Depletion of neurocan in the prefrontal cortex impairs temporal order recognition, cognitive flexibility and perisomatic GABAergic innervation

The condensed form of neural extracellular matrix (ECM), called perineuronal nets (PNNs), is predominantly associated with parvalbumin-expressing (PV+) interneurons in the cortex and hippocampus. PNNs are enriched in several lecticans, including neurocan (Ncan). A polymorphism in the human Ncan gene has been associated with alterations in hippocampus-dependent memory function, variation of prefrontal cortex structure, and a higher risk for schizophrenia or bipolar disorder. Constitutive Ncan knockout (KO) mice show related behavioral abnormalities, such as hyperactivity. Here, we focused on studying how dysregulation of Ncan specifically in the infralimbic cortex of mice, which is considered homologous to the dorsomedial region of the human medial prefrontal cortex (mPFC), may affect cognitive and synaptic functions. Intracortical adeno-associated virus (AAV) delivery was used to express shRNA against Ncan. Ncan knockdown reduced the intensity of Wisteria floribunda agglutinin (WFA)-positive PNNs around PV+ interneurons in the infralimbic cortex, impaired the mPFC-dependent temporal order recognition capacity, and worsened the consolidation of spatial memory after reversal learning in a labyrinth (dry maze) task. As a potential synaptic substrate of these cognitive abnormalities, we report a robust reduction in the perisomatic GABAergic innervation of PV+ cells in Ncan shRNA-injected mice. We also observed an increase in the density of vGLUT1-immunopositive synaptic puncta in the neuropil of Ncan shRNA-injected mice, which was compensated in Ncan KO mice. Thus, our findings highlight a functional role of Ncan in supporting perisomatic GABAergic innervation, temporal order recognition memory and cognitive flexibility, important cognitive resources impaired in neuropsychiatric disorders.