p75NTR upregulation following perinatal hypoxia leads to deficits in parvalbumin-expressing GABAergic cell maturation, cortical activity and cognitive abilities in adult mice

Children who experienced moderate perinatal hypoxia are at risk of developing long lasting subtle cognitive and behavioral 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 the social, recognition memory and cognitive flexibility domain. 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, one week treatment with a p75NTR inhibitor starting after MPH completely rescues the cognitive and cortical activity deficits in adult mice. All together this data reveals a potential molecular target for the treatment of the cognitive alterations caused by MPH. ### Competing Interest Statement F.M.L. is listed as an inventor on patents related to LM11A-31 that are assigned to the University of North Carolina, University of California, San Francisco and the Dept of Veterans Affairs. He is also entitled to royalties distributed by UC and the VA per their standard agreements. Dr. Longo is a principal of, and has financial interest in PharmatrophiX, a company focused on the development of small molecule ligands for neurotrophin receptors that has licenced several related patents.