Neuron‐specific caveolin‐1 overexpression improves motor function and preserves memory in mice subjected to brain trauma

Abstract

Studies and demonstrate that membrane/lipid rafts and caveolin (Cav) organize progrowth receptors, and, when overexpressed specifically in neurons, Cav-1 augments neuronal signaling and growth and improves cognitive function in adult and aged mice; however, whether neuronal Cav-1 overexpression can preserve motor and cognitive function in the brain trauma setting is unknown. Here, we generated a neuron-targeted Cav-1-overexpressing transgenic (Tg) mouse [synapsin-driven Cav-1 (SynCav1 Tg)] and subjected it to a controlled cortical impact model of brain trauma and measured biochemical, anatomic, and behavioral changes. SynCav1 Tg mice exhibited increased hippocampal expression of Cav-1 and membrane/lipid raft localization of postsynaptic density protein 95, NMDA receptor, and tropomyosin receptor kinase B. When subjected to a controlled cortical impact, SynCav1 Tg mice demonstrated preserved hippocampus-dependent fear learning and memory, improved motor function recovery, and decreased brain lesion volume compared with wild-type controls. Neuron-targeted overexpression of Cav-1 in the adult brain prevents hippocampus-dependent learning and memory deficits, restores motor function after brain trauma, and decreases brain lesion size induced by trauma. Our findings demonstrate that neuron-targeted Cav-1 can be used as a novel therapeutic strategy to restore brain function and prevent trauma-associated maladaptive plasticity.-Egawa, J., Schilling, J. M., Cui, W., Posadas, E., Sawada, A., Alas, B., Zemljic-Harpf, A. E., Fannon-Pavlich, M. J., Mandyam, C. D., Roth, D. M., Patel, H. H., Patel, P. M., Head, B. P. Neuron-specific caveolin-1 overexpression improves motor function and preserves memory in mice subjected to brain trauma.

Neuron‐targeted caveolin‐1 improves neuromuscular function and extends survival in SOD1 G93A mice

“…Previous work from our group demonstrated, at minimum, 12 mo of gene expression using a 1-time intraparenchymal dose of adeno-associated virus serotype 9 (AAV9)-SynCav1 (19). Intrathecal delivery, direct spinal cord, and brain injections have all demonstrated safety.…”

“…These primers were used to detect a product size of 800 and 600 base pair (bp) for mouse and human SOD1, respectively. SynCav1 transgenic mice were generated in C57BL/6 background through the UCSD mouse transgenic core (19). Full-length Cav-1 cDNA (537 bp) was cloned into a vector containing the human neuron-specific synapsin promoter (495 bp) (20) and termed SynCav1 as previously described in refs.…”

“…Electrophoresis was performed on the samples using 4-12% acrylamide gels (Thermo Fisher Scientific) and transferred to PVDF membranes (MilliporeSigma) by electroelution. Membranes were blocked in blocking solution [20 mM Trisbuffered saline with Tween 20 (TBST) (0.1%) containing 3% bovine serum albumin] and then incubated with primary antibodies Cav-1 (3238; 1:1000; Cell Signaling Technology), TrkB (610102; 1:1000; BD Biosciences, San Jose, CA, USA), and CT-B (C-22841, 1:1000; Thermo Fisher Scientific) overnight at 4°C as previously described in Egawa et al (19). After 3 washes with TBST, the membrane was incubated with species-specific infrared-dye-labeled secondary antibody for 1 h at room temperature in dark.…”

Caveolins as Regulators of Stress Adaptation

“…In addition to a neuroprotective role, additional studies have shown that Cav-1 promotes neuronal and synaptic plasticity and improves neurobehavior Egawa et al, 2017a,b;Mandyam et al, 2017). Using a neuronspecific synapsin promoter to express Cav-1 (termed SynCav1) specifically in neurons, Cav-1 overexpression enhanced cellular cholesterol accumulation and raft formation, augmented receptor-mediated cAMP production, functional NMDAR (P-Src, P-CaMKII, P-ERK1/2) and TrkB signaling (P-TrkB, P-Akt), dendritic growth and arborization in vitro and in vivo (Mandyam et al, 2017) and prevented hippocampal-dependent learning and memory loss and improved motor function in a murine model of traumatic brain injury (Egawa et al, 2017a). Further work from our group showed that when delivered to the hippocampus in vivo, AAV9-SynCav1 increased hippocampal neuroplasticity, improved fear learning and memory in adult and aged mice (Mandyam et al, 2017), and promoted ultrastructural and functional indicators of synaptic plasticity (Egawa et al, 2017b), suggesting that Cav-1 and raft microdomains alter aspects of synapse biology necessary for functional neuronal and synaptic plasticity.…”

Synapsin-caveolin-1 Mitigates Cognitive Deficits and Neurodegeneration in PSAPP Mice

“…Enhancing MLR-localization of NTRs may augment prosurvival and pro-growth signaling, enhance structural and functional neuroplasticity, or even increase the efficacy of exogenous or already present endogenous growth factors, which in turn may restore cognitive function in AD. One such gene therapy candidate is caveolin-1 (Cav-1), a MLR scaffolding protein that organizes NTRs (Trk) and neurotransmitter receptor signaling complexes in MLRs [12][13][14]. Both pre-clinical and clinical findings revealed that Cav-1 and Cav-1 associated signaling complexes (NTRs and neurotransmitter receptors) were decreased in degenerating neurons in AD, chronic traumatic encephalopathy (CTE), and amyotrophic lateral sclerosis (ALS) [15][16][17][18].…”