A truncating Aspm allele leads to a complex cognitive phenotype and region-specific reductions in parvalbuminergic neurons

Lillian Garrett,Helmut Fuchs,Sabine M Hölter,Yoon Jeung Chang,Kristina M Niedermeier,Valerie Gailus-Durner,Wolfgang Enard,Martin Hrabě De Angelis,Wolfgang Wurst,Wieland B Huttner,Tamara Heermann

doi:10.1038/s41398-020-0686-0

Abstract

Neurodevelopmental disorders are heterogeneous and identifying shared genetic aetiologies and converging signalling pathways affected could improve disease diagnosis and treatment. Truncating mutations of the abnormal spindle-like microcephaly associated (ASPM) gene cause autosomal recessive primary microcephaly (MCPH) in humans. ASPM is a positive regulator of Wnt/β-Catenin signalling and controls symmetric to asymmetric cell division. This process balances neural progenitor proliferation with differentiation during embryogenesis, the malfunction of which could interfere with normal brain development. ASPM mutations may play a role also in other neurodevelopmental disorders, nevertheless, we lack the details of how or to what extent. We therefore assessed neurodevelopmental disease and circuit endophenotypes in mice with a truncating Aspm1–7 mutation. Aspm1–7 mice exhibited impaired short- and long-term object recognition memory and markedly enhanced place learning in the IntelliCage®. This behaviour pattern is reminiscent of a cognitive phenotype seen in mouse models and patients with a rare form of autism spectrum disorder (ASD) as well as in mouse models of altered Wnt signalling. These alterations were accompanied by ventriculomegaly, corpus callosum dysgenesis and decreased parvalbumin (PV)+ interneuron numbers in the hippocampal Cornu Ammonis (CA) region and thalamic reticular nucleus (TRN). PV+ cell number correlated to object recognition (CA and TRN) and place learning (TRN). This opens the possibility that, as well as causing MCPH, mutant ASPM potentially contributes to other neurodevelopmental disorders such as ASD through altered parvalbuminergic interneuron development affecting cognitive behaviour. These findings provide important information for understanding the genetic overlap and improved treatment of neurodevelopmental disorders associated with ASPM.

Highlights

The overlap in symptoms between neurodevelopmental disorders (NDDs) suggests that there is at least partial overlap in genetic aetiology and affected signalling networks during brain development
In the open field, a test of spontaneous reactions to a novel mildly stressful environment, there was a significant decrease in locomotor activity and speed in the mutant mice (two-way ANOVA, genotype effect total distance: F(1,37) = 7.14, p = 0.01, genotype effect velocity: F(1,37) = 6.56, p = 0.02, Fig. 1d, e)
The locomotor difference effect was more pronounced in the mutant mice with access to a running wheel (two-way ANOVA, distance travelled genotype × exercise interaction effect: F(1,37) = 4.24, p = 0.047, post hoc Tukey’s test, WT running wheels (RWs) vs. Aspm[1,2,3,4,5,6,7] RW, p = 0.01)

Summary

Introduction

The overlap in symptoms between neurodevelopmental disorders (NDDs) suggests that there is at least partial overlap in genetic aetiology and affected signalling networks during brain development. Abnormal spindle-like microcephaly associated (ASPM) truncating mutations are the most common cause of the NDD autosomal recessive primary microcephaly (MCPH) in humans[2]. This is a rare, genetically heterogeneous, disease where patients exhibit a smaller, albeit structurally normal, brain closely linked with intellectual disability. Limited association study data imply an ASPM contribution to the pathogenesis of Garrett et al Translational Psychiatry (2020)10:66 other NDDs including schizophrenia[3], communication disorder[4] and ASD5,6. This has not been reinforced by additional patient data, validated empirically nor is it clear through what mechanism ASPM could contribute to features of these NDDs

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Results