Table 4 Olfactory vs. visual system: tissue specific MECP2 influence

Observation: A study on olfactory bulb biopsies of RTT females revealed less olfactory receptors indicating less sensitive olfactory sense [119]. The olfactory epithelium in postnatal rodents experiences strong upregulation of MECP2 [120, 121].

Observation: Vertebrate eyes are originally specialized brain tissue. Though being expected to be subjected to MECP2 dysfunctionality symptoms the visual system, retina, visual nerve and visual cortex seem to be less affected by RTT. Patients are able to focus, blink, eye-track, and do not perform worse in visual tests than healthy population [122]. Their families report often that they are using eye contact as communication method and therefore eye tracking systems are a promising method to improve communication.

Molecular/histological data: MECP2 deficiency induces also an imbalance in glutamatergic/GABAergic innervation in the olfactory bulb. The excitation in MECP2 KO mice is reduced and there is generally an imbalance between excitatory and inhibitory pathways observed leading to premature death of olfactory neurons in RTT mice models [121]. MECP2 seems to regulate the activity dependent transcriptional responses in olfactory sensory neurons the same way as in central nervous system and model systems [123]. This cycle of neuronal activity dependent transcription activation (fast feedback loop based on Ca²⁺/calmodulin) seems to be responsible for neuronal circuitry refinement, playing a role in olfactory sensory nerve maturation and olfactory learning. MECP2 affects the expression of olfactory sensory cell adhesion molecules KIRREL2 and PCHD20 directly, KIRREL3, and CNTN4 indirectly. It represses KIRREL2 but is required for activity dependent upregulation of KIRREL2 after odor stimulation [123]. KIRREL3 is an autism related gene [124] and the family of KIRREL genes is known to be widely expressed in neuronal tissue for synaptogenesis and synaptic specificity [125].

Molecular/histological data: Jain et al. investigated ocular MECP2 expression in post mortem brains of RTT females and compared it to healthy controls. Although the RTT females show the typical severe neurological deficits their visual functions are well preserved. There were no gross or microscopic aberrations detected and no significant MECP2 level differences [101]. Another study investigating MECP2 expression levels in many neuronal and non-neuronal tissues found MECP2 to be expressed weak or moderate in the nucleoplasm of retinal cells while there were peaks of strong MECP2 presence in chromocenters [126]. Although it was shown in a previous study with MECP2 KO mice that their visual system (acuity) is affected with disorder onset [127] and visual systems also need refinement by circuits and MECP2 dependent synapse remodeling [128] this was not confirmed by the study of Song et al. [126]. Their retina samples from MECP2 deficient mice did not show any differences to control concerning immunochemical markers, cellular and histological anatomy, synapsis formation and neurotransmitters [126].

Conclusion: Data indicates that the olfactory sense is less functional in Rett females due to the strong dependency of the molecular signal processing pathways on MECP2.

Conclusion: Together with the measured visual performance in human RTT females [122] these observations indicate that MECP2 surprisingly does not play a major role in ocular function.

Gap: Why is the olfactory sensory system affected in RTT females? Is there a measurable difference in response to olfactory stimulants of Rett females and controls?

Gap: What is the mechanistic explanation of the rather unaffected visual system? Why do neuronal cells of the visual system not need MECP2 for proper function?