Review ArticlesSugarcoated Perineuronal Nets Regulate “GABAergic” Transmission: Bittersweet Hypothesis in Autism Spectrum DisorderBurket, Jessica A. MS; Urbano, Maria R. MD; Deutsch, Stephen I. MD, PhD Author Information Department of Psychiatry and Behavioral Sciences, Eastern Virginia Medical School, Norfolk, VA. Address correspondence and reprint requests to Stephen I. Deutsch, MD, PhD, Department of Psychiatry and Behavioral Sciences, Eastern Virginia Medical School, 825 Fairfax Ave, Suite 710, Norfolk, VA 23507; E-mail: [email protected] Conflicts of Interest and Source of Funding: The authors have no conflicts of interest to declare. Clinical Neuropharmacology: 5/6 2017 - Volume 40 - Issue 3 - p 120-130 doi: 10.1097/WNF.0000000000000209 Buy Metrics Abstract 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. Copyright © 2017 Wolters Kluwer Health, Inc. All rights reserved.