LONGITUDINAL ANALYSIS OF PERINEURONAL NET DYNAMICS AND NEURODEVELOPMENTAL PLASTICITY IN <EM >NF1<SUP>+/−</SUP></EM> MICE

Autism spectrum disorders (ASD) are characterized by behavioral and molecular alterations that affect neurodevelopment. Neurofibromatosis type 1 (NF1) is a syndromic model of ASD and has been associated with impaired synaptic plasticity. Perineuronal nets (PNNs) are extracellular matrix structures that predominantly surround parvalbumin-expressing (PV) interneurons. They are known for the regulation of the timing of critical periods (CPs). Previous studies in Nf1^+/− mice suggested PV interneuron and ocular dominance alterations.
We conducted a longitudinal analysis of Nf1^+/− mice to assess neurodevelopment at behavioral and molecular levels. Behavioral assessments included locomotor and cognitive milestone evaluation, 3-chamber social interaction and elevated plus maze tests. From a molecular perspective, we quantified PNNs using Wisteria floribunda agglutinin (WFA) labeling and analyzed PV interneuron density across multiple brain regions, including from prelimbic and to somatomotor areas.
Analyses were performed at postnatal days 10, 21, 38, and 90 to cover postnatal development, CP onset and closure, and young adulthood. Our results revealed a significant increase in PNN coverage in the central amygdala of female Nf1^+/− mice compared with wild-type littermates (unpaired t-test, p = 0.01). In contrast, a significant reduction in PNN coverage was observed in the retrosplenial cortex of female Nf1^+/− mice at P38 (unpaired t-test p=0.003). These region- and sex-specific alterations in PNN maturation suggest disrupted circuit development in this model. Ongoing in vivo electrophysiological and functional magnetic resonance imaging studies aim to investigate how PNNs influence barrel cortex recruitment following whisker deprivation, with future work focusing on enzymatic PNN manipulation.