The subthreshold activity of hippocampal CA1 pyramidal neurons is regulated by the persistent sodium current ( INaP) and the h-current ( Ih), carried by tetrodotoxin-sensitive sodium channels and hyperpolarization-activated cyclic-nucleotide-gated channels, respectively. Recently, Yamada-Hanff and Bean ( J Neurophysiol 114: 2376–2389, 2015) used pharmacological methods to discern the roles of Ih and INaP at subthreshold voltages during naturalistic stimuli. We discuss these findings in the context of dorsoventral heterogeneity in the hippocampus and suggest further applications of the method.