Persistent Na⁺ and M-type K⁺ currents opposingly control spike gain in CA3 pyramidal cells

Neural firing response gain and spike threshold are critical intrinsic cell properties that define input-output relations in neurons. Alterations of these cellular properties in hippocampal pyramidal cells (PCs) may strongly influence network dynamics in health and disease. Here we investigated how specific voltage-gated conductance affect these properties in adult rat CA3 pyramidal cells (PCs) in hippocampal slices under near-physiological conditions. We examined currents activated at near-threshold potential – persistent sodium current (I_NAP), T-type Ca²⁺ current (I_CaT), M-type K⁺ current (I_M), SK Ca²⁺ − dependent current (I_SK), and h-type cationic current (I_h) through pharmacological modulation and analysis of resulting changes. CA3 PCs showed high heterogeneity in firing response gain, likely reflecting individual variations in active conductance at rest. Blocking I_NAP by riluzole decreased firing response gain, an effect associated with a reduction in the depolarizing shift (DS) underlying evoked spike trains. Conversely, blocking I_M with XE991 markedly increased firing response gain, decreased the DS, increased input resistance, and lowered spike threshold. Enhancing I_M by retigabine produced opposite effects. Blocking I_SK with apamin moderately augmented firing response gain, while blocking I_CaT and I_h exerted no effect on discharge. Our findings identify I_NaP and I_M as key determinants of spike response gain and threshold of CA3 PCs, suggesting that modulators of these currents may effectively modify neuronal input-output relations in both normal and pathological states of hippocampal hypo- or hyperexcitability.