Differential Regulation of MeCP2 Phosphorylation in the CNS by Dopamine and Serotonin

Abstract

Systemic administration of amphetamine (AMPH) induces phosphorylation of MeCP2 at Ser421 (pMeCP2) in select populations of neurons in the mesolimbocortical brain regions. Because AMPH simultaneously activates multiple monoamine neurotransmitter systems, here we examined the ability of dopamine (DA), serotonin (5-HT), and norepinephrine (NE) to induce pMeCP2. Selective blockade of the DA transporter (DAT) or the 5-HT transporter (SERT), but not the NE transporter (NET), was sufficient to induce pMeCP2 in the CNS. DAT blockade induced pMeCP2 in the prelimbic cortex (PLC) and nucleus accumbens (NAc), whereas SERT blockade induced pMeCP2 only in the NAc. Administration of selective DA and 5-HT receptor agonists was also sufficient to induce pMeCP2; however, the specific combination of DA and 5-HT receptors activated determined the regional-and cell-type specificity of pMeCP2 induction. The D 1 -class DA receptor agonist SKF81297 induced pMeCP2 widely; however, coadministration of the D 2 -class agonist quinpirole restricted the induction of pMeCP2 to GABAergic interneurons of the NAc. Intra-striatal injection of the adenylate cyclase activator forskolin was sufficient to induce pMeCP2 in medium-spiny neurons, suggesting that the combinatorial regulation of cAMP by different classes of DA and 5-HT receptors may contribute to the cell-type specificity of pMeCP2 induction. Consistent with the regulation of pMeCP2 by multiple monoamine neurotransmitters, genetic disruption of any single monoamine transporter in DAT-, SERT-, and NETknockout mice failed to eliminate AMPH-induced pMeCP2 in the NAc. Together, these studies indicate that combinatorial signaling through DA and 5-HT receptors can regulate the brain region-and cell-type specific pMeCP2 in the CNS.

Rett syndrome – biological pathways leading from MECP2 to disorder phenotypes

“…2). Hutchinson et al [81] demonstrated that phosphorylation of MECP2 is dependent on dopamine, serotonin and norepinephrine activated pathways (Fig. 2, MECP2 phosphorylation).…”

MeCP2 phosphorylation in the brain: from transcription to behavior

“…Because psychostimulants such as cocaine and amphetamine act on the monoamine neurotransmitter system, the differential roles of dopamine (DA), serotonin (5-HT), and norepinephrine (NE) have been investigated. Although enhanced NE signaling failed to induce pS421 MeCP2, individual activation of DA or 5-HT sufficiently evoked MeCP2 phosphorylation (Deng et al, 2010;Hutchinson et al, 2011). It turned out that DA and 5-HT independently induce pS421 MeCP2 in selective brain regions and a combination of agents targeting specific classes of DA and 5-HT receptors could alone reproduce the pS421 MeCP2 pattern of amphetamine.…”

Regulation and function of stimulus-induced phosphorylation of MeCP2

“…Such type of integration also appears to be responsible for the neuronal subtype specificity of AMPH-induced S421 phosphorylation in the NAc. AMPH activates multiple monoamine neurotransmitter systems, among which activation of the dopamine (DA) and serotonin (5-HT) systems, but not the norepinephrine (NE) system, are sufficient to induce S421 phosphorylation (Hutchinson et al, 2012a). A separate study by Mao et al (2011) has implicated the NMDA receptor as the mediator of cocaine-induced S421 phosphorylation in the dorsal, but not the ventral striatum.…”

“…RTT patients develop anxiety, aggression, and mood alterations (Chahrour and Zoghbi, 2007), accompanied with reduced levels of dopamine and serotonin (5-HT) metabolite (Fyffe et al, 2008). The activation of dopamine or 5-HT receptor is sufficient to induce MeCP2 S421 phosphorylation in NAc (Hutchinson et al, 2012a). Antidepressants, such as imipramine, increase the extracellular levels of monoamine neurotransmitters and induce S421 phosphorylation selectively in GABAergic interneurons of the ventral structure of nucleus accumbens (NAc) (Hutchinson et al, 2012b).…”