Deficiency of Autism-Related Gene Dock4 Leads to Impaired Spatial Memory and Hippocampal Function in Mice at Late Middle Age.

Scientists studied mice missing a gene called DOCK4 that's linked to autism. They found that autism-like behaviors (social difficulties, anxiety, memory problems) continued as the mice got older. The older mice also had worse spatial memory and changes in their brain cells. This research helps us understand how autism might affect people as they age.

This preclinical study investigated the long-term effects of DOCK4 gene deficiency on autism-related behaviors and brain changes in aging mice. DOCK4 is an autism risk gene highly expressed in the hippocampus. Researchers compared late-middle-aged (15-17 months) DOCK4 knockout mice with wild-type controls. Results showed that autism-like behaviors (social deficits, elevated anxiety, disrupted object location memory) persisted into late middle age.

Notably, DOCK4-deficient mice showed age-related decline in hippocampal-dependent spatial memory and specific brain changes including decreased mature neurons and oligodendrocytes but increased astrocytes in the hippocampus. This research provides new insights into how aging may affect behavioral and neurological characteristics in autism spectrum disorder.

This preclinical research suggests autism characteristics may persist with age and that specific cognitive domains like spatial memory may be particularly vulnerable. However, human studies are needed to confirm these findings and develop appropriate aging-related supports for autistic individuals.

Animal model study using only male mice; sample size not reported; findings may not directly translate to humans; study limited to one specific autism-related gene (DOCK4); no comparison with typical aging processes.

Autism spectrum disorder (ASD) is a neurodevelopmental disorder that lasts lifelong and causes noticeably higher premature mortality. Although the core symptoms and other behavioral deficits of ASD can persist or be deteriorated from early development to old age, how aging affects the behaviors and brain anatomy in ASD is largely unknown. DOCK4 is an ASD risk gene highly expressed in the hippocampus, and Dock4 knockout (KO) mice display ASD-like behaviors in adulthood (4- to 6-month-old). In this study, we evaluated the behavioral and hippocampal pathological changes of late-middle-aged (15- to 17-month-old) Dock4 male KO mice.

Aged Dock4 KO mice continuously showed similar social deficit, elevated anxiety, and disrupted object location memory as observed in the adulthood, when compared to their wild-type (WT) littermates. Notably, Dock4 KO mice displayed an age-related decline of hippocampal dependent spatial memory, showing decreased spatial memory in Barnes maze than their WT littermates at late middle age. Morphological analysis from WT and Dock4 KO littermates revealed that Dock4 deficiency led to decreased mature neurons and oligodendrocytes but increased astrocytes in the hippocampus of late-middle-aged mice. Together, we report that ASD-like behaviors mostly persist into late-middle age in Dock4 KO mice, with specific alterations of spatial memory and hippocampal anatomy by age, thus providing new evidence for understanding age differences in behavioral deficits of ASD.