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Perineuronal Nets: Plasticity, Protection, and Therapeutic Potential

Reichelt AC, Hare DJ, Bussey TJ, Saksida LM (2019) Cell. 2019 June; 

Web URL: Read the research on Cell here


  • Perineuronal nets (PNNs) are extracellular matrix structures serving multiple functions, including regulating synaptic plasticity, stabilizing synapses, and protecting neurons from oxidative stress and neurotoxins.
  • Through their physiological roles, PNNs are also involved in cognition – including encoding, maintaining, and updating memories.
  • Removal of PNNs can render neurons vulnerable to damage – particularly in neurodegenerative conditions involving increased oxidative stress or neurotoxins.
  • Removal or digestion of PNNs in animal models increases plasticity, leading to enhanced memory interference from competing information during the encoding process.
  • Environmental factors, such as physical activity, drugs, and nutrition, can influence brain plasticity, and some of these effects may be mediated by changes in PNN structure.
  • Defining molecular targets that modify PNN structure may aid development of interventions for individuals experiencing cognitive decline linked to aberrant neural plasticity, such as in dementia.
The relationship between neurons and perineuronal nets (PNNs) is attracting attention as a central mechanism controlling brain plasticity. In the cortex, PNNs primarily surround inhibitory parvalbumin interneurons, playing roles as both a regulator of synaptic plasticity and a protective barrier. PNNs have a delayed developmental trajectory and are key components in the closure of critical periods of heightened neuroplasticity. In animal models, manipulating PNNs outside this critical window can enhance cognition, suggesting a potentially therapeutic approach for attenuating cognitive decline. However, the crucial role of PNNs in plasticity and protection means that such therapeutic modulation must strike a careful balance: manipulation of PNNs to promote plasticity may have unintended negative consequences resulting from excessive plasticity or from exposure of neurons to neurotoxins.


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