Autism spectrum disorder related phenotypes in a mouse model lacking the neuronal actin binding protein profilin 2

Walter Witke ¹ Marina Di Domenico ² Laura Maggi ³ Alessia Di Nardo ⁴ Valentin Stein ⁵ Pietro Pilo Boyl ^1*

• ¹ Institute of Genetics, Faculty of Mathematics and Natural Sciences, University of Bonn, Bonn, Germany
• ² European Brain Research Institute Fondazione Rita Levi Montalcini, Rome, Italy
• ³ Dipartimento di Fisiologia e Farmacologia, Facoltà di Medicina e Chirurgia, Università di Roma Sapienza,, Roma, Italy
• ⁴ Biogen Inc., Cambridge, United States
• ⁵ Institute of Physiology II, Faculty of Medicine, University of Bonn, Bonn, Germany

Profilin 2 (PFN2) is an actin binding protein highly expressed in the brain that participates in actin dynamics. It has been shown in vitro and in vivo that in neurons it functions both post-synaptically to shape and maintain dendritic arborizations and spine density and plasticity, as well as presynaptically to regulate vesicle exocytosis. PFN2 was also found in protein complexes with proteins that have been implicated in or are causative of autism spectrum disorder. In this work we show that, in agreement with these physiological functions and biochemical features, PFN2 deficiency in the mouse reproduces a number of autistic-like phenotypes, such as social behavior impairment, stereotypic behavior, altered vocal communication, and deficits in motor performance and coordination. Our studies correlate the behavioral phenotypes with increased excitation/inhibition ratio in the brain, due to brain-wide hyperactivity and excitability of glutamatergic neurons and increased glutamate release not compensated by increased activityenhanced of GABAergic neuronsneurotransmission. Consequently, lack of PFN2 caused seizures behavior and age-dependent loss of cerebellar Purkinje cells, comorbidities observed in a subset of autistic patients, which can be attributed to the effect of excessive glutamatergic neurotransmission. Our data directly link altered pre-synaptic actin dynamics to autism spectrum disorder in the mouse model and support the hypothesis that synaptic dysfunctions that asymmetrically increase the excitatory drive in neuronal circuits can lead to autistic-like phenotypes. Interestingly, the observed increased excitation/inhibition ratio in profilin 2 mutant mice does not affect learning and memory. Our findings inspire to consider novel potential pathways for therapeutic approaches in ASD.