Perineuronal nets (PNNs) are specialized structures within the brain’s extracellular matrix. These lattice-like formations surround specific neurons, particularly in the central nervous system. PNNs contribute to the stability of neural circuits and help regulate various brain processes, maintaining their precise organization and function.
Understanding Perineuronal Nets
Perineuronal nets possess a highly organized lattice-like structure that encases the soma and proximal dendrites of certain neurons. These specialized components of the extracellular matrix are primarily composed of chondroitin sulfate proteoglycans (CSPGs), hyaluronan, and link proteins, which help anchor the CSPGs to the hyaluronan backbone. The CSPGs, such as aggrecan, neurocan, brevican, and versican, contribute significantly to the net’s dense and stable framework.
PNNs preferentially ensheath fast-spiking, parvalbumin-positive (PV+) inhibitory interneurons, which regulate the timing and synchronization of neural activity. They are found across various brain regions, including the cerebral cortex, hippocampus, and cerebellum, with a distribution specific to these neuron types. PNNs form during brain development, generally after the peak of synaptic plasticity, and mature alongside neural circuits.
Roles in Brain Function
Perineuronal nets play an important role in regulating synaptic plasticity, particularly in “closing” critical periods during brain development. Critical periods are specific time windows when the brain is highly susceptible to environmental input, allowing for rapid learning and circuit refinement. PNNs emerge as these periods conclude, acting as a structural “brake” that stabilizes neural connections and reduces their malleability.
This stabilization is achieved by limiting the movement of synaptic receptors and adhesion molecules, thereby consolidating learned behaviors and memories. For instance, in the visual cortex, PNNs mature at the end of the critical period for ocular dominance plasticity, preventing further major reorganization of visual pathways.
PNNs also contribute to the precision of neural signaling by regulating the diffusion of molecules in the extracellular space around neurons. This ensures that neurotransmitters and other signaling molecules act within defined spatial limits, enhancing the fidelity of synaptic transmission. By stabilizing the connections of PV+ interneurons, PNNs ensure these inhibitory cells can precisely control neural network oscillations, which are important for cognitive functions like attention and memory.
Perineuronal Nets and Brain Health
Alterations or degradation of perineuronal nets have been observed in various neurological and psychiatric conditions, suggesting their involvement in brain health and disease. In Alzheimer’s disease, for example, there is evidence of PNN degradation, particularly around vulnerable neurons in affected brain regions. This breakdown may contribute to the synaptic dysfunction and neuronal loss characteristic of the disorder.
Schizophrenia is associated with altered distribution or composition of PNNs, especially around PV+ interneurons in the prefrontal cortex and hippocampus. These changes might disrupt the precise inhibitory control exerted by these interneurons, potentially contributing to cognitive deficits and altered neural oscillations seen in patients. Research indicates that a reduction in certain CSPGs within PNNs could impair the function of these fast-spiking neurons.
Changes in PNNs have also been implicated in autism spectrum disorder, where atypical PNN development or maintenance might contribute to altered circuit connectivity and sensory processing issues. Similarly, in epilepsy, PNN degradation can increase neuronal excitability and contribute to seizure susceptibility by disrupting the balance between excitation and inhibition. Understanding how PNNs are affected in these conditions offers new avenues for developing therapeutic strategies, potentially by stabilizing or restoring these extracellular structures to improve brain function.