Somatodendritic autoreceptor regulation of serotonergic neurons: dependence on l‐tryptophan and tryptophan hydroxylase‐activating kinases

Abstract

The somatodendritic 5-HT(1A) autoreceptor has been considered a major determinant of the output of the serotonin (5-HT) neuronal system. However, recent studies in brain slices from the dorsal raphe nucleus have questioned the relevance of 5-HT autoinhibition under physiological conditions. In the present study, we found that the difficulty in demonstrating 5-HT tonic autoinhibition in slice results from in vitro conditions that are unfavorable for sustaining 5-HT synthesis. Robust, tonic 5-HT(1A) autoinhibition can be restored by reinstating in vivo 5-HT synthesizing conditions with the initial 5-HT precursor l-tryptophan and the tryptophan hydroxylase co-factor tetrahydrobiopterin (BH(4)). The presence of tonic autoinhibition under these conditions was revealed by the disinhibitory effect of a low concentration of the 5-HT(1A) antagonist WAY 100635. Neurons showing an autoinhibitory response to L-tryptophan were confirmed immunohistochemically to be serotonergic. Once conditions for tonic autoinhibition had been established in raphe slice, we were able to show that 5-HT autoinhibition is critically regulated by the tryptophan hydroxylase-activating kinases calcium/calmodulin protein kinase II (CaMKII) and protein kinase A (PKA). In addition, at physiological concentrations of L-tryptophan, there was an augmentation of 5-HT(1A) receptor-mediated autoinhibition when the firing of 5-HT cells activated with increasing concentrations of the alpha(1) adrenoceptor agonist phenylephrine. Increased calcium influx at higher firing rates, by activating tryptophan hydroxylase via CaMKII and PKA, can work together with tryptophan to enhance negative feedback control of the output of the serotonergic system.

Genotype-Dependent Activity of Tryptophan Hydroxylase-2 Determines the Response to Citalopram in a Mouse Model of Depression

“…However, other studies failed to con- firm this and suggested that some other 5-HT receptor subtype contributes (Moret and Briley, 1997;Stenfors et al, 2001). Interestingly, TRP and the activation of TPH by Ca/calmodulin kinase II and protein kinase A enhanced 5-HT 1A receptor-mediated inhibition of dorsal raphe 5-HT neurons (Liu et al, 2005). Thus, autoreceptor-mediated inhibition of brain 5-HT synthesis is quite likely impaired in DBA/2J and BALB/c mice.…”

Reduced 5-HT1A- and GABABReceptor Function in Dorsal Raphé Neurons Upon Chronic Fluoxetine Treatment of Socially Stressed Rats

“…In our experiments, 89% (n ϭ 196) of the cells displayed the characteristic electrophysiological profile of 5-HT neurons. The vast majority of these cells fired spontaneously at the onset of recordings, unless slices were exposed to tryptophan prior to recording (Liu et al 2005) (n ϭ 15, not shown). In that case, DRN neurons secrete 5-HT within the nucleus, which hyperpolarizes DRN neurons and reduce spontaneous activity (Johnson et al 2002;Liu et al 2005).…”

“…The vast majority of these cells fired spontaneously at the onset of recordings, unless slices were exposed to tryptophan prior to recording (Liu et al 2005) (n ϭ 15, not shown). In that case, DRN neurons secrete 5-HT within the nucleus, which hyperpolarizes DRN neurons and reduce spontaneous activity (Johnson et al 2002;Liu et al 2005). In the absence of the 5-HT precursor tryptophan, endogenous paracrine 5-HT release is low or absent in DRN slices (Johnson et al 2002), providing a good starting point for quantitative measures of the exogenous 5-HT-induced GIRK responses.…”

“…2-5 was 5 M 5-HT, wash, 100 M 5-HT, or 1 mM BAC. For this study, we performed our recordings in the absence of tryptophan loading (Liu et al 2005). These conditions, which are unfavorable for sustaining endogenous 5-HT synthesis, make it unlikely that endogenous 5-HT secretion through spontaneous firing of 5-HT have contributed to basal current responses in the absence of exogenous 5-HT application.…”

Modulation of αCaMKII signaling by rapid ERα action

“…It is known that αCaMKII phosphorylates a wide variety of substrates involved in numerous neuronal processes (McGlade-McCulloh, 1993;Omkumar, 1996;Stefani, 1997;Liu, 2005) and we have identified ERK1/2, CREB, and MAP2 as proteins targeted by E2-induced αCaMKII autophosphorylation in NLT and primary hippocampal neurons. Like αCaMKII, all three proteins are involved in neuronal differentiation, and ERK1/2 and CREB have also been shown to play a role in LTP and memory processes (Trifilieff, 2006).…”