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

Abstract

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.

Mild membrane depolarization in neurons induces immediate early gene transcription and acutely subdues responses to successive stimulus

“…After 2 and 4 hours, this depression of Arc pre-mRNA had disappeared. (For DMSO treated samples; Interaction F(4,25) = 1.151, P = 0.3561; TIME F(2,25) = 0.4571, P = 0.6383; KCL (F(2,25) = 4.558, P = 0.0205). 5mM and 30mM KCl treated samples were significantly different ( P = 0.0154).)…”

“…N = 3 for 10’ samples and N = 4 for 15’ samples. For Arc pre-mRNA: Interaction (F(4,25) = 0.9513, P = 0.4511); TIME (F(1,25) = 9.632, P = 0.0047); TREATMENT (F(4,25) = 18.34, P < 0.0001). Main effects analysis of TREATMENT showed 10mM ( P = 0.0009), 20mM ( P < 0.0001), and 30mM KCl ( P = 0.0115) induced significantly more Arc pre-mRNA than the mechanical control.…”

“…Many signaling pathways that respond to KCl-mediated depolarization also regulate intrinsic plasticity in response to ongoing activity (36). Also, the distribution and phosphorylation status of ion channels like the L-type channels alter the firing patterns of the cell (3, 25, 69). Interestingly, CA3 neurons in organotypic cultures modulate their intrinsic firing pattern depending on their history of ongoing subthreshold activity and kinase activity (25).…”

“…Also, the distribution and phosphorylation status of ion channels like the L-type channels alter the firing patterns of the cell (3, 25, 69). Interestingly, CA3 neurons in organotypic cultures modulate their intrinsic firing pattern depending on their history of ongoing subthreshold activity and kinase activity (25). Here, organotypic cultures of rat CA3 neurons experienced paired pulses applied at 1 Hz and repeated 500 times for a total of ∼8 minutes.…”

“…The activity history of a neuron may include suprathreshold membrane polarization resulting in orthodromic or backpropagating action potentials, and also, subthreshold graded potential changes. While action potentials are traditionally viewed as key mediator of neuronal operations, studies have shown that subthreshold graded changes in membrane potential can effectively recruit neuronal second messengers (24), alter intrinsic properties (25), and modulate synaptic communication (26–28). Most activity-induced gene transcription studies have involved suprathreshold stimulation, including direct membrane depolarization using 55mM extracellular potassium chloride (KCl), homeostatic potentiation of synaptic activity by prolonged Tetrodotoxin (TTX) treatment followed by its washout, or disinhibition of inhibitory synapses using Bicuculline (Bic) (11, 29).…”