Differential modulation of I-h by 5-HT receptors in mouse CA1 hippocampal neurons

CA1 pyramidal neurons of the hippocampus express various types of serotonin (5-HT) receptors, such as 5-HT1A, 5-HT4 and 5-HT7 receptors, which couple to Galpha(i) or Galpha(s) proteins and operate on different intracellular signalling pathways. In the present paper we verify such differential serotonergic modulation for the hyperpolarization-activated current I-h . Activation of 5-HT1A receptors induced an augmentation of current-induced hyperpolarization responses, while the responses declined after 5-HT4 receptors were activated. The resting potential of neurons hyperpolarized (-2.3 +/- 0.7 mV) after 5-HT1A receptor activation, activation of 5-HT4 receptors depolarized neurons (+3.3 +/- 1.4 mV). Direct activation of adenylyl cyclase (AC) by forskolin also produced a depolarization. In voltage clamp, the I-h current was identified by its characteristic voltage- and time-dependency and by blockade with CsCl or ZD7288. Activation of 5-HT1A receptors reduced I-h and shifted the activation curve to a more negative voltage by -5 mV at half-maximal activation. Activation of 5-HT4 and 5-HT7 receptors increased I-h and shifted the activation curve to the right by +5 mV. Specific activation of 5-HT4 receptors by BIMU8 increased membrane conductance and showed an increase in I-h in a subset of cells, but did not induce a significant alteration in the activation curve. In order to verify spatial differences, we applied BIMU8 selectively to the soma and to the dendrites. Only somatic application induced receptor activation. These data are confirmed by immunofluorescence stainings with an antibody against the 5-HT4A receptor, revealing receptor expression at the somata of the CA1 region. A similar expression pattern was found with a new antibody against 5-HT7 receptors which reveals immunofluorescence staining on the cell bodies of pyramidal neurons.