The p75 Neurotrophin Receptor in Preadolescent Prefrontal Parvalbumin Interneurons Promotes Cognitive Flexibility in Adult Mice

Chehrazi, Pegah; Lee, Karen Ka Yan; Lavertu-Jolin, Marisol; Abbasnejad, Zahra; Carreno-Muñoz, Maria Isabel; Chattopadhyaya, Bidisha; Cristo, Graziella Di

doi:10.1016/j.biopsych.2023.04.019

Cited by 7 publications

(3 citation statements)

References 72 publications

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“…Adult naïve Nkx2.1-Cre:p75NTR lox/lox cKO mice did not show significant differences in the behaviors tested as compared to their naïve control and cKO littermates. In a previous study from our lab, where Cre is expressed under the PV promoter, PV cell-specific p75NTR knockout mice show impaired cognitive flexibility in the same behavioral task we used in this study (Chehrazi et al, 2023). Since there are significant differences in the manner of P75NTR deletion given that a) PV expression starts only after the first postnatal week and peaks just before adolescence in mice, while the Nkx2.1 promoter drives Cre expression embryonically, and b) the Nkx2.1 promoter expresses not only in PV but also in somatostatin-expressing interneurons, it is therefore possible that the developmental age at which p75NTR is deleted differently affects the time course of PV cell maturation, thereby leading to different behavioral outcomes.…”

Section: Discussionmentioning

confidence: 92%

“…This test was performed as described in Chehrazi et al, 2023. Briefly, behavioral experiments were performed in a home-made acrylic rectangular-shaped maze (30 cm long × 20 cm wide × 18 cm high) divided in half by a guillotine-like door that extended through the width of the maze.…”

Section: Methodsmentioning

confidence: 99%

“…Odor, medium combination and location (left or right) of the baited bowl was determined as in Chehrazi et al, 2023. At each stage of the task, while the particular odor-medium combination present in each of the two bowls may have changed, the particular stimulus that signaled the presence of food reward remained constant over each portion of the task (initial association, rule shift, and rule reversal).…”

Section: Methodsmentioning

confidence: 99%

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

Chattopadhyaya,

Lee,

Carreño-Muñoz

et al. 2024

Preprint

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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.

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Section: Discussionmentioning

confidence: 92%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

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

Chattopadhyaya,

Lee,

Carreño-Muñoz

et al. 2024

Preprint

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Fluoxetine and Ketamine Enhance Extinction Memory and Brain Plasticity by Triggering the p75 Neurotrophin Receptor Proteolytic Pathway

Diniz,

Crestani,

Casarotto

et al. 2025

Biological Psychiatry

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Syngap1regulates the synaptic drive and membrane excitability of Parvalbumin-positive interneurons in mouse auditory cortex

Francavilla,

Chattopadhyaya,

Kamda

et al. 2024

Preprint

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SYNGAP1 haploinsufficiency-related intellectual disability (SYNGAP1-ID) is characterized by moderate to severe ID, generalized epilepsy, autism spectrum disorder, sensory processing dysfunction and other behavioral abnormalities. While most studies, so far, have focussed on the role of Syngap1 in cortical excitatory neurons, recent studies suggest that Syngap1 plays a role in GABAergic inhibitory neuron development as well. However, the molecular pathways by which Syngap1 acts on GABAergic neurons, and whether they are similar or different from the mechanisms underlying its effects in excitatory neurons, is unknown. Here we examined whether, and how, embryonic-onsetSyngap1haploinsufficiency restricted to GABAergic interneurons derived from the medial ganglionic eminence (MGE) impacts their synaptic and intrinsic properties in adulthood. We found thatSyngap1haploinsufficiency affects the intrinsic properties, overall leading to increased firing threshold, and decreased excitatory synaptic drive of Parvalbumin (PV)+ neurons from Layer IV auditory cortex in adult mice, whilst Somatostatin (SST)+ interneurons were mostly resistant toSyngap1haploinsufficiency. Further, the AMPA component of thalamocortical evoked-EPSC was decreased in PV+ cells from mutant mice. Finally, we found that targeting the Kv1 family of voltage-gated potassium channels was sufficient to rescue PV+ mutant cell-intrinsic properties to wild-type levels. Together, these data suggest thatSyngap1plays a specific role in the maturation of PV+ cell intrinsic properties and synaptic drive, and its haploinsufficiency may lead to reduced PV cell recruitment in the adult auditory cortex, which could thus underlie the auditory processing alterations found in SYNGAP1-ID preclinical models and patients.

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The p75 Neurotrophin Receptor in Preadolescent Prefrontal Parvalbumin Interneurons Promotes Cognitive Flexibility in Adult Mice

Cited by 7 publications

References 72 publications

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

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

Fluoxetine and Ketamine Enhance Extinction Memory and Brain Plasticity by Triggering the p75 Neurotrophin Receptor Proteolytic Pathway

Syngap1regulates the synaptic drive and membrane excitability of Parvalbumin-positive interneurons in mouse auditory cortex

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