Loss of GDE2 leads to complex behavioral changes including memory impairment

Area of Science:

• Neuroscience
• Biochemistry

Background:

• Alzheimer's disease (AD) and amyotrophic lateral sclerosis/frontotemporal dementia (ALS/FTD) are neurodegenerative diseases with unknown causes for most sporadic cases.
• Glycerophosphodiester phosphodiesterase 2 (GDE2) dysfunction, indicated by abnormal intracellular accumulation in AD/ALS/FTD brains, is implicated in disease pathophysiology.
• GDE2 cleaves GPI anchors, tethering proteins to cell membranes; its loss may contribute to neurodegeneration.

Purpose of the Study:

• To investigate the behavioral consequences of GDE2 deficiency in mice.
• To determine if GDE2 loss impacts learning, memory, and social behavior relevant to neurodegenerative conditions.

Main Methods:

• Glycerophosphodiester phosphodiesterase 2 knockout (Gde2KO) and wild-type (WT) mice were assessed using various behavioral tests.
• Behavioral analyses were conducted on mice aged 7 to 16 months.
• Tests included novelty-induced activity, startle response, prepulse inhibition, anxiety, sociability, and spatial/cued fear memory.

Main Results:

• Gde2KO mice exhibited age-dependent hyperactivity and reduced startle response.
• Female Gde2KO mice showed impaired prepulse inhibition, and both sexes displayed reduced sociability.
• Aged Gde2KO mice demonstrated significant deficits in short/long-term spatial memory and fear conditioning.

Conclusions:

• Loss of GDE2 function leads to a range of behavioral deficits in mice.
• These deficits, including hyperactivity and memory impairment, overlap with phenotypes observed in neurodegenerative disease models.
• GDE2 deficiency may be a significant contributing factor to the pathophysiology of neurodegenerative diseases.