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

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 Aspm 1-7 mutation. Aspm 1-7 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.

The Parvalbumin Hypothesis of Autism Spectrum Disorder

“…While membrane potential-dependent differences in firing behavior of TRN neurons are correlated with decreased PV level in Gclm −/− TRN neurons, a causal relationship between these events has yet to be established. Notably, a decrease in the number of PV + neurons in the TRN has been reported in other ASD models showing behavioral phenotypes such as the Engrailed-2 KO mice (En2 −/− ) and abnormal spindlelike microcephaly-associated gene (Aspm1-7) mutants (Garrett et al, 2020;Pirone et al, 2020). Whether this is due to PV downregulation-and the electrophysiological consequences thereof-remains unclear.…”

A mouse model of Timothy syndrome exhibits altered social competitive dominance and inhibitory neuron development

“…The IntelliCage has been widely used to assess chemical, environmental, and genetic mouse models for neuropsychiatric diseases [20,21,[28][29][30]. This system allows observation of mouse behavior while minimizing human intervention and isolation stress.…”

Updates on Clinical and Genetic Heterogeneity of ASPM in 12 Autosomal Recessive Primary Microcephaly Families in Pakistani Population

“…This gene plays a vital role in the division of neural progenitor cells and in controlling the cell cycle by helping symmetric proliferative division, as well as asymmetric neurogenic divisions. ASPM knockdown in animal models leads to a decrease in cortical area and microcephaly as observed in humans ( 10 , 11 ).…”