Neurodevelopmental synaptopathies: Insights from behaviour in rodent models of synapse gene mutations

Highlights

• Human mutations in pre- and postsynaptic genes impact multiple developmental disorders.

• Behavioural and cognitive analysis of mouse genetic models reveal complex findings.

• Requirement for standardisation of behavioural and cognitive assays and analyses.

• Need for more comprehensive analysis of multiple behavioural and cognitive domains.

Abstract

The genomic revolution has begun to unveil the enormous complexity and heterogeneity of the genetic basis of neurodevelopmental disorders such as such epilepsy, intellectual disability, autism spectrum disorder and schizophrenia. Increasingly, human mutations in synapse genes are being identified across these disorders. These neurodevelopmental synaptopathies highlight synaptic homeostasis pathways as a convergence point underlying disease mechanisms. Here, we review some of the key pre- and postsynaptic genes in which penetrant human mutations have been identified in neurodevelopmental disorders for which genetic rodent models have been generated. Specifically, we focus on the main behavioural phenotypes that have been documented in these animal models, to consolidate our current understanding of how synapse genes regulate key behavioural and cognitive domains. These studies provide insights into better understanding the basis of the overlapping genetic and cognitive heterogeneity observed in neurodevelopmental disorders.

Introduction

Neuroscience has been transformed by the genomic revolution, which has provided an unprecedented platform from which to unravel the brain and its disorders. Combined with advancements in whole exome and deep sequencing technologies, deciphering the genetic architecture of diseases using large patient cohorts is now routinely achievable. These methods have unveiled the enormous complexity and heterogeneity of the genetic basis of brain disorders. From these data, key overlapping molecular and cellular pathways that are impacted across mental disorders are emerging, with dysfunction at the synapse being a convergence point, leading to the idea of ‘synaptopathies’ (Grant, 2012) or diseases of the synapse to collectively view these disorders.

The burden of mental health diseases, particularly neurodevelopmental disorders that affect individuals across the lifespan are enormous, and pose greater financial and societal impacts than almost all other disorders. Human mutations in genes encoding synaptic proteins are being increasingly identified in neurodevelopmental disorders, such as epilepsy, intellectual disability, autism spectrum disorder and schizophrenia. While these disorders each present with unique symptoms (e.g. seizures in epilepsy), importantly they also all exhibit cognitive and behavioural symptoms which potentially lie at the heart of the disorder. Moreover, there is increasing appreciation for the overlapping co-morbidities between these disorders, as well as the large genetic heterogeneity observed within these disorders. As highlighted in Fig. 1, mutations in both pre- and postsynaptic genes have been reported to impact the same disorder and furthermore, mutations in the same gene are documented in more than one disorder. Therefore, viewing these disorders collectively through their common underlying mechanisms may be the key to effectively developing therapies that will address the overlapping symptoms observed across disorders.

Animal models of disorders are essential in elucidating underlying disease mechanisms and most importantly, for the development of effective therapies for the complex cognitive symptoms that are core to many brain disorders. Modelling human behaviour and cognition in animals is complex, however rodent models provide practical and powerful model systems to dissect these complexities due to their highly conserved genomic mechanisms.

A plethora of rodent models to understand gene mutations and dysfunction have been generated and characterised over the last 25 years. Here, we review some of the key pre- and postsynaptic genes in which 1) penetrant mutations have been identified in individuals diagnosed with developmental disorders (namely, epilepsy, intellectual disability, autism spectrum disorder and schizophrenia) and 2) where mouse models with mutations in these same pre- and postsynaptic genes have been generated and characterised. In particular, we focus on the key behavioural and cognitive phenotypes that have been documented with a goal to highlight our current understanding from these animal models on the importance of these genes in regulating behaviour and cognition.