Fani Koukouli: Targeting Interneurons to Treat Brain Diseases

In the brain, inhibitory interneurons are cells that are few in number but essential for regulating neural networks. When they become dysfunctional, these « checkpoints » promote the onset of psychiatric or neurodegenerative diseases. Fani Koukouli is studying how they work, with the goal of developing new treatments.

At first glance, schizophrenia and Alzheimer’s disease appear to be two very different conditions, with the former usually appearing in early adulthood, and the latter affecting the elderly. The first signs of schizophrenia are hallucinations or delusions, while those of Alzheimer’s are memory problems. Yet they have one thing in common: both can be linked to the dysfunction of a particular group of neurons, known as interneurons. A minority among the brain’s nerve cells, interneurons possess very important inhibitory properties for the correct balance of local neural circuits – particularly those of the prefrontal cortex which are associated with superior cognitive functions (language, reasoning, working memory, etc.). It is to these interneurons that Inserm researcher Fani Koukouli has devoted her scientific career since her PhD in neuroscience, which she did at Institut Pasteur. « Back then, the goal of my research was to understand nicotine’s role in brain activity. I showed that it can locally modulate the activation or inhibition of neurons in the prefrontal cortex. More specifically, nicotine binds to receptors on interneurons, thus modifying their activity. I also observed cortical underactivation in mice whose nicotine receptors carry a mutation that predisposes humans to nicotine dependence and schizophrenia, explains the researcher. In mice, it’s possible to restore normal prefrontal cortex activity by modulating the activation of mutated nicotinic receptors. It’s thought that the same could be true in patients with the mutation. »

A vocation born in middle school

For Koukouli, this therapeutic outlook is all the more exciting as it echoes her original vocation. « I’ve been hoping to develop pharmacological treatments for psychiatric illnesses since middle school, she confides. The idea came to me after our singing teacher took my class to a psychiatric ward to give a Christmas concert. Before going, I had many preconceptions. But after meeting the patients and discovering the artwork they exhibited there, I was fascinated. I wanted to understand how the brain works in these situations. » So she decided to study pharmacy and then specialize in neuroscience. And after completing her master’s degree at Aristotle University of Thessaloniki in Greece, she came to France.

With her PhD under her belt, she continued her research at Institut Pasteur in Uwe Maskos’ team, focusing more specifically on Alzheimer’s disease. She observed that certain nicotinic receptors are the target of beta-amyloid peptides – proteins whose neural accumulation is toxic and leads to the onset of dementia. She then joined Alberto Bacci’s team at the Brain Institute, where she deepened her expertise in inhibitory interneurons. Because in reality, « there are several types of inhibitory interneurons. Each has different properties and receptors. Learning more about their diversity gives us deeper insights into the different roles they play in cognition. » In this unit, she works to broaden knowledge of several families of interneurons and receptors, and uses new methods of experimentation. The originality and fruits of her work have already been honored by various awards, including those of « Gandy de la Chancellerie des Universités de Paris », L’Oréal-UNESCO, Unafam, and France Alzheimer.

Between bench and clinic

Thanks to this wealth of expertise, Koukouli obtained Atip-Avenir funding in 2023 which enabled her to establish herself permanently in France by creating her own research group at the Institute of Psychiatry and Neuroscience of Paris (IPNP). With this team, which now counts two post-docs, a doctoral student, a study engineer and several master’s students, she continues to explore how acetylcholine – a key neurotransmitter of cognition – acts on the different types of interneurons, depending on their location, type and the receptors they express. « We’re also studying how these pathways can be modified in psychiatric or neurodegenerative diseases », she explains. To do this, she combines genetic tools, imaging tools and behavioral or electrophysiological experiments. « We’re also looking to find out how signals coming from other regions of the brain influence these interneurons. »

And the researcher keeps the therapeutic perspectives in focus: « We’ve been able to test different molecules capable of binding to nicotinic receptors and restoring normal prefrontal function », she reports. Some may soon be tested in humans. Established at the heart of the Sainte-Anne hospital campus, Koukouli and her team benefit from having clinicians close by: “It’s the ideal environment for establishing collaborations and launching translational research projects. Based on the mechanisms we’ve identified in mice, we’re currently setting up a project for schizophrenia patients who suffer from less cognitive flexibility than those without the condition, i.e. difficulties adapting their behavior in a given situation, or quickly moving from one idea to another.We’re going to test molecules which are already proven to be safe, and which have shown their ability to modulate receptors carrying genetic characteristics that promote the disease. »