Long-Term Inactivation of Sodium Channels as a Mechanism of Adaptation in CA1 Pyramidal Neurons

Abstract

Many hippocampal CA1 pyramidal cells function as place cells, increasing their firing rate when a specific place field is traversed. The dependence of CA1 place cell firing on position within the place field is asymmetric. We investigated the source of this asymmetry by injecting triangular depolarizing current ramps to approximate the spatially-tuned, temporally-diffuse depolarizing synaptic input received by these neurons while traversing a place field. Ramps were applied to CA1 pyramidal neurons from male rats in vitro (slice electrophysiology) and in silico (multicompartmental NEURON model). Under control conditions, CA1 neurons fired more action potentials at higher frequencies on the up-ramp versus the down-ramp. This effect was more pronounced for dendritic compared to somatic ramps. We incorporated a four-state Markov scheme for Na V 1.6 channels into our model and calibrated the spatial dependence of long-term inactivation according to the literature; this spatial dependence was sufficient to explain the difference in dendritic versus somatic ramps. Long-term inactivation reduced the firing frequency by decreasing open-state occupancy, and reduced spike amplitude during trains by decreasing occupancy in closed states, which comprise the available pool. PKC activator phorbol-dibutyrate, known to reduce Na V long-term inactivation, removed spike amplitude attenuation in vitro more visibly in dendrites and greatly reduced adaptation, consistent with our hypothesized mechanism. Intracellular application of a peptide inducing long-term Na V inactivation elicited spike amplitude attenuation during spike trains in the soma and greatly enhanced adaptation. Our synergistic experimental/computational approach shows that longterm inactivation of Na V 1.6 is a key mechanism of adaptation in CA1 pyramidal cells.

Cholinergic Modulation Shifts the Response of CA1 Pyramidal Cells to Depolarizing Ramps via TRPM4 Channels with Potential Implications for Place Field Firing

“…The cascade of events that follow cholinergic activation in these neurons includes the suppression of a number of outward currents (Brown and Adams, 1980; Hoffman and Johnston, 1998; Buchanan et al, 2010; Giessel and Sabatini, 2010) some of which are also involved in firing rate adaptation (Stocker et al, 1999; Gu et al, 2005; Pedarzani et al, 2005; Otto, 2006; Chen et al, 2014). We have previously examined the contribution of small-conductance calcium-activated potassium (SK) current, M-type potassium current, and A-type potassium current with respect to the asymmetric firing in response to symmetric current ramps (Upchurch et al, 2022). We found that, in the relatively low range of firing frequencies evoked by this type of stimulation, the adaptation induced by these currents does not play a role in shifting action potentials to earlier times during the ramp.…”

“…Figure 7A2, 7B2, and 7C2 show the nanomolar [Ca 2+ ] increases in the outer shell, both in the simulated control and CCh conditions. Note that in control (A2) and with high IP 3 but no nanodomain (C2), the Ca 2+ concentration in the outer shell begins to decrease prior to cessation of spiking (see red arrows), due to the decrease in frequency during the down-ramp because of the Na + channel long-term inactivation (Upchurch et al, 2022). Figure 7A3 shows no noticeable micromolar increase in Ca 2+ concentration in the nanodomain under control conditions.…”

“…Experimental data were recorded and analyzed with Igor Pro software (WaveMetrics). Left or rightward shifts in firing along the current ramp were quantified as an adaptation index, as previously described (Upchurch et al, 2022): …”

“…We have previously used triangular-shaped current ramps (Upchurch et al, 2022) to emulate the depolarizing input received by a place cell during a place field traversal (Epsztein et al, 2011), adjusting the amplitude of the ramps for each cell and condition to produce peak frequencies between 10 and 25 Hz as observed in place cells in vivo (Hargreaves et al, 2007;Resnik et al, 2012;Bittner et al, 2015).…”

“…Regardless of whether these ramps are injected at the soma or in the dendrites of CA1 pyramidal neurons, they elicit fewer spikes on the down-ramp than on the up-ramp, due to adaptation mediated by long-term sodium channel inactivation (Fernandez and White, 2010;Venkatesan et al, 2014;Upchurch et al, 2022).…”