PDZD8 and its role in intellectual disability

Intellectual disability is the most common childhood neurodevelopmental disorder that affects learning ability, impairs cognitive functioning, and is defined by an intelligence quotient below 70. Four children from two unrelated families were diagnosed with intellectual disability, developmental delay, macrocephaly, and other autistic features caused by a specific mutation in PDZ domain containing protein 8 (PDZD8) gene. Pdzd8 is an endoplasmic reticulum-mitochondria tethering protein which regulates calcium dynamics in mammalian neurons and has not previously been associated with any human disease. As PDZD8 mutation is a novel mutation linked to intellectual disability, a mouse model with a mutation in Pdzd8 was used to characterise the disruption of Pdzd8 from a molecular, behavioural, and neural activity perspective. Pdzd8 mutant mice displayed changes in the relative brain volume, decreased neurogenesis, and increased spine density. On a molecular level, Pdzd8 mice exhibited an increase in mRNA expression in multiple genes linked to cerebral development, neurogenesis, mitochondria function, endoplasmic reticulum stress and Pdzd8 interactors. From a behavioural perspective, Pdzd8 mice presented hyperactivity, repetitive behaviours, decreased anxiety, impaired long-term memory, altered associative learning, and distorted social discrimination. In vivo imaging of neuronal dynamics revealed altered spontaneous excitatory activity compared to wild type controls. Overall, the myriad of changes observed in Pdzd8 mice, from molecular and structural abnormalities to neuronal and behavioural impairments, strongly characterize deficits observed in intellectual disability and autism spectrum disorders.