[Show abstract][Hide abstract] ABSTRACT: The cadherin/β-catenin adhesion complex is a key mediator of the bidirectional changes in synapse strength which are believed to underlie complex learning and memory. In the present study, we demonstrate that stabilization of β-catenin in the hippocampus of adult mice results in significant impairments in cognitive flexibility and spatial reversal learning, including impaired extinction during the reversal phase of the Morris water maze and deficits in a delayed nonmatch to place T-maze task. In accordance with these deficits, β-catenin stabilization was found to abolish long-term depression by stabilizing cadherin at the synaptic membrane and impairing AMPA receptor endocytosis, while leaving basal synaptic transmission and long-term potentiation unaffected. These results demonstrate that the β-catenin/cadherin adhesion complex plays an important role in learning and memory and that aberrant increases in synaptic adhesion can have deleterious effects on cognitive function.
Proceedings of the National Academy of Sciences 05/2014; 111(23). DOI:10.1073/pnas.1404670111 · 9.67 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The secreted growth factor progranulin (PGRN) has been shown to be important for regulating neuronal survival and outgrowth, as well as synapse formation and function. Mutations in the PGRN gene that result in PGRN haploinsufficiency have been identified as a major cause of frontotemporal dementia (FTD). Here we demonstrate that PGRN is colocalized with dense-core vesicle markers and is co-transported with brain-derived neurotrophic factor (BDNF) within axons and dendrites of cultured hippocampal neurons in both anterograde and retrograde directions. We also show that PGRN is secreted in an activity-dependent manner from synaptic and extrasynaptic sites, and that the temporal profiles of secretion are distinct in axons and dendrites. Neuronal activity is also shown to increase the recruitment of PGRN to synapses and to enhance the density of PGRN clusters along axons. Finally, treatment of neurons with recombinant PGRN is shown to increase synapse density, while decreasing the size of the presynaptic compartment and specifically the number of synaptic vesicles per synapse. Together, this indicates that activity-dependent secretion of PGRN can regulate synapse number and structure.
[Show abstract][Hide abstract] ABSTRACT: Frontotemporal dementia (FTD) has been linked to mutations in the progranulin gene (GRN) that lead to progranulin (PGRN) haploinsufficiency. Thus far, our understanding of the effects of PGRN depletion in the brain has been derived from investigation of gross pathology, and more detailed analyses of cellular function have been lacking. We report that knocking down PGRN levels in rat primary hippocampal cultures reduces neural connectivity by decreasing neuronal arborization and length as well as synapse density. Despite this, the number of synaptic vesicles per synapse and the frequency of mEPSCs are increased in PGRN knockdown cells, suggesting an increase in the probability of release at remaining synapses. Interestingly, we demonstrate that the number of vesicles per synapse is also increased in postmortem brain sections from FTD patients with PGRN haploinsufficiency, relative to controls. Our observations show that PGRN knockdown severely alters neuronal connectivity in vitro and that the synaptic vesicle phenotype observed in culture is consistent with that observed in the hippocampus of FTD patients.
The Journal of Neuroscience : The Official Journal of the Society for Neuroscience 08/2011; 31(31):11126-32. DOI:10.1523/JNEUROSCI.6244-10.2011 · 6.34 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Subtle changes in cellular and extracellular pH within the physiological range have profound impacts on synaptic activities. However, the molecular mechanisms underlying local pH regulation at synapses and their influence on synaptic structures have not been elucidated. Dendritic spines undergo dynamic structural changes in response to neuronal activation, which contributes to induction and long-term maintenance of synaptic plasticity. Although previous studies have indicated the importance of cytoskeletal rearrangement, vesicular trafficking, cell signaling, and adhesion in