Abstract SNACC-44

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Neuron-targeted caveolin-1 remodels hippocampal neurons and enhances hippocampal plasticity and cognition

1Egawa J, 1Schilling J, 1Posadas E, 2Mandyam C, 1Patel P, 1Head B
1VASDHS/UCSD, San DIego, CA, USA; 2The Scrips Research Institute, La Jolla, CA, USA

Background: Membrane/lipid rafts (MLRs) play an essential role for neuronal growth cone motility and guidance. Previous work from our group demonstrated that neuron-targeted Cav-1 enhances MLR formation, increases pro-growth signaling, and promotes dendritic arborization in primary neurons. In aged mice, there is a decrease in MLR, reduced pro-growth signaling and synaptic plasticity, and reduced cognition. It is conceivable that Cav-1 over-expression might mitigate the adverse effects of aging. This study was conducted to test whether in vivo delivery of neuron-targeted Cav-1 would promote functional neuronal growth and plasticity and reduce cognitive deficits in aged mice.

Methods: The protocol was approved by our institutional committee. Four and 10 m old mice (C57BL/6 wild type) received bilateral stereotactic hippocampal injections of AAV9 encoding either RFP (control) or Cav-1. In 4 m old mice, long term potentiation, LTP, was determined by recording potentials in the CA1 sector in response to stimulation of Schaffer collaterals, 2 m post injection (6 m age). Dendritic growth (Golgi-Cox stain and MAP2 immunofluorescence (IF) confocal microscopy) and synaptic protein expression (sucrose density fractionation and Western blot) were also determined 2 m post injection (6 m age). In 10 m old mice, behavioral function was evaluated in the fear conditioning, open field, balance beam, and wire grip paradigms, 10 m post injection (20 m age).

Results: Sucrose density fractionation and Western blot analysis of hippocampal tissue 2 m post injection (6 m age) revealed an increase in Cav-1 and post-synaptic density 95 expression in the MLR fractions. A significant increase in MLRs was observed. LTP was significantly greater in slices from SynCav1 versus SynRFP-injected mice, indicating improved functional plasticity. Golgi-Cox stain analysis (n=6) demonstrated that SynCav1 significantly increased basal dendrite length (p=0.006) and apical dendritic arborization in CA1 pyramidal neurons at 70 um (p=0.0006) and 90 um (p=0.002) from soma, and significantly increased apical dendritic arborization granule cells at 190 um (p=0.007) and 210 um (p=0.009) distance from soma 2 m post injection. These results were furthered confirmed by IF microscopy, which demonstrated enhanced MAP2-labeled neurites and Cav-1 expression in apical dendrites from CA1 pyramidal neurons. A significant increase in dendritic length, volume and area in the CA1 region with SynCav1 versus SynRFP (*p<0.01, n=3) was observed. Increased dendritic growth was confirmed by MAP2 IF and confocal microscopy. Behavioral analysis (n=20 mice/group) revealed that SynCav1 significantly enhanced hippocampal-dependent contextual fear conditioning (p=0.003) in 20 m old mice. There was no significant difference in the open field, balance beam nor wire grip between the two groups.

Conclusion: Our study demonstrates that neuron-targeted overexpression of caveolin-1 in the hippocampus enhances functional neuronal growth and plasticity in vivo and improves cognitive function in aged mice.

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