Depletion of Neurocan in the Prefrontal Cortex Impairs Temporal Order Recognition, Cognitive Flexibility and Perisomatic GABAergic Innervation

AI Summary

Region-specific Ncan depletion in the infralimbic PFC reduces WFA-labelled perineuronal nets around PV+ interneurons, indicating altered PNN composition.
Ncan knockdown produces mild but consistent impairments in medial PFC-dependent temporal order recognition memory and reversal spatial learning.
Ncan reduction decreases perisomatic GABAergic innervation of PV+ cells and increases vGLUT1 puncta; constitutive knockout lacks these structural changes.

AI Summary

Genetic variation in the human Ncan gene has been linked to alterations in hippocampus-dependent memory, structural differences in the prefrontal cortex (PFC), and increased risk for schizophrenia and bipolar disorder.

Behaviorally, mice with reduced Ncan expression exhibited mild but consistent impairments in medial PFC-dependent temporal order recognition memory and in aspects of reversal spatial learning in a labyrinth task.

Together, 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.

Basic summary

Cell Mol Neurobiol. 2026 Jun 9;46(1):103. doi: 10.1007/s10571-026-01762-2.

ABSTRACT

The condensed form of the neural extracellular matrix (ECM), known as perineuronal nets (PNNs), is predominantly associated with parvalbumin-expressing (PV+) interneurons in the cortex and hippocampus. PNNs are enriched in lecticans, including neurocan (Ncan). Genetic variation in the human Ncan gene has been linked to alterations in hippocampus-dependent memory, structural differences in the prefrontal cortex (PFC), and increased risk for schizophrenia and bipolar disorder. However, the specific contribution of Ncan to PFC-dependent cognitive functions and synaptic organization remains incompletely understood. Here, we investigated the consequences of region-specific reduction of Ncan in the infralimbic cortex of mice, a region considered homologous to the dorsomedial part of the human medial PFC. Using intracortical adeno-associated virus delivery of shRNA targeting Ncan, we examined PNN-associated markers, synaptic organization, and PFC-dependent behaviors. Ncan knockdown was associated with reduced Wisteria floribunda agglutinin (WFA) labeling of PNNs surrounding PV+ interneurons, suggesting alterations in PNN composition. Behaviorally, mice with reduced Ncan expression exhibited mild but consistent impairments in medial PFC-dependent temporal order recognition memory and in aspects of reversal spatial learning in a labyrinth task. At the cellular level, immunohistochemical analyses revealed a reduction in markers associated with perisomatic GABAergic innervation of PV+ interneurons, together with an increase in the density of vGLUT1-immunopositive puncta in the surrounding neuropil. These structural changes were not observed in constitutive Ncan knockout mice, suggesting the presence of compensatory mechanisms in this model. Together, 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.

PMID:42260248 | DOI:10.1007/s10571-026-01762-2

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