Brain protein deficiency promotes compulsive behaviour

Our behaviour is controlled through neural circuits in the brain, with molecular disturbances in these circuits leading to neuropsychiatric disorders like obsessive-compulsive and autism spectrum disorders. German researchers have now demonstrated that the absence of two proteins in mice, Intersectin1 and Intersectin2, leads to disrupted neural signalling and compulsive repetitive behaviour, which is also observed in patients with Intersectin 1 mutations. This research, published in Proceedings of the National Academy of Sciences, supports the idea that such defects can cause neuropsychiatric diseases.

Our brain is essentially our body’s computer. Through a complex interplay of various nerve cells in different areas, it controls and regulates all vital functions, such as breathing, how we move and speak, and how we respond to environmental stimuli with specific behavioural patterns. The so-called cortico-striatal circuit, which connects the cortex and striatum, two parts of the cerebrum, plays a key role in guiding goal-directed behaviour.

“We already know that human behavioural disorders, in which a specific behaviour is compulsively repeated, are associated with this circuit or network,” said Prof Dr Tanja Maritzen, from the University of Kaiserslautern-Landau (RPTU). However, much of what happens in this part of the brain at the molecular level remains a mystery to science.

In the current study, Maritzen and her team closely collaborated with the laboratory of Prof Dr Volker Haucke from Leibniz-Forschungsinstitut für Molekulare Pharmakologie (FMP), Charité Universitätsmedizin Berlin and Freie Universität Berlin. The researchers focused on two specific proteins that play a crucial role in this circuit.

“Intersectin 1 and Intersectin 2 are large scaffold proteins that have many interaction sites,” Haucke said. “Previous research has shown that their mutation in humans correlates with behavioural abnormalities.”

To explore their exact role, the team inhibited the production of these proteins in mice. The results showed that the Intersectin proteins are vital for the organism, as some of the mice died early. A different subset displayed behavioural abnormalities: they stood on their hind legs in the corner and repeatedly jumped up and down.

“Such symptoms, where a particular, essentially pointless behaviour is compulsively repeated, are also known in neuropsychiatric diseases,” Maritzen said, citing autism spectrum disorders and obsessive-compulsive disorders as examples.

In order to assess what goes wrong at the molecular level, the team specifically looked at the NMDA receptor.

“We observed that the absence of the two proteins results in fewer of these receptors at the ends of nerve cells, the synapses,” Haucke said. This is crucial for the transmission of signals from one nerve cell to another — neurotransmitters, or chemical messengers, carry the excitation between cells by binding to receptors.

“The Intersectin proteins, as scaffold proteins, are important to stabilise the NMDA receptor at the synapse,” Haucke continued.

The deficiency of these proteins isn’t solely responsible for the onset of behavioural abnormalities; it is rather one component in a complex molecular system. The study has helped to understand a part of this system better, reinforcing the notion that mutations in Intersectin can lead to neurological symptoms. Moreover, the study suggests that the NMDA receptor is a potential candidate for developing drug therapies for neuropsychiatric disorders.

Image credit: FMP, Claudia Knorr.