There is growing evidence linking alterations in serotonergic signaling in the prefrontal cortex to the etiology of schizophrenia. Prefrontal pyramidal neurons are richly innervated by serotonergic fibers and express high levels of serotonergic 5-HT2-class receptors. It is unclear, however, how activation of these receptors modulates cellular activity. To help fill this gap, whole cell voltage-clamp and single-cell RT-PCR studies of acutely isolated layer V-VI prefrontal pyramidal neurons were undertaken. The vast majority (>80%) of these neurons had detectable levels of 5-HT2A or 5-HT2C receptor mRNA. Bath application of 5-HT2 agonists inhibited voltage-dependent Ca2+ channel currents. L-type Ca2+ channels were a particularly prominent target of this signaling pathway. The L-type channel modulation was blocked by disruption of Gαq signaling or by inhibition of phospholipase Cβ. Antagonism of intracellular inositol trisphosphate signaling, chelation of intracellular Ca2+, or depletion of intracellular Ca2+ stores also blocked this modulation. Inhibition of the Ca2+-dependent phosphatase calcineurin prevented receptor-mediated modulation of L-type currents. Last, the 5-HT2 receptor modulation vas robustly expressed in neurons from Cav1.3 knockout mice. These findings argue that 5-HT2 receptors couple through Gαq proteins to trigger a phospholipase Cβ/inositol trisphosphate signaling cascade resulting in the mobilization of intracellular Ca2+, activation of calcineurin, and inhibition of Cav1.2 L-type Ca2+ currents. This modulation and its blockade by atypical neuroleptics could have wide-ranging effects on synaptic integration and long-term gene expression in deep-layer prefrontal pyramidal neurons.
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