Mutations in neuroligin-3 in male mice impact behavioral flexibility but not relational memory in a touchscreen test of visual transitive inference

Abstract

Cognitive dysfunction including disrupted behavioral flexibility is central to neurodevelopmental disorders such as Autism Spectrum Disorder (ASD). A cognitive measure that assesses relational memory, and the ability to flexibly assimilate and transfer learned information is transitive inference. Transitive inference is highly conserved across vertebrates and disrupted in cognitive disorders. Here, we examined how mutations in the synaptic cell-adhesion molecule neuroligin-3 (Nlgn3) that have been documented in ASD impact relational memory and behavioral flexibility. We first refined a rodent touchscreen assay to measure visual transitive inference, then assessed two mouse models of Nlgn3 dysfunction (Nlgn3−/y and Nlgn3R451C). Deep analysis of touchscreen behavioral data at a trial level established we could measure trajectories in flexible responding and changes in processing speed as cognitive load increased. We show that gene mutations in Nlgn3 do not disrupt relational memory, but significantly impact flexible responding. Our study presents the first analysis of reaction times in a rodent transitive inference test, highlighting response latencies from the touchscreen system are useful indicators of processing demands or decision-making processes. These findings expand our understanding of how dysfunction of key components of synaptic signaling complexes impact distinct cognitive processes disrupted in neurodevelopmental disorders, and advance our approaches for dissecting rodent behavioral assays to provide greater insights into clinically relevant cognitive symptoms.

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

“…The decreased perseverative behaviour observed in Nlgn3 −/Y mice during reversal learning in the current study is similar to what we reported previously during a test for visual transitive inference, 40 suggesting heightened sensitivity to non‐reward feedback. Further, the longer response latencies in Nlgn3 −/Y mice observed here are also in accord with similar observations we described in this mutant during the early (A + B − ) stage of the transitive interference test 40 …”

“…Therefore, in addition to our key measures of learning, we examined latencies to make correct and incorrect responses, as well as to collect rewards. While most studies employing the touchscreen visual discrimination and reversal learning tasks commonly report latencies pooled across sessions for the whole task (task‐level), we sought to assess latencies at both task (Figures S4 and S5) and session‐by‐session levels (Figures 4 and 5) as we have previously seen response latencies, but not reward collection latencies, alter with the progression of testing on tasks 18,40 …”

“…Towards unravelling this genetic and phenotypic complexity, mice with genetically engineered mutations in genes encoding postsynaptic proteins provide valuable models to understand the impact of discrete mutations on the symptom profile in a mammalian organism 34 . Furthermore, the development of innovative behavioural tools, such as the touchscreen cognitive battery, has enabled the measurements of more complex cognitive behaviours disrupted in NDDs in rodent models 35‐40 . The combination of these genetic and behavioural testing tools provides opportunities for unravelling the genetic basis of complex behaviours and disease.…”

The effect of background strain on the behavioral phenotypes of the MDGA2+/− mouse model of autism spectrum disorder

“…Mutant and transgenic mouse models of ASD are engineered using different background strains (JAX SFARI website) and these background strains differ in their behavioral phenotypes 68,69 . For example, NRXN and NLGN mouse models of ASD have been constructed on the C57BL/6J background, 57,70‐ the C57BL/6NCrl background, 72 the 129s6/SvEvTac/C57BL6J background 73 ; the Sv129/C57BL6 background 56 and the 129S2/SvPasCrl background 74 . Host genetic backgrounds themselves can influence diverse neurological responses.…”

FMRP y las neuroliginas: la influencia de la actividad sensorial en las dinámicas del neurodesarrollo

“…Dichas mutaciones se han asociado con el desequilibrio excitatorio/ inhibitorio característico del autismo y la epilepsia, donde se encuentran conexiones cerebrales menos inhibidas (1,81,82). En ratones, la sobreexpresión y la eliminación de las Nlg lleva a deficiencias en la interacción social o la comunicación, a comportamientos repetitivos, a ansiedad y a problemas de aprendizaje y memoria (83,84). En Drosophila, el KO de dnlg2 produce una disminución en los botones sinápticos, desarrollo aberrante de las uniones neuromusculares y una transmisión sináptica afectada; en tanto que los receptores de glutamato están disminuidos y hay una reducción de los potenciales de unión excitatoria.…”