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Garrett, Lillian; Chang, Yoon Jeung; Niedermeier, Kristina M.; Heermann, Tamara; Enard, Wolfgang; Fuchs, Helmut; Gailus-Durner, Valerie; Hrabe de Angelis, Martin; Huttner, Wieland B.; Wurst, Wolfgang and Hoelter, Sabine M. (2020): A truncating Aspm allele leads to a complex cognitive phenotype and region-specific reductions in parvalbuminergic neurons. In: Translational Psychiatry, Vol. 10, No. 1, 66 [PDF, 1MB]


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/beta-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 (R). 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.

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