p75NTR modulation prevents cellular, cortical activity and cognitive dysfunctions caused by perinatal hypoxia

Abstract

Children who experienced moderate perinatal hypoxia are at risk of developing long-lasting subtle cognitive and behavioural deficits, including learning disabilities and emotional problems. Understanding the underlying mechanisms is an essential step for designing targeted therapy. Fast-spiking, parvalbumin-positive (PV) GABAergic interneurons modulate the generation of gamma oscillations, which in turn regulate many cognitive functions including goal-directed attentional processing and cognitive flexibility. Due to their fast-firing rate, PV cell function requires high levels of energy, which may render them highly vulnerable to conditions of metabolic and oxidative stress caused by perinatal hypoxia. Here, we show that adult mice that experienced moderate perinatal hypoxia (MPH) have decreased cortical PV expression levels in addition to specific impairments in social behaviour, recognition memory and cognitive flexibility. We further found that the expression level of the neurotrophin receptor p75NTR, which limits PV cell maturation during the first postnatal weeks, is increased in MPH mice. Genetic deletion of p75NTR in GABAergic neurons expressing the transcription factor Nkx2.1, which include PV cells, protects mice from PV expression loss and the long-term cognitive effects of MPH. Finally, treatment with a p75NTR inhibitor starting after MPH and lasting for a week, prevented PV expression loss and the occurrence of cognitive and cortical activity deficits in adult mice. Altogether our data reveals p75NTR-mediated signaling, as a potential molecular target, for the treatment of the cognitive alterations caused by MPH.