Neuron-Targeted Caveolin-1 Improves Molecular Signaling, Plasticity, and Behavior Dependent on the Hippocampus in Adult and Aged Mice

Abstract

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.

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

“…To achieve this, we generated a SynCav1 transgenic (SynCav1 Tg) mouse and subjected it to a controlled cortical impact (CCI) model of brain trauma (12). Similar to what we observed with the SynCav1 gene construct in vitro and in vivo (17, 18), biochemical characterization of SynCav1 Tg mice demonstrated higher Cav‐1 expression and increased MLR localization of synaptic components [ e.g. , PSD95, NMDA receptor (NMDAR), and TrkB] in the Hpc, a brain region that is necessary for learning and memories.…”

“…We have previously shown that neuron‐targeted overexpression of Cav‐1—achieved by linking it to a neuron‐specific synapsin promoter [synapsin‐driven caveolin‐1 ( SynCav1 )]—enhances MLR formation, augments receptor‐mediated cAMP production, tropomyosin receptor kinase B (TrkB) signaling, and dendritic growth and arborization even in the presence of myelin‐associated growth inhibitors in vitro (17). Moreover, SynCav1 delivery to the hippocampus (Hpc) in vivo increased MLR and MLR‐localized expression of TrkB, promoted structural and functional hippocampal neuroplasticity, and improved Hpc‐dependent learning and memory in aged mice (18). More recent work from our group has shown that SynCav1 delivery to the Hpc in vivo or to differentiated human neurons in vitro —derived from induced pluripotent stem cells—increased expression of pre‐ and postsynaptic proteins that are essential for synaptic plasticity, such as synaptobrevin, synaptophysin, syntaxin 1A, neurexin, and postsynaptic density protein 95 (PSD95) (19).…”

Caveolins and caveolae in ocular physiology and pathophysiology

“…However, under some conditions it may be important to therapeutically augment caveolin expression. For example, Cav-1 expression in the brain declines with age and neuron-targeted re-expression promotes neuronal structural and functional improvement (Head et al, 2011; Head et al, 2010; Mandyam et al, 2015). Furthermore, there is a significant body of evidence that caveolins are necessary for ischemic- and anesthetic-induced preconditioning in the heart and brain (reviewed in (Schilling et al, 2015; Stary et al, 2012)).…”

Methamphetamine reduces expression of caveolin-1 in the dorsal striatum: Implication for dysregulation of neuronal function

“…Recent reports from experiments conducted in adult rats demonstrate that D1Rs in the striatum and cortical areas are localized almost exclusively to detergent-resistant membrane fractions (Voulalas et al, 2011), where MLRs and Cavs are expressed (Mandyam et al, 2015). Most notable, is the alteration in the expression patterns of D1Rs to detergent-soluble membrane fractions devoid of Cavs after noncontingent cocaine administration, suggesting enhanced expression/proportion of D1Rs after psychostimulant insult (Voulalas et al, 2011).…”