Sugarcoated Perineuronal Nets Regulate "GABAergic" Transmission: Bittersweet Hypothesis in Autism Spectrum Disorder.

Fast-spiking, parvalbumin-expressing "GABAergic" interneurons regulate synchronous oscillatory output of pyramidal neurons. Metabolic demands of these GABAergic projections are great because local ion concentrations must be optimally maintained; in addition, high rates of mitochondrial respiration necessitate exquisite redox regulation. Interestingly, only fast-spiking, parvalbumin-expressing basket cells coexpressing 3 metalloproteinases seem to be preferentially enwrapped in perineuronal nets (PNNs), a specialized lattice-like structure of the extracellular matrix. The PNNs maintain optimal local concentrations of ions, protect against oxidative stress, and concentrate transcription factors and chemorepulsive axon guidance cues. The PNNs mediate opening and closing of periods of heightened plasticity. Therapeutic strategies in autism spectrum disorders include promoting both maintenance and deliberate disruption of PNNs to promote new learning and cognitive flexibility.