Competition between persistent Na⁺ and muscarine-sensitive K⁺ currents shapes perithreshold resonance and spike tuning in CA1 pyramidal neurons

Neurons from many brain regions display intrinsic subthreshold theta-resonance, responding preferentially to theta-frequency oscillatory stimuli. Resonance may contribute to selective communication among neurons and to orchestrate brain rhythms. CA1 pyramidal neurons receive theta activity, generating place fields. In these neurons the expression of perithreshold frequency preference is controversial, particularly in the spiking regime, with evidence favoring either non-resonant (integrator-like) or resonant behavior. Perithreshold dynamics depends on the persistent Na⁺ current I NaP developing above −70 mV and the muscarine-sensitive K⁺ current I_M activating above −60 mV. We conducted current and voltage clamp experiments in slices to investigate perithreshold excitability of CA1 neurons under oscillatory stimulation. Around 20% of neurons displayed perithreshold resonance that is expressed in spiking. The remaining neurons (∼80%) acted as low-pass filters lacking frequency preference. Paired voltage clamp measurement of I NaP and I M showed that perithreshold activation of I M is in general low while I NaP is high enough to depolarize neurons toward threshold before resonance expression, explaining the most abundant non-resonant perithreshold behavior. Partial blockade of I NaP by pharmacological tools or dynamic clamp changed non-resonant to resonant behavior. Furthermore, shifting I M activation toward hyperpolarized potentials by dynamic clamp also transformed non-resonant neurons into resonant ones. We propose that the relative levels of I NaP and I M control perithreshold behavior of CA1 neurons constituting a gating mechanismfor theta resonance in the spiking regime. Both currents are regulated by intracellular signaling and neuromodulators which may allow dynamic switching of perithreshold behavior between resonant and non-resonant.