Astrocytic ApoE underlies maturation of hippocampal neurons and cognitive recovery after traumatic brain injury in mice

Polymorphisms in the apolipoprotein E (ApoE) gene confer a major genetic risk for the development of late-onset Alzheimer’s disease (AD) and are predictive of outcome following traumatic brain injury (TBI). Alterations in adult hippocampal neurogenesis have long been associated with both the development of AD and recovery following TBI and ApoE is known to play a role in this process. In order to determine how ApoE might influence hippocampal injury-induced neurogenesis, we generated a conditional knockout system whereby functional ApoE from astrocytes was ablated prior to injury. While successfully ablating ApoE just prior to TBI in mice, we observed an attenuation in the development of the spines in the newborn neurons. Intriguingly, animals with a double-hit, i.e. injury and ApoE conditionally inactivated in astrocytes, demonstrated the most pronounced impairments in the hippocampal-dependent Morris water maze test, failing to exhibit spatial memory after both acquisition and reversal training trials. In comparison, conditional knockout mice without injury displayed impairments but only in the reversal phase of the test, suggesting accumulative effects of astrocytic ApoE deficiency and traumatic brain injury on AD-like phenotypes. Together, these findings demonstrate that astrocytic ApoE is required for functional injury-induced neurogenesis following traumatic brain injury.