The medial septum and diagonal band of Broca (MSDB) send glutamatergic axons to medial entorhinal cortex (MEC). We found that this pathway provides speed-correlated input to several MEC cell-types in layer 2/3. The speed signal is integrated most effectively by pyramidal cells but also excites stellate cells and interneurons. Thus, the MSDB conveys speed information that can be used by MEC neurons for spatial representation of self-location.

NaV1.3 is a subtype of the voltage-gated sodium channel family. It has been implicated in the pathogenesis of neuropathic pain, although the contribution of this channel to neuronal excitability is not well understood. Tf2, a β-scorpion toxin previously identified from the venom of Tityus fasciolatus, has been reported to selectively activate NaV1.3. Here, we describe the activity of synthetic Tf2 and assess its suitability as a pharmacological probe for NaV1.3. As described for the native toxin, synthetic Tf2 (1 µM) caused early channel opening, decreased the peak current, and shifted the voltage dependence of NaV1.3 activation in the hyperpolarizing direction by −11.3 mV, with no activity at NaV1.1, NaV1.2, and NaV1.4-NaV1.8. Additional activity was found at NaV1.9, tested using the hNav1.9_C4 chimera, where Tf2 (1 µM) shifted the voltage dependence of activation by −6.3 mV. In an attempt to convert Tf2 into an NaV1.3 inhibitor, we synthetized the analogue Tf2[S14R], a mutation previously described to remove the excitatory activity of related β-scorpion toxins. Indeed, Tf2[S14R](10 µM) had reduced excitatory activity at NaV1.3, although it still caused a small −5.8 mV shift in the voltage dependence of activation. Intraplantar injection of Tf2 (1 µM) in mice caused spontaneous flinching and swelling, which was not reduced by the NaV1.1/1.3 inhibitor ICA-121431 nor in NaV1.9-/- mice, suggesting off-target activity. In addition, despite a loss of excitatory activity, intraplantar injection of Tf2[S14R](10 µM) still caused swelling, providing strong evidence that Tf2 has additional off-target activity at one or more non-neuronal targets. Therefore, due to activity at NaV1.9 and other yet to be identified target(s), the use of Tf2 as a selective pharmacological probe may be limited.

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Voltage-gated sodium channels are responsible not only for the fast upstroke of the action potential, 2 but they also modify cellular excitability via persistent and resurgent currents. Insecticides act via 3 permanently opening sodium channels to immobilize the animals. Cellular recordings performed 4 decades ago revealed distinctly hooked tail currents induced by these compounds. Here, we applied 5 the classical type-II pyrethroid deltamethrin on human cardiac Nav1.5 and observed resurgent-like 6 currents at very negative potentials in the absence of any pore-blocker, which resemble those hooked 7 tail currents. We show that deltamethrin dramatically slows both fast inactivation and deactivation of 8 Nav1.5 and thereby induces large persistent currents. Using the sea anemone toxin ATx-II as a tool to 9 prevent all inactivation-related processes, resurgent-like currents were eliminated while persistent 10 currents were preserved. Our experiments suggest that, in deltamethrin-modified channels, recovery 11 from inactivation occurs faster than delayed deactivation, opening a brief window for sodium influx 12 and leading to hooked, resurgent-like currents, in the absence of an open channel blocker. Thus, we 13 now explain with pharmacological methods the biophysical gating changes underlying the 14 deltamethrin induced hooked tail currents. 15