Biogenic Amines in Rett Syndrome: The Usual Suspects

Abstract

Rett syndrome (RTT) is a severe postnatal neurological disorder caused by mutations in the methyl-CpG binding protein 2 (MECP2) gene. In affected children, most biological parameters, including brain structure, are normal (although acquired microcephaly is usually present). However, in recent years, a deficit in bioaminergic metabolism has been identified at the cellular and molecular levels, in more than 200 patients. Recently available transgenic mouse strains with a defective Mecp2 gene also show abnormalities, strongly suggesting that there is a direct link between the function of the MECP2 protein and the metabolism of biogenic amines. Biogenic amines appear to have an important role in the pathophysiology of Rett syndrome, for several reasons. Firstly, biogenic amines modulate a large number of autonomic and cognitive functions. Secondly, many of these functions are affected in RTT patients. Thirdly, biogenic amines are the only neurotransmitters that have repeatedly been found to be altered in RTT patients. Importantly, pharmacological interventions can be envisaged to try to counteract the deficits observed. Here, we review the available human and mouse data and present how they have been and could be used in the development of pharmacological treatments for children affected by the syndrome. Given our current knowledge and the tools available, modulating biogenic amine metabolism may prove to be the most promising strategy for improving the life quality of Rett syndrome patients in the short term.

Rescue of behavioral and EEG deficits in male and female Mecp2-deficient mice by delayed Mecp2 gene reactivation

“…This is consistent with recent morphological results in male ‘Rescue’ mice showing the attenuated neuronal complexity of Mecp2-deficient neurons increases following Mecp2 reactivation (30), and with previous results showing hippocampal LTP levels also improve following delayed Mecp2 reactivation (16). Collectively, these results support a model in which Mecp2-deficient networks are either stalled at an immature state, or have failed to properly mature during the normal window of synaptic development (38,42–44), but retain the potential to restructure and generate neural networks largely consistent with that of the normal mature brain following the reintroduction of functional Mecp2.…”

“…Given that impaired autonomic regulation is a cornerstone feature of Rett syndrome (37,38), we assessed whether these thermoregulatory deficits would also be rescued by delayed Mecp2 reactivation. Consistent with our previous findings (19), significant differences in daily thermoregulatory patterns were observed between wild-type and Mecp2-deficient mice.…”

Effect of desipramine on patients with breathing disorders in RETT syndrome

“…Moreover, the knockout male mouse models also recapitulate other key RTT symptoms such as motor dysfunctions, osteoporosis and epilepsy. At the neurochemical level, the amount of available NE in the CNS is reduced in both RTT patients and knockout male mouse, which is evidence that the biogenic amines stimulation is a high‐potential target for the pharmacological treatment in RTT 14, 16, 25, 26…”

The emerging role of AMPK in the regulation of breathing and oxygen supply

“…Yet extensive investigations have demonstrated that following carotid body resection, hypoxia-responsive catecholaminergic neurons of the caudal brainstem may underpin partial recovery of the hypoxic ventilatory response [115], at least in rodents, and it is recognized that loss of these neurons underpins ventilatory dysfunctions associated with Rett syndrome, including hypoventilation and apnoea, which are exacerbated during hypoxia [116]. …”