Ask the Doctor: Is There a Link Between Albinism and Idiopathic Hypersomnia (IH)?

January 21, 2020 in Ask the Doctor, Idiopathic Hypersomnia, Research

Is there a link between albinism and idiopathic hypersomnia (IH)? Are GABA_A receptor responses involved in both albinism and IH? How have these responses been measured in scientific studies and what are the differences in the mechanisms? We are pleased to have Dr. Amanda Freeman, a PhD neuroscientist and professor at Emory University, answer these questions. Dr. Freeman has extensive experience in researching GABA-related hypersomnias and has previously appeared in our Ask The Doctor feature answering questions about what Emory researchers are looking for in spinal fluid.

QUESTION:

I read somewhere that albinism might have an impact on GABA. Is there a link between albinism and idiopathic hypersomnia (IH)?

RESPONSE:

I am unaware of any research that has examined this possibility directly, but I believe that a link between albinism and idiopathic hypersomnia (IH) is unlikely. Studies of the visual system, which has been studied in the greatest depth, reveal alterations in GABAergic signaling in albinism.^3,4 Specifically, albinism is associated with decreased inhibitory GABA_A receptor-mediated current,^2,8 which is opposite from the increased inhibitory GABA_A receptor-mediated currents observed in IH.¹²

There are important mechanistic differences underlying these findings that should be considered. The studies of GABA_A receptor responses in albinism (mentioned above) are based on recordings of brain slices, which allow examinination of the physiological response of an intact neuron. These recordings from albino animals were compared to recordings from pigmented animals under identical conditions. The observed differences indicate that GABA_A receptors in the neurons of albino animals function differently than those of pigmented animals. These physiological differences, however, are not the result of alterations in the GABA_A receptors; rather, they reflect alterations in the concentrations of chloride ions within the neurons themselves.^2,5,6 You may recall from the GABA 102 video that shifts in the ion balance between inside and outside the neuron underlie neuronal activity and that chloride ions play a role in inhibiting neuronal activity. So, while GABA_A receptor-mediated currents are altered in albinism, this is an indirect effect of alterations in the physiology of the neuron as a whole that occurs during development.

Alternatively, the study that identified a correlation between altered GABA_A receptor-mediated currents and IH was conducted on cells that had been experimentally manipulated to express GABA_A receptors. The recorded current conducted through the GABA_A receptors under control conditions was compared to the response following exposure to the cerebrospinal fluid (CSF) of individuals with IH. This means that, in contrast to the studies of albinism, the composition of the cells was kept constant, while the response of the GABA_A receptors was examined under different conditions. The increased inhibitory response of GABA_A receptors when exposed to CSF from people with IH demonstrates that the same cell and the same receptor responded differently under the two conditions.¹² Since this experiment was conducted in isolated cells with extremely short exposures to the CSF (<5 seconds), these findings suggest that the altered response resulted directly from an interaction between a substance in the CSF and the GABA_A receptor.

Overall, the differences in these experimental designs and findings indicate that an interaction between CSF from people with IH and GABA_A receptors results in an increased inhibitory response through different mechanisms than those that lead to the decreased GABA_A receptor-mediated current in albinism. So, although albinism does appear to have an impact on GABA_A receptor responses, there does not seem to be a link between albinism and IH.

References:

1. Andersson, H. (2008). Chapter 21 – Clinical Reproductive Endocrinology. In Clinical Biochemistry of Domestic Animals (Sixth Edition), J.J. Kaneko, J.W. Harvey, and M.L. Bruss, eds. (San Diego: Academic Press), pp. 635-662.
2. Barmashenko, G., Schmidt, M., and Hoffmann, K.P. (2005). Differences between cation-chloride co-transporter functions in the visual cortex of pigmented and albino rats. Eur J Neurosci 21, 1189-1195.
3. Blaszczyk, W.M., Straub, H., and Distler, C. (2004). GABA content in the retina of pigmented and albino rats. Neuroreport 15, 1141-1144.
4. Burbridge, T., Choudhury, B.P., and Collard, K.J. (1996). The uptake of gamma-aminobutyric acid and glutamate by synaptosomes from the visual cortex of albino and pigmented rabbits. J Neural Transm (Vienna) 103, 299-305.
5. Diykov, D., Barmashenko, G., and Hoffmann, K.P. (2008a). Development of chloride homeostasis in albino and pigmented rat visual cortex neurons. Neuroreport 19, 595-598.
6. Diykov, D., Turchinovich, A., Zoidl, G., and Hoffmann, K.P. (2008b). Elevated intracellular chloride level in albino visual cortex neurons is mediated by Na-K-Cl co-transporter. BMC Neurosci 9, 57.
7. Hayaishi, O. (2000). Molecular mechanisms of sleep-wake regulation: a role of prostaglandin D2. Philos Trans R Soc Lond B Biol Sci 355, 275-280.
8. Krause, M., and Hoffmann, K.P. (2009). Shift of chloride reversal potential in neurons of the accessory optic system in albinotic rats. Exp Brain Res 199, 345-353.
9. Pandey, H.P., Ram, A., Matsumura, H., and Hayaishi, O. (1995). Concentration of prostaglandin D2 in cerebrospinal fluid exhibits a circadian alteration in conscious rats. Biochem Mol Biol Int 37, 431-437.
10. Pecchi, E., Dallaporta, M., Jean, A., Thirion, S., and Troadec, J.D. (2009). Prostaglandins and sickness behavior: old story, new insights. Physiol Behav 97, 279-292.
11. Ram, A., Pandey, H.P., Matsumura, H., Kasahara-Orita, K., Nakajima, T., Takahata, R., Satoh, S., Terao, A., and Hayaishi, O. (1997). CSF levels of prostaglandins, especially the level of prostaglandin D2, are correlated with increasing propensity towards sleep in rats. Brain Res 751, 81-89.
12. Rye, D.B., Bliwise, D.L., Parker, K., Trotti, L.M., Saini, P., Fairley, J., Freeman, A., Garcia, P.S., Owens, M.J., Ritchie, J.C., et al. (2012). Modulation of vigilance in the primary hypersomnias by endogenous enhancement of GABA_A receptors. Sci Transl Med 4, 161ra151.
13. Sadam, H., Pihlak, A., Kivil, A., Pihelgas, S., Jaago, M., Adler, P., Vilo, J., Vapalahti, O., Neuman, T., Lindholm, D., et al. (2018). Prostaglandin D2 Receptor DP1 Antibodies Predict Vaccine-induced and Spontaneous Narcolepsy Type 1: Large-scale Study of Antibody Profiling. EBioMedicine 29, 47-59.
14. Ueno, R., Ishikawa, Y., Nakayama, T., and Hayaishi, O. (1982). Prostaglandin D2 induces sleep when microinjected into the preoptic area of conscious rats. Biochem Biophys Res Commun 109, 576-582.

EDITOR’S NOTE: If you enjoy this Ask the Doctor series, please consider donating to the Hypersomnia Foundation now. Finally, if you have IH or a related sleep disorder, please join our registry at CoRDS and be sure to update your responses at least yearly.

Disclaimer for Ask The Doctor: The medical information provided is meant for educational purposes only and is not a substitute for professional medical care and advice. Each person is different, and questions about a personal health condition should be discussed with your own healthcare professional.

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