Is KCC2 the bad guy in neurodevelopmental disorders?
Involved in very important processes during normal brain maturation, KCC2 has been found to be dysfunctional or dysregulated in a large number of neurological and neurodevelopmental disorders, including epilepsy, schizophrenia, autism spectrum disorders, as well as Fragile X, Rett, and Down syndromes. However, the direct pathological contribution of KCC2 to the cognitive deficits remained difficult to establish for a long time, given the numerous molecular and cellular alterations observed in these diseases. Nevertheless, we have identified a rare form of human neurological disorder caused by mutations in the KCC2-encoding gene. Patients exhibit intellectual disability, variable neurodevelopmental symptoms, and epileptic seizures. This family represents the first documented case of a KCC2-dependent neurodevelopmental disorder. However, the neuronal- and network-level mechanisms by which KCC2 mutations lead to cognitive symptoms remains unknown. In order to better understand the disease, we have developed a line of mice that reproduces the genetic and cognitive alterations observed in patients. Using this line, we will study the properties of neurons and circuits in a key region called the hippocampus. Our overarching goal is to define the direct pathological role that KCC2 may play, and to evaluate its therapeutic potential not only in the rare genetic form we have reported, but also in the many neurological and neuropsychiatric diseases that involve KCC2 dysregulation or dysfunction (including Down syndrome).

Williams syndrome (WS) is a genetic condition that happens by chance before birth, when a small piece of genetic material is missing. People with WS often share certain heart and brain differences. Because of this, they may experience challenges with learning, thinking, and behavior. Today, people with WS are living longer than ever before, which makes it important to understand how their brains change as they grow older.
As people age, it is normal for memory, learning, and coordination to slowly change. In people with WS, these changes can be more noticeable, especially when high blood pressure is present. High blood pressure is very common in WS—affecting about half of children and many adults. It is linked to changes in hormones and stress-related systems in the body that control blood pressure and also affect the brain.
Research shows that some blood pressure medicines may help not only control blood pressure, but also support brain health. Certain medications have been linked to better memory, attention, and problem-solving skills, and may slow down age-related thinking changes. These benefits may come from improving blood flow in the brain, reducing inflammation, and helping brain cells communicate better. While no single blood pressure medication works best for everyone with WS, doctors often choose medicines that target the hormone systems involved in WS.
High blood pressure in WS is also linked to higher levels of harmful molecules in the body that can damage cells over time. Because of this, researchers are exploring treatments that reduce this damage. One such medication, already widely used for gout, is being studied as a possible additional treatment to help protect brain health in people with WS.
Overall, this research aims to improve long-term health and quality of life for people with Williams syndrome by better understanding aging, brain health, and the effects of treatments over time.

Mosaic Variegated Aneuploidy (MVA) is an extremely rare childhood genetic disorder in which many cells in the body carry a wrong number of chromosomes. Unlike Down syndrome, where all cells carry the same extra chromosome 21, in MVA, each affected cell may lose or gain different chromosomes, creating a complex “mosaic” that affects patients in many ways. Patients with MVA usually show developmental delay, small head size, intelectual disability and, in some cases, a higher risk of cancer. Because fewer than 100 cases are known worldwide, families often struggle to find clear information, a diagnosis, or treatment options. Our recent research suggests that the problems in MVA may not be caused only by chromosome mistakes. The constant presence of abnormal cells appears to disrupt how the body produces energy in the mitochondria and may trigger chronic inflammation throughout the immune system. These two processes—energy imbalance and inflammation—could be key drivers of many symptoms. In this project, we will analyze blood samples from MVA patients at single cell resolution, examining thousands of individual cells to understand how different chromosomal errors affect their energy production and immune activity. We will also study patient cells grown in the lab to see whether existing mitochondrial‐boosting medicines could help cells function more normally and reduce inflammation. Our goal is to uncover what truly drives this disease and to open new possibilities for diagnosis and future treatments. Above all, we hope this work brings meaningful progress and hope to families living with a condition that is poorly understood and currently has no therapeutic options

The ability to form meaningful relationships is essential for survival and everyday life. Social interactions allow individuals to recognize others, cooperate, and adapt to their environment. A brain region called the hippocampus plays an important role in these processes by helping us build memories of places, experiences, and the people we encounter.
Social abilities can be strongly affected in brain disorders. For example, individuals with intellectual disabilities often experience difficulties in social interaction, which can greatly impact their quality of life. Many intellectual disabilities are caused by genetic changes. One common form, known as X-linked intellectual disability, is due to mutations in genes located on the X chromosome. One of these genes is Oligophrenin-1 (OPHN1). When this gene does not function properly, brain circuits do not develop or communicate normally, leading to cognitive and social difficulties. However, how this genetic alteration affects brain activity during social behavior is still poorly understood.
In this project, we will study brain activity in mice lacking the Ophn1 gene to understand how the hippocampus processes social information. Using advanced imaging techniques, we will observe how brain cells work together while animals interact and explore their environment. This research will help clarify how the brain represents oneself and others and how these processes are altered in intellectual disability. In the long term, these findings may support the development of better strategies to improve social functioning and quality of life for individuals affected by OPHN1-related intellectual disability.

