4 August 2020

BRIC researchers discover role of metabolism gene in brain dysfunction

Researchers from Khodosevich group at BRIC and Perrier’s group at Department of Neuroscience have discovered that the function of neurons most affected by mental disorders are dependent of a specific molecule. This molecule protects these neurons against stress, ensuring their normal development and function. Without this molecule the neuron function is impaired and resembles to dysfunction, which is seen in disease models of mental disorders.

Tiny molecule keeps brain cells energized

Information in the brain flows via a type of neurons, called excitatory neurons, that have properties depending on their anatomical location. For example, a neuron related to our vision will respond to visual stimuli, and a neuron related to our hearing will respond to auditory stimuli.
However, in order for the brain to filter stimuli, the activity of the excitatory neurons needs to be tightly controlled. This is done by a type of neurons called inhibitory neurons. The most important inhibitory neurons for cognitive function are so-called fast-spiking neurons, and thanks to their inhibitory regulation, humans and other mammals can filter stimuli from the surrounding environment, learn new things,  or socialize with other peers.

When the brain fails to filter stimuli, due to alterations in the activity of fast-spiking neurons, it is associated with mental disorders such as schizophrenia or attention deficit hyperactivity disorder (ADHD).

In order for fast-spiking neurons to function and help the brain filter stimuli, these neurons require much more energy than other neurons. However, until now it has been unknown how these fast-spiking interneurons get more energy than other neurons.

In our study, we demonstrated for the first time that fast-spiking interneurons possess a unique molecule in the powerhouse of the cell, the mitochondria, which helps them to generate energy more efficiently than other brain cells”, says Konstantin Khodosevich, group leader.

The molecule that proves to be a key factor for energy generation in fast-spiking neurons is called Cox6a2. This molecule was previously known to be expressed only in the heart and muscles where it regulates their metabolism. However, now the researchers discovered that Cox6a2 is also expressed in fast-spiking neurons in the brain, but not in any other neurons.

When the researchers deleted Cox6a2 in disease models, they found numerous alterations in the functions of fast-spiking neurons including a lower maximal firing rate of nerve impulses” says Jean-François Perrier, group leader.

These changes are most likely caused by their inability to keep energy balance, which suggests that fast-spiking neurons depends on Cox6a2 in order to produce sufficient energy.
Additionally, it was shown that the disease models lacking Cox6a2 became hyperactive. These results might translate into mental disorders in humans, since it was demonstrated that a patient harboring mutations in Cox6a2 might exhibit a form of intellectual disability that is associated with mental/neurological abnormalities. Therefore, the discovery of this metabolism-associated molecule, and it’s key role in energy production for fast-spiking neurons, potentially sheds new light on what drives mental disorders.

Further investigating the link between unenergized brain cells and mental disorder

Mental disorders such as schizophrenia and attention deficit hyperactivity disorder are highly prevalent in highly industrialized countries, and the malfunction of fast-spiking neurons has been consitently associated with these and other mental disorders.

The researchers now aim to define the link between the Cox6a2 absence/deficient function and mental disorders. They will also continue studies in disease models with mutations in Cox6a2 for a comprehensive characterization of cognitive impairment in these models.

In the near future, we would like to identify a larger cohort of subjects harboring mutations in Cox6a2 and assess their brain function and cognitive abilities by non-invasive techniques (e.g. MRI) and interviews, respectively, as well as studying impact of such mutations on neuronal function in human iPSC-derived neurons”, says Konstantin Khodosevich, group leader.

In this study, most experiments were carried out by the following researchers: Berta Sanz-Morello (PhD student in Khodosevich group), Nikolaj Winther Hansen (PhD student in Perrier group) and Ulrich Pfisterer (postdoc in Khodosevich group).

Read full study in EMBO

Contact: Konstantin Khodosevich or Jean-François Perrier