In the adult brain, the extracellular matrix (ECM) influences recovery after injury, susceptibility to mental disorders, and is in general a strong regulator of neuronal plasticity. The proteoglycan aggrecan is a core component of the condensed ECM structures termed perineuronal nets (PNNs), and the specific role of PNNs on neural plasticity remains elusive. Here, we genetically targeted the Acan gene encoding for aggrecan using a novel animal model. This allowed for conditional and targeted loss of aggrecan in vivo, which ablated the PNN structure and caused a shift in the population of parvalbumin-expressing inhibitory interneurons toward a high plasticity state. Selective deletion of the Acan gene in the visual cortex of male adult mice reinstated juvenile ocular dominance plasticity, which was mechanistically identical to critical period plasticity. Brain-wide targeting improved object recognition memory.SIGNIFICANCE STATEMENT The study provides the first direct evidence of aggrecan as the main functional constituent and orchestrator of perineuronal nets (PNNs), and that loss of PNNs by aggrecan removal induces a permanent state of critical period-like plasticity. Loss of aggrecan ablates the PNN structure, resulting in invoked juvenile plasticity in the visual cortex and enhanced object recognition memory.

Biological Sciences University of Southampton Southampton SO17 1BJ United Kingdom

Department of Biosciences University of Oslo 0316 Oslo Norway

Department of Biosciences University of Oslo 0316 Oslo Norway Institute of Basic Medical Sciences University of Oslo 0317 Oslo Norway and

Institute of Basic Medical Sciences University of Oslo 0317 Oslo Norway and

John van Geest Centre for Brain Repair University of Cambridge Robinson Way Cambridge CB2 0PY United Kingdom

John van Geest Centre for Brain Repair University of Cambridge Robinson Way Cambridge CB2 0PY United Kingdom Centre for Reconstructive Neuroscience Institute for Experimental Medicine CAS Prague Czech Republic

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