phaidra.vetmeduni.ac.at o:3238 DOI 10.1371/journal.pbio.3002668 Shared behavioural impairments in visual perception and place avoidance across different autism models are driven by periaqueductal grey hypoexcitability in Setd5 haploinsufficient mice Despite the diverse genetic origins of autism spectrum disorders (ASDs), affected individuals share strikingly similar and correlated behavioural traits that include perceptual and sensory processing challenges. Notably, the severity of these sensory symptoms is often predictive of the expression of other autistic traits. However, the origin of these perceptual deficits remains largely elusive. Here, we show a recurrent impairment in visual threat perception that is similarly impaired in 3 independent mouse models of ASD with different molecular aetiologies. Interestingly, this deficit is associated with reduced avoidance of threatening environments-a nonperceptual trait. Focusing on a common cause of ASDs, the Setd5 gene mutation, we define the molecular mechanism. We show that the perceptual impairment is caused by a potassium channel (Kv1)-mediated hypoexcitability in a subcortical node essential for the initiation of escape responses, the dorsal periaqueductal grey (dPAG). Targeted pharmacological Kv1 blockade rescued both perceptual and place avoidance deficits, causally linking seemingly unrelated trait deficits to the dPAG. Furthermore, we show that different molecular mechanisms converge on similar behavioural phenotypes by demonstrating that the autism models Cul3 and Ptchd1, despite having similar behavioural phenotypes, differ in their functional and molecular alteration. Our findings reveal a link between rapid perception controlled by subcortical pathways and appropriate learned interactions with the environment and define a nondevelopmental source of such deficits in ASD. eng Keywords: Animals; Disease Models, Animal; Mice; Visual Perceptionphysiology; Haploinsufficiencygenetics; Avoidance Learningphysiology; Autism Spectrum Disordergeneticsphysiopathology; Male; Behavior, Animalphysiology; Mice, Inbred C57BL; Histone-Lysine N-Methyltransferasegeneticsmetabolism; Autistic Disordergeneticsphysiopathology 2024-07-15T07:39:00.765Z LOMv1.0 Author BEGIN:VCARD VERSION:3.0 N:Burnett;Laura E.; FN:Laura E. Burnett END:VCARD BEGIN:VCARD VERSION:3.0 N:Joesch;Maximilian; FN:Maximilian Joesch X-ORCID:https://orcid.org/0000-0002-3937-1330 END:VCARD BEGIN:VCARD VERSION:3.0 N:Novarino;Gaia; FN:Gaia Novarino END:VCARD BEGIN:VCARD VERSION:3.0 N:Shigemoto;Ryuichi; FN:Ryuichi Shigemoto END:VCARD BEGIN:VCARD VERSION:3.0 N:Rülicke;Thomas; FN:Thomas Rülicke X-ORCID:https://orcid.org/0000-0002-2121-9496 END:VCARD BEGIN:VCARD VERSION:3.0 N:Contreras;Ximena; FN:Ximena Contreras END:VCARD BEGIN:VCARD VERSION:3.0 N:Vega-Zuniga;Tomas; FN:Tomas Vega-Zuniga END:VCARD BEGIN:VCARD VERSION:3.0 N:Masson;Tomás; FN:Tomás Masson END:VCARD BEGIN:VCARD VERSION:3.0 N:Symonova;Olga; FN:Olga Symonova END:VCARD BEGIN:VCARD VERSION:3.0 N:Koppensteiner;Peter; FN:Peter Koppensteiner END:VCARD https://w3id.org/kim/hcrt/scheme https://w3id.org/kim/hcrt/text Textdokument Text LOMv1.0 yes https://creativecommons.org/licenses/by/4.0 application/pdf 3884533 https://phaidra.vetmeduni.ac.at/o:3238 https://phaidra.vetmeduni.ac.at/api/object/o:3238/thumbnail LOMv1.0 discipline