Learning and reaction times in mouse touchscreen tests are differentially impacted by mutations in genes encoding postsynaptic interacting proteins SYNGAP1, NLGN3, DLGAP1, DLGAP2 and SHANK2

Genes Brain Behav. 2021 Jan;20(1):e12723. doi: 10.1111/gbb.12723. Epub 2020 Dec 29.


The postsynaptic terminal of vertebrate excitatory synapses contains a highly conserved multiprotein complex that comprises neurotransmitter receptors, cell-adhesion molecules, scaffold proteins and enzymes, which are essential for brain signalling and plasticity underlying behaviour. Increasingly, mutations in genes that encode postsynaptic proteins belonging to the PSD-95 protein complex, continue to be identified in neurodevelopmental disorders (NDDs) such as autism spectrum disorder, intellectual disability and epilepsy. These disorders are highly heterogeneous, sharing genetic aetiology and comorbid cognitive and behavioural symptoms. Here, by using genetically engineered mice and innovative touchscreen-based cognitive testing, we sought to investigate whether loss-of-function mutations in genes encoding key interactors of the PSD-95 protein complex display shared phenotypes in associative learning, updating of learned associations and reaction times. Our genetic dissection of mice with loss-of-function mutations in Syngap1, Nlgn3, Dlgap1, Dlgap2 and Shank2 showed that distinct components of the PSD-95 protein complex differentially regulate learning, cognitive flexibility and reaction times in cognitive processing. These data provide insights for understanding how human mutations in these genes lead to the manifestation of diverse and complex phenotypes in NDDs.

Keywords: Dlgap1; Dlgap2; Nlgn3; Shank2; Syngap1; autism; intellectual disability; postsynaptic density; reversal learning; visual discrimination.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Adhesion Molecules, Neuronal / genetics
  • Female
  • Learning*
  • Loss of Function Mutation*
  • Male
  • Membrane Proteins / genetics
  • Mice
  • Mice, Inbred C57BL
  • Nerve Tissue Proteins / genetics*
  • Reaction Time
  • SAP90-PSD95 Associated Proteins / genetics
  • ras GTPase-Activating Proteins / genetics


  • Cell Adhesion Molecules, Neuronal
  • Dlgap1 protein, mouse
  • Dlgap2 protein, mouse
  • Membrane Proteins
  • Nerve Tissue Proteins
  • SAP90-PSD95 Associated Proteins
  • Shank2 protein, mouse
  • Syngap1 protein, mouse
  • neuroligin 3
  • ras GTPase-Activating Proteins