SynCav1 gene delivery enhances granule cell neuron dendritic arborization (neuron branching in adult mice. Scale bar: 20 micrometers. (credit: Chitra D. Mandyam et al./Biological Psychiatry)
Using gene therapy to increase a crucial cholesterol-binding membrane protein called caveolin-1 (Cav-1) in neurons in the hippocampus* of the brain improved learning and memory in aged mice, according to findings from a new study led by scientists at The Scripps Research Institute (TSRI), the Veterans Affairs San Diego Healthcare System (VA) and University of California (UC) San Diego School of Medicine.
The result for treated mice was improved neuron growth and better retrieval of contextual memories — they froze in place, an indication of fear, when placed in a location where they’d once received small electric shocks.
The researchers believe that this type of gene therapy may be a path toward treating age-related memory loss, including loss resulting from alcohol and drug use. The researchers are now testing this gene therapy in mouse models of Alzheimer’s disease and expanding it to possibly treat injuries such as spinal cord injury and traumatic brain injury. ”
The study, published recently online ahead of print in the journal Biological Psychiatry, expands scientists’ understanding of neuroplasticity, the ability of neural pathways to grow in response to new stimuli.
* The hippocampus is a structure in the brain thought to participate in the formation of contextual memories — for example, if one remembers a past picnic when later visiting a park.
Abstract of Neuron-targeted caveolin-1 improves molecular signaling, plasticity and behavior dependent on the hippocampus in adult and aged mice
Background: Studies in vitro demonstrate that neuronal membrane/lipid rafts (MLRs) establish cell polarity by clustering pro-growth receptors and tethering cytoskeletal machinery necessary for neuronal sprouting. However, the effect of MLR and MLR-associated proteins on neuronal aging is unknown.
Methods: Here we assessed the impact of neuron-targeted overexpression of a MLR scaffold protein, caveolin-1 (via a synapsin promoter; SynCav1), in the hippocampus in vivo in adult (6-months-old) and aged (20-month-old) mice on biochemical, morphologic and behavioral changes.
Results: SynCav1 resulted in increased expression of Cav-1, MLRs, and MLR-localization of Cav-1 and tropomyosin-related kinase B (TrkB) receptor independent of age and time post gene transfer. Cav-1 overexpression in adult mice enhanced dendritic arborization within the apical dendrites of hippocampal CA1 and granule cell neurons, effects that were also observed in aged mice, albeit to a lesser extent, indicating preserved impact of Cav-1 on structural plasticity of hippocampal neurons with age. Cav-1 overexpression enhanced contextual fear memory in adult and aged mice demonstrating improved hippocampal function.
Conclusions: Neuron-targeted overexpression of Cav-1 in the adult and aged hippocampus enhances functional MLRs with corresponding roles in cell signaling and protein trafficking. The resultant structural alterations in hippocampal neurons in vivo are associated with improvements in hippocampal dependent learning and memory. Our findings suggest Cav-1 as a novel therapeutic strategy in disorders involving impaired hippocampal function.