Characterisation of Hyperpolarization-Activated Currents (Ih) in the Medial Septum/Diagonal Band Complex in the Mouse

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Hyperpolarization-activated cyclic nucleotide gated (HCN) channel subunits are distributed widely, but selectively, in the central nervous system, and underlie hyperpolarization-activated currents (Ih) that contribute to rhythmicity in a variety of neurons. This study investigates, using current and voltage-clamp techniques in brain slices from young mice, the properties of Ih currents in medial septum/diagonal band (MS/DB) neurons. Subsets of neurons in this complex, including GABAergic and cholinergic neurons, innervate the hippocampal formation, and play a role in modulating hippocampal theta rhythm. In support of a potential role for Ih in regulating MS/DB firing properties and consequently hippocampal neuron rhythmicity, Ih currents were present in around 60% of midline MS/DB complex neurons. The Ih currents were sensitive to the selective blocker ZD7288 (10 μM). The Ih current had a time constant of activation of around 220 ms (at −130 mV), and tail current analysis revealed a half-activation voltage of −98 mV. Notably, the amplitude and kinetics of Ih currents in MS/DB neurons were insensitive to the cAMP membrane permeable analogue 8-bromo-cAMP (1 mM), and application of muscarine (100 μM). Immunofluoresence using antibodies against HCN1, 2 and 4 channel subunits revealed that all three HCN subunits are expressed in neurons in the MS/DB, including neurons that express the calcium binding protein parvalbumin (marker of fast spiking GABAergic septo-hippocampal projection neurons).The results demonstrate, for the first time, that specific HCN channel subunits are likely to be coexpressed in subsets of MS/DB neurons, and that the resultant Ih currents show both similarities, and differences, to previously described Ih currents in other CNS neurons.