title: Reduction in parvalbumin expression not loss of the parvalbumin-expressing GABA interneuron subpopulation in genetic parvalbumin and shank mouse models of autism.
abstract: BACKGROUND
  A reduction of the number of parvalbumin (PV)-immunoreactive (PV(+)) GABAergic interneurons or a decrease in PV immunoreactivity was reported in several mouse models of autism spectrum disorders (ASD). This includes Shank mutant mice, with SHANK being one of the most important gene families mutated in human ASD. Similar findings were obtained in heterozygous (PV+/-) mice for the Pvalb gene, which display a robust ASD-like phenotype. Here, we addressed the question whether the observed reduction in PV immunoreactivity was the result of a decrease in PV expression levels and/or loss of the PV-expressing GABA interneuron subpopulation hereafter called "Pvalb neurons". The two alternatives have important implications as they likely result in opposing effects on the excitation/inhibition balance, with decreased PV expression resulting in enhanced inhibition, but loss of the Pvalb neuron subpopulation in reduced inhibition.
  
  
  METHODS
  Stereology was used to determine the number of Pvalb neurons in ASD-associated brain regions including the medial prefrontal cortex, somatosensory cortex and striatum of PV-/-, PV+/-, Shank1-/- and Shank3B-/- mice. As a second marker for the identification of Pvalb neurons, we used Vicia Villosa Agglutinin (VVA), a lectin recognizing the specific extracellular matrix enwrapping Pvalb neurons. PV protein and Pvalb mRNA levels were determined quantitatively by Western blot analyses and qRT-PCR, respectively.
  
  
  RESULTS
  Our analyses of total cell numbers in different brain regions indicated that the observed "reduction of PV(+) neurons" was in all cases, i.e., in PV+/-, Shank1-/- and Shank3B-/- mice, due to a reduction in Pvalb mRNA and PV protein, without any indication of neuronal cell decrease/loss of Pvalb neurons evidenced by the unaltered numbers of VVA(+) neurons.
  
  
  CONCLUSIONS
  Our findings suggest that the PV system might represent a convergent downstream endpoint for some forms of ASD, with the excitation/inhibition balance shifted towards enhanced inhibition due to the down-regulation of PV being a promising target for future pharmacological interventions. Testing whether approaches aimed at restoring normal PV protein expression levels and/or Pvalb neuron function might reverse ASD-relevant phenotypes in mice appears therefore warranted and may pave the way for novel therapeutic treatment strategies.
authors.affiliation: Anatomy, Department of Medicine, University of Fribourg, Route Albert-Gockel 1, CH-1700, Fribourg, Switzerland. Federica.Filice@unifr.ch.
authors.forename: Federica
authors.initials: F
authors.lastname: Filice
authors.affiliation: Behavioral Neuroscience, Faculty of Psychology, Philipps-University of Marburg, Gutenbergstraβe 18, D-35032, Marburg, Germany. voerckel@staff.uni-marburg.de.
authors.forename: Karl Jakob
authors.initials: KJ
authors.lastname: Vörckel
authors.affiliation: Behavioral Neuroscience, Faculty of Psychology, Philipps-University of Marburg, Gutenbergstraβe 18, D-35032, Marburg, Germany. sungur@staff.uni-marburg.de.
authors.forename: Ayse Özge
authors.initials: AÖ
authors.lastname: Sungur
authors.affiliation: Behavioral Neuroscience, Faculty of Psychology, Philipps-University of Marburg, Gutenbergstraβe 18, D-35032, Marburg, Germany. woehrm@staff.uni-marburg.de.
authors.forename: Markus
authors.initials: M
authors.lastname: Wöhr
authors.affiliation: Anatomy, Department of Medicine, University of Fribourg, Route Albert-Gockel 1, CH-1700, Fribourg, Switzerland. Beat.Schwaller@unifr.ch.
authors.forename: Beat
authors.initials: B
authors.lastname: Schwaller
mesh_terms: D000818:Animals; D001321:Autistic Disorder / Q000378:metabolism* / Q000473:pathology*; D002452:Cell Count; D002540:Cerebral Cortex / Q000473:pathology; D004195:Disease Models, Animal; D005455:Fluorescent Antibody Technique; D059330:GABAergic Neurons / Q000378:metabolism*; D007395:Interneurons / Q000378:metabolism*; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D008840:Microfilament Proteins; D009419:Nerve Tissue Proteins / Q000172:deficiency / Q000378:metabolism*; D010320:Parvalbumins / Q000172:deficiency / Q000378:metabolism*; D017397:Prefrontal Cortex / Q000378:metabolism
chemical_list: D008840:Microfilament Proteins; D009419:Nerve Tissue Proteins; D010320:Parvalbumins; C512412:SHANK1 protein, mouse; C492356:Shank3 protein, mouse
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