Parvalbumin down-regulation as a common pathophysiological mechanism in autism spectrum disorders

  • Awarded: 2018
  • Award Type: Explorer
  • Award #: 603695

Although a strong genetic component is evident in the etiology of autism spectrum disorders (ASD), mutations in any given ‘ASD susceptibility gene’ account for less than 1% of ASD cases. Fully understanding the biological complexity of ASD will require the identification of common and unifying dysfunctions/pathways underlying the core ASD symptoms.

A large body of evidence suggests that impairments in neuronal excitatory/inhibitory (E/I) balance play a role in ASD pathology and altered functioning of the parvalbumin (PV)-expressing subgroup of GABAergic interneurons is a common cause of E/I imbalance. PV-immunoreactive (PV+) neurons have been shown to be decreased in postmortem brain tissue of individuals affected by ASD, and PV mRNA is among the most strongly downregulated transcripts in ASD. Further, several ASD mouse models, including Shank3, Shank1 and Cntnap2 knockout mice exhibit a downregulation of PV expression levels in various brain regions1-3. Combined, these data suggest that downregulation of PV expression may represent a pathogenic molecular hub for ASD4. In further support of this hypothesis, PV+/- and PV-/- mice exhibit repetitive behaviors and deficits in social behaviors; 17-b estradiol-mediated upregulation of PV in the PV+/- mice was shown to significantly attenuate these behaviors5.

Beat Schwaller’s laboratory thus argues that upregulating PV expression might serve as a useful therapeutic approach for ASD. To address this systematically, Schwaller’s laboratory will take advantage of a transgenic mouse model in which PV expression can be modulated in a temporally precise manner6. PV levels will be decreased at different time points during postnatal development, and behaviors will be assessed to see whether any changes in ASD core symptoms are observed. These experiments are expected to reveal windows of opportunities with respect to time periods of PV upregulation that may prove therapeutically beneficial for ASD.


  1. Filice F. et al. Mol. Brain 9, 10 (2016) PubMed
  2. Lauber E. et al. Front. Mol. Neurosci. 9, 150 (2016) PubMed
  3. Lauber E. et al. Front. Mol. Neurosci. 11, 262 (2018) PubMed
  4. Lauber E. et al. J. Neurosci. Res. 96, 360-361 (2018) PubMed
  5. Filice F. et al. Mol. Autism 9, 15 (2018) PubMed
  6. Filice F. et Eur. J. Neurosci. Epub ahead of print (2019) PubMed
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