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

Abstract

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.

Cognitive behavioral markers of neurodevelopmental trajectories in rodents

“…We have previously shown the utility of using the mouse PAL touchscreen task for enhancing translation [ 36 , 49 ]. Our recent work has also highlighted that these touchscreen behavioral tools can be used to dissect reaction times and processing speed in rodents [ 35 , 37 , 50 ]. While learning and motivation can be dissociated as we have previously shown using our parallel assessment of learning performance and latency measures [ 35 ], in the current study we see that these two processes are correlated across the developmental trajectory in mice.…”

Increased levels of the synaptic proteins PSD-95, SNAP-25, and neurogranin in the cerebrospinal fluid of patients with Alzheimer’s disease

“…Altered PSD-95 expression modulates receptor retention at the synapse and PSD-95 is an important factor in synaptic plasticity and the stabilization of synaptic changes during long-term potentiation [ 8 ]. Animal studies suggest that PSD-95 disruption is associated with cognitive and learning deficits [ 9 ]. Reduced expression of PSD-95 has been observed in brain tissue from AD subjects [ 10 , 11 ] and in mouse models of AD [ 11 ].…”

8p23.2-pter Microdeletions: Seven New Cases Narrowing the Candidate Region and Review of the Literature

“…Both DLGAP2 and ARHGEF10 could be potential candidates for behavioral disorders, in accordance with the phenotype of Dlgap2 -/- and Arhgef10 -/- mice [ 54 , 55 , 56 ]. Accordingly, our Patients 2, 4, 5 and 7, which carry 8p23.2-pter microdeletions involving DLGAP2 and/or ARHGEF10 , are characterized by hyperactivity/hyperkinetic behavior and/or aggressiveness ( Table 1 ).…”