MONTREAL, August 5, 2025 – A newly published research study, jointly led by research scientist Bidisha Chattopadhyaya and principal investigator Graziella Di Cristo, conducted at the Centre de recherche Azrieli du CHU Sainte-Justine, reveals a novel molecular mechanism underlying cognitive disorders observed in school-age children following moderate oxygen deprivation at birth – a condition known as hypoxia. While a certain proportion of children go on to develop cerebral palsy or other major disabilities at a young age, others may exhibit more subtle long-term effects, which are often overlooked, and not diagnosed or followed medically.
Following fruitful discussions with healthcare professionals, Di Cristo’s lab set up an experimental strategy to replicate the hypoxia phenomenon in an animal model to understand how and why, even a moderate loss of oxygen during this critical time could affect the long-term development of the brain. The results in the model showed that even a short-period of hypoxia can cause memory deficits, and cognitive flexibility impairments similar to those seen in school-aged children. Cognitive flexibility is crucial in daily life when we face sudden changes and need to adapt to new tasks. The research team then looked deeper to understand the mechanisms underlying these deficits. .
A molecular clue
While looking for why hypoxia leads to long-term changes in the brain and affects behaviour, the researchers observed that moderate oxygen deprivation particularly affects the development of a subtype of neurons known as parvalbumin-positive (PV) GABAergic interneurons, which are essential for learning, memory, and cognitive function. Disruption of these cells has already been linked to several neurodevelopmental conditions such as autism and epilepsy. In mice who experienced oxygen restriction at birth, PV interneurons remained in a more immature state in adulthood. “While hypoxia is generally considered a global trauma, these specific effects on a subgroup of interneurons represent a central research avenue for understanding the development of long-term brain disorders,” explains Bidisha Chattopadhyaya, first author and co-principal investigator of the study.
Using a combination of molecular analyses techniques, the team identified a key receptor, p75NTR, which responds to neurotrophic signals and is important for cell growth and communication. This receptor regulates multiple functions during the first weeks of life. Oxygen deprivation at birth increases the expression of p75NTR, especially in PV neurons, thereby slowing their maturation and changing the developmental trajectory of the brain, which could explain some of the deficits observed in adulthood.
The researchers first used a genetic strategy to reduce p75NTR in PV neurons early in brain development and rescued both memory deficits and cognitive impairments. Moreover, treatment with a p75NTR inhibitor for one week immediately after oxygen deprivation also prevented the development of cognitive disorders in adulthood. These findings open up promising avenues for improving early care for babies who have experienced moderate oxygen deprivation, potentially preventing the onset of cognitive disorders.
“Although we are not yet at the stage of developing a clinical treatment, our results offer promising directions for future research,” says Graziella Di Cristo, also Professor at Université de Montréal. “Moreover, our study suggests that closer monitoring of these children during early childhood could help better identify those who would benefit from targeted support during their school years.”
Left to right: Co author Maria Isabel Carreño-Muñoz, with first authors Graziella Di Cristo and Bidisha Chattopadhyaya. © CHU Sainte-Justine (Véronique Lavoie)