A balance between excitement and inhibition

The researchers clarified, for the first time, the mechanism behind a very rare brain disorder called MICPCH syndrome (microcephaly, disproportionate pontine hypoplasia and cerebellar hypoplasia) in animal models. The information collected in this study could also inform research on other more common neurological diseases such as mental retardation, epilepsy and autism.

MICPCH has only touched 53 women and seven men in the world so far. It is characterized by several developmental symptoms, including a small head, slowed growth, cognitive delays, epilepsy, seizures, vision and hearing problems, decreased muscle tone and muscle tone. # 39; autism. MICPCH is linked to irregularities or mutations on the X chromosome that ultimately lead to chromosome inactivation.

The study was published in the journal Molecular psychiatry.

Brain cells, or neurons, communicate constantly by sending messages. There are two types of neurons in the brain: those that increase activity in other cells (excitatory neurons) and those that decrease it (inhibitory neurons). The mechanism to maintain the balance between excitation and inhibition in the brain is very similar to that of a thermostat used to maintain a balanced temperature in a home. This mechanism is important because the imbalances between excitation and inhibition can lead to several serious disorders such as epilepsy and autism.

One of the most important molecules that maintain the balance between excitation and inhibition is a protein present in the outer membrane of neurons, called calcium-dependent serine protein kinase / calmodulin ( CASK). Mutations in the CASK-producing gene thus cause several neurodevelopmental disorders such as mental retardation. The lack of protein in the brain has been found to be the cause of the MICPCH syndrome.

"The purpose of the study was to understand the pathophysiology of CASK deficiency disorders in women, such as the MICPCH syndrome, which are thought to be influenced by X-chromosome inactivation," said Dr. Corresponding Author Katsuhiko Tabuchi, Professor in the Department of Molecular and Cell Physiology at the Institute of Medicine, Academic Assembly of Shinshu University in Nagano, Japan.

However, the details of the consequences of a CASK deficiency have so far been difficult to study because mice devoid of any protein die before they are sufficiently developed to be studied.

In order to understand the mechanism underlying the CASK deficiency, researchers at Shinhsu University in Japan and Kafr Elsheikh University in Egypt used gene manipulation techniques that block the CASK gene by X chromosome inactivation. female mice without lethal consequences.

They found that neurons lacking CASK exhibit an excited equilibrium / disrupted inhibition. They also found that this is due to a decrease in the concentration of a specific receptor on the membrane that receives signals from other neurons. As receptor concentration increased, excitatory and inhibitory equilibrium was reestablished, leading researchers to believe that the receptor plays a central role in the mechanism of CASK-deficient neurons.

In the future, researchers hope to examine in more detail the effects of a CASK deficiency by examining its effects on neural circuits. "We hope to highlight the effect of two different types of neurons in a brain as well as the pathophysiology of CASK deficiency disorders at the level of neuronal circuits," added Professor Tabuchi.

This article has been republished from material provided by Shinshu University. Note: Content may have changed for length and content. For more information, please contact the cited source.

Reference: Takuma Mori, Enas A. Kasem, Suzuki-Kouyama Emi, Xueshan Cao, Li Xue, Taiga Kurihara, Takeshi Uemura, Toru Yanagawa and Katsuhiko Tabuchi. 2019. Calcium / calmodulin-dependent protein kinase-serine deficiency disrupts the excitatory-inhibitory balance of synapses by down-regulating GluN2B. Molecular psychiatry. DOI: http://dx.doi.org/10.1038/s41380-018-0338-4.