Pinpointing brainstem mechanisms responsible for autonomic dysfunction in Rett syndrome: therapeutic perspectives for 5-HT1A agonists

Abstract

Rett syndrome is a neurological disorder caused by loss of function of methyl-CpG-binding protein 2 (MeCP2). Reduced function of this ubiquitous transcriptional regulator has a devastating effect on the central nervous system. One of the most severe and life-threatening presentations of this syndrome is brainstem dysfunction, which results in autonomic disturbances such as breathing deficits, typified by episodes of breathing cessation intercalated with episodes of hyperventilation or irregular breathing. Defects in numerous neurotransmitter systems have been observed in Rett syndrome both in animal models and patients. Here we dedicate special attention to serotonin due to its role in promoting regular breathing, increasing vagal tone, regulating mood, alleviating Parkinsonian-like symptoms and potential for therapeutic translation. A promising new symptomatic strategy currently focuses on regulation of serotonergic function using highly selective serotonin type 1A (5-HT1A) "biased agonists." We address this newly emerging therapy for respiratory brainstem dysfunction and challenges for translation with a holistic perspective of Rett syndrome, considering potential mood and motor effects.

Keywords: 5-HT1A receptor; Rett syndrome; anxiety; brainstem; breathing; motor activity; serotonin; vagal tone.

Figure 1

Suggested mechanisms for respiratory rhythm disease in Rett syndrome and network targets of 5-HT_1A agonists. Populations of respiratory neurons are shown in white circles (see below). Blue arrows indicate excitatory drive; red connectors with circle-ends indicate inhibitory drive. A healthy respiratory rhythm and pattern are critically dependent on the balance between excitatory and inhibitory synaptic drives to the “core” of mutually inhibitory respiratory neurons located in the BötC and pre-BötC (Smith et al., 2013). The disturbed rhythm in Rett syndrome seems to arise from an imbalance of drives to this core circuitry (indicated by black “X” when reduced, or blue “+” when enhanced); many mechanisms contribute to this: (i) weakened excitatory synaptic drives to and within the inspiratory “kernel” (Viemari et al., 2005), (ii) reduced CO₂ sensitivity (Zhang et al., ; Toward et al., ; Bissonnette et al., 2014); (iii) excess descending post-inspiratory drive from the pontine parabrachial complex (Stettner et al., ; Voituron et al., ; Dhingra et al., 2013); which could be a consequence of loss of inhibitory drives to this area, including KF (Stettner et al., ; Abdala et al., 2010). In combination, these mechanisms would lead to disinhibition of PI populations, disruption of timing for termination of inspiration and expiratory length irregularity. Studies in humans and mice suggest that breath-holds and Valsalva maneuvers may be linked to active closure of the glottis implicating a failure in the ponto-medullary gating of central post-inspiratory activity, for a review; see Ramirez et al. (2013). 5-HT_1A receptors suppress specific inhibitory glycinergic neuron populations in the “core” of mutually inhibitory neurons with consequent disinhibition of inspiratory populations (Shevtsova et al., 2011). In addition, 5-HT_1A receptors can directly reduce the activity of neuron populations contributing to the descending post-inspiratory drive from the pons. I, inspiratory neuron population; PI, post-inspiratory neuron population; E2, late expiratory neuron population; PR, pulmonary stretch relay; LBP, lateral parabrachial nu; KF, Kölliker-Fuse nu; NTS, nucleus of the solitary tract; RTN, retrotrapezoid nu; BötC, Bötzinger complex; pre-BötC, pre-Bötzinger complex.