Serotonin, by activating different receptor subtypes, regulates membrane excitability in the central nervous system in a complex manner (Andrade, 1998
). The involvement of various voltage-gated channels in this action of serotonin receptors has been revealed (Colino and Halliwell, 1987
; Penington and Kelly, 1990
; Haj-Dahmane and Andrade, 1996
; Carr et al., 2002
). However, application of a low concentration of the 5-HT1A
agonist alone fails to alter the AP firing elicited by somatic current injection in PFC pyramidal neurons (), suggesting that the low level of 5-HT1A
activation is not sufficient to trigger the change of voltage-gated channels that affects neuronal excitability.
It is largely unknown whether serotonin could affect neuronal firing activity by interacting with ligand-gated channels. Previous studies have shown that the NMDAR channel is an important target of 5-HT2
receptors (Blank et al., 1996
; Arvanov et al., 1999
; Yuen et al., 2005
). Thus, we examined the effect of serotonin receptors on the excitability of PFC pyramidal neurons when NMDA receptors are co-activated. In the presence of NMDA, application of a low concentration of the 5-HT1A
agonist exerts a reducing or enhancing effect on the AP firing respectively, suggesting that NMDAR activation provides a “gate” to facilitate the opposing regulation of neuronal excitability by the low level of 5-HT1A
activation. Interestingly, dopamine D1 and D2 receptors can also modulate PFC pyramidal cell excitability, by interacting with different glutamate receptor subtypes (Kuei and O'Donnell, 2004
How does 5-HT1A or 5-HT2A/C receptor regulate AP firing in the presence of NMDA? One possible mechanism is through the direct action on NMDAR channels. However, we found that the low concentration of 5-HT1A or 5-HT2A/C agonist (e.g. 1 μM of 8-OH-DPAT or 0.8 μM of α-Me-5HT) failed to cause a significant change in the NMDAR-mediated ionic current (data not shown). Thus, the reason why NMDA facilitates serotonergic regulation of neuronal excitability is likely to be the change of intracellular signaling molecule(s) downstream of the Ca2+ flow through NMDAR channels.
Our electrophysiological and biochemical evidence show that the opposing actions of 5-HT1A
on neuronal excitability are mediated by the differential regulation of a converging target, ERK. ERK can be regulated by the PKA or PKC cascade (Roberson et al., 1999
) downstream of 5-HT1A
receptors. However, application of the low concentration of 5-HT1A
agonist (e.g. 1 μM of 8-OH-DPAT or 0.8 μM of α-Me-5HT) alone was insufficient to significantly change the ERK activity (). Again, NMDAR activation provides a “gate” to facilitate the opposing regulation of ERK activity by 5-HT1A
receptors (), probably via facilitating their coupling to the PKA or PKC cascade. Since ERK activation can increase the amplitude of backpropagating action potentials by phosphorylating dendritic A-type K+ channel Kv4.2 subunits (Yuan et al., 2002
), we speculate that one possible mechanism underlying the regulation of neuronal excitability by 5-HT-NMDA interactions is through the ERK modification of dendritic K+ channels.
To understand the potential implication of the regulation of neuronal excitability by 5-HT-NMDA interactions in cognitive and emotional processes, we examined animals exposed to acute stress, since many mental illnesses are exacerbated by stress conditions (Mazure, 1995
; Arnsten 1998
). Several lines of evidence have shown that stress interferes with serotonin neurotransmission by changing serotonin release or serotonin receptor functions (Adell et al., 1997
; Maswood et al., 1998
; Lowry et al., 2000
; Tan et al., 2004
). The forced swim test, a behavioral paradigm often used to evaluate antidepressant/anxiolytic efficacy, was used as a stressor in our studies. The effect of 5-HT2A/C
, but not 5-HT1A
, on AP firing is lost in stressed animals, which is associated with the selective loss of 5-HT2A/C
increase of ERK activity. It suggests that 5-HT2A/C
receptors are probably desensitized and inactivated by elevated levels of serotonin in response to stress stimulation. The persevered 5-HT1A
decrease of AP firing will help to dampen the excitability of PFC pyramidal neurons, which will lead to the suppression of PFC output under stress conditions.
Serotonin-glutamate interaction has been proposed to be a new target for antipsychotic drugs (Aghajanian and Marek, 1999
). In this study, we demonstrate that different serotonin receptors, by interacting with NMDA receptors, influence the excitability of PFC pyramidal neurons via converging on ERK. It provides a potential mechanism that underlies the functional role of both serotonin system and NMDA receptors in normal cognition and mental disorders.