Abstract
Nerve growth factor (NGF) gene therapy has been used in clinical trials of Alzheimer’s disease. Understanding the underlying mechanisms of how NGF influences memory may help develop new strategies for treatment. Both NGF and the cholinergic system play important roles in learning and memory. NGF is essential for maintaining cholinergic innervation of the hippocampus, but it is unclear whether the supportive effect of NGF on learning and memory is specifically dependent upon intact hippocampal cholinergic innervation. Here we characterize the behavior and hippocampal measurements of volume, neurogenesis, long-term potentiation, and cholinergic innervation, in brain-specific Ngf-deficient mice. Our results show that knockout mice exhibit increased anxiety, impaired spatial learning and memory, decreased adult hippocampal volume, neurogenesis, short-term potentiation, and cholinergic innervation. Overexpression of Ngf in the hippocampus of Ngf gene knockout mice rescued spatial memory and partially restored cholinergic innervations, but not anxiety. Selective depletion of hippocampal cholinergic innervation resulted in impaired spatial memory. However, Ngf overexpression in the hippocampus failed to rescue spatial memory in mice with hippocampal-selective cholinergic fiber depletion. In conclusion, we demonstrate the impact of Ngf deficiency in the brain and provide evidence that the effect of NGF on spatial memory is reliant on intact cholinergic innervations in the hippocampus. These results suggest that adequate cholinergic targeting may be a critical requirement for successful use of NGF gene therapy of Alzheimer’s disease.
Highlights
Nerve growth factor (NGF), a neurotrophic growth factor first identified in the 1950s, promotes neurite outgrowth and stimulates nerve cell differentiation in culture experiments[1,2,3]
It remains unknown whether the effects of NGF on learning depend on these cholinergic projections to the hippocampus. Clarification of this may provide a better understanding for developing treatment for Alzheimer’s disease. We addressed this question by using brain-specific Ngf conditional knockout mice to reveal the importance of NGF in anxiety and spatial memory
We showed that mice with brainspecific Ngf deletion (Ngf conditional knockout (cKO)) present with increased anxiety and a deficit in spatial learning
Summary
Nerve growth factor (NGF), a neurotrophic growth factor first identified in the 1950s, promotes neurite outgrowth and stimulates nerve cell differentiation in culture experiments[1,2,3]. To better understand the effects of Ngf cKO in anxiety and learning, we subjected mice to open field, EPM, water maze testing, and novel object recognition. Overexpression of Ngf in the hippocampus of cKO mice rescues spatial memory, but not anxiety
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