Tyrosine Hydroxylase Deficiency (THD) is a rare genetic disorder that prevents the brain from producing dopamine, a neurotransmitter essential for brain function. While current treatments can improve some motor symptoms, many children continue to experience lasting movement and learning difficulties, suggesting that the disorder may interfere with the formation of brain circuits early in life. Dopamine plays a critical role in shaping developing brain circuits by supporting the maturation of specialized cells that regulate brain activity and helping establish balanced and coordinated communication between neurons. When dopamine is lacking during critical stages of development, brain circuits may not form correctly, contributing to persistent neurological problems observed in THD patients. However, when these abnormal developmental trajectories begin and whether they can be redirected if treated early, remains unknown. In this project, we will investigate how early dopamine deficiency alters brain circuit development using a mouse model carrying a human TH mutation. We will also test whether early treatment can prevent or reverse these changes. By identifying when and how brain alterations arise, this research aims to open new possibilities for earlier and more effective interventions for children with severe THD.

Intellectual Disability (ID) is a developmental condition that affects learning ability, reasoning, and everyday adaptive skills. One of the genes linked to certain forms of ID is OPHN1, which produces a protein essential for proper communication between brain cells. This protein helps regulate the structure of neurons and supports key processes required for memory and learning.
In many patients, mutations in OPHN1 prevent the protein from being produced. However, we have identified several patient mutations in which the protein is still present but behaves abnormally. Instead of being missing, the protein adopts an altered shape that affects how it functions inside neurons. One specific mutation, called G412D, changes the protein’s structure and disrupts the organization of connections between neurons. Importantly, by designing a small corrective change that restores the protein’s normal shape, we were able to reverse these defects in laboratory experiments. This suggests that, in some patients, the problem is not the absence of the protein, but its faulty regulation. Our project aims to understand how different OPHN1 mutations alter the protein structure and how these changes impact brain cell function. By combining structural studies with detailed analyses of neuronal activity, we will build a clearer picture of how these mutations lead to disease.
This research challenges the current view that OPHN1-related ID is simply caused by loss of the protein. Instead, it suggests that abnormal protein shape and regulation may represent an additional disease mechanism. Understanding this distinction is important because it could open the way to more precise therapeutic strategies aimed at restoring proper protein function rather than simply increasing its levels.

Dravet syndrome (DS) is a severe form of childhood epilepsy characterized by seizures that are difficult to control, as well as intellectual disability, movement problems, and an increased risk of sudden death. This disease is caused by a genetic mutation in the SCN1A gene, which leads to a reduced amount of encoded protein called Nav1.1. This protein is essential for the proper function of nerve cells in the brain, and its deficiency disrupts the balance between nerve cell signals, leading to the symptoms of DS.
Current genetic therapies for DS aim to increase the amount of Nav1.1 protein, but they require repeated, lifelong treatments. Our research offers a new, permanent approach using a technology called gene editing. We discovered that there are genetic “stop signs” (called upstream open reading frames or uORFs) in the SCN1A gene that limit how much Nav1.1 protein is made. By using a tool called Adenine Base Editor (ABE), we can permanently remove these stop signs, allowing the nerve cells to produce more Nav1.1 protein.
We have preliminary data showing that this single gene editing approach successfully restored Nav1.1 protein levels and improved nerve cell function in mouse model of Dravet syndrome, where it also significantly reduced seizures and the risk of sudden death.
In this project, we plan to test the effect of ABE-uORF treatment delivered at more proper dose on multiple aspects of Dravet phenotype, including seizures, behavioral alterations and circuit activity in the brain.
The success of this project can lead to a one-time, permanent gene editing therapy for all Dravet syndrome patients with different loss-of-function mutations. In additon similar approaches can be applied to other neurodevelopmental disorders characterized by similar genetic mechanism.

Christianson syndrome (CS) is a rare, genetic disorder that leads to severe intellectual disability, seizures, cell death in a brain region important for motor coordination, progressive incoordination, absent speech, and behaviour consistent with autism. CS is caused by genetic mutations in a specific gene that plays a role in creating a transporter that regulates the amount of sodium and hydrogen within specific areas inside cells, especially neurons. When this gene doesn’t work normally, too many hydrogen ions can build up inside of specific compartments inside brain cells. This disrupts the cell’s recycling and disposal systems, which heavily impacts cellular function and can even lead to cell death. Our team studies a specific type of rat called shaker rats that have a naturally occurring mutation in the same gene as CS, which makes them a rat model of CS. We have previously shown that we could prevent brain cells from dying and improve function at both the molecular and behavioural level. We do this by replacing the missing gene in cell targets using a special, non-infectious type of laboratory-created virus. This type of virus has already been used in other human genes to carry missing genes and treat other neurological disorders, and we propose to use it to develop a treatment specifically for human disease. We have developed a version of this virus that is specifically designed for the human disorder, and we have generated this new version to match other viruses already used in human disease as closely as possible. We plan to test it for both safety and efficacy in shaker rats so that it can be advanced on a path towards human treatment. In this application, we propose a number of experiments that will determine how well the virus can treat CS in terms of epileptic seizures and protection of the brain itself, as well as evaluating safety of this approach.

Des anomalies génétiques affectant le gène DYRK1A causent une forme fréquente de troubles du neurodéveloppement (TND). Pour comprendre comment ces mutations génétiques pourraient conduire à un TND, nous avons étudié leurs conséquences dans des modèles cellulaires humains de développement du cerveau (organoïdes cérébraux), différenciés à partir de cellules souches pluripotentes induites porteuses ou non d’anomalies génétiques dans le gène DYRK1A. Nos résultats préliminaires montrent que les mutations du gène DYRK1A entraînent des changements importants dans ces organoïdes : on observe une augmentation du nombre de cellules souches cérébrales (appelées cellules gliales radiales) et des précurseurs de cellules de soutien des neurones (les astrocytes), ainsi qu’une diminution du nombre de cellules tapissant les cavités cérébrales (les cellules épendymaires ciliées). Cela suggère que les mutations accélèrent le développement des cellules cérébrales, créant un déséquilibre qui pourrait expliquer les anomalies observées chez les patients, comme une taille réduite du cerveau et des ventricules élargis. Nous avons également constaté une activation excessive d’une voie de signalisation cellulaire appelée signalisation Notch. Pour l’instant, ces résultats proviennent d’organoïdes cérébraux d’un seul type de cellules souches. Afin de confirmer leur fiabilité, nous prévoyons de répéter ces expériences avec des cellules souches issues d’autres individus, y compris de patients avec mutations de DYRK1A, ou traitées avec une molécule bloquant l’action de DYRK1A. Dans une deuxième étape, nous examinerons si l’activation excessive de la voie Notch est responsable de l’accélération du développement des cellules cérébrales et si bloquer cette voie pourrait aider à rétablir un développement cérébral normal dans nos modèles. Ce projet contribuera non seulement à mieux comprendre comment les mutations du gène DYRK1A perturbent le développement du cerveau, mais fournira également des outils.

Donnai-Barrow syndrome is a rare genetic condition caused by mutations in a gene called LRP2. Children affected by this disorder suffer from brain malformations and intellectual disability. One of the most puzzling aspects of the disease is that its severity varies greatly. Even individuals carrying the same genetic mutation can be affected very differently. At present, we do not understand why.
Our research focuses on a key communication system that developing brain cells use to coordinate growth and organization. This system, called Sonic Hedgehog (SHH) signalling, acts like a molecular instruction pathway that tells cells when and how to form specific brain regions. In Donnai–Barrow syndrome, this signalling process does not function properly. However, our previous work in animal models has shown that some genetic backgrounds can “buffer” or stabilize this signalling pathway, preventing severe brain defects. This suggests that natural protective mechanisms may influence how severely a person is affected.
In this project, we will use human stem cell-derived brain cells generated from different donors to understand why some cells are more resilient than others. By precisely switching off the LRP2 gene in these cells, we can model the disease in the laboratory and measure how strongly the SHH pathway responds. We will also examine how tiny cellular structures, called primary cilia, and specific protective genes contribute to stabilizing this pathway.
Finally, we will test whether early instability in this signalling system leads to measurable differences in the structure and activity of human neurons.
By identifying the biological mechanisms that influence disease severity, this research aims to explain why Donnai–Barrow syndrome affects individuals so differently and to uncover potential targets for future therapeutic strategies.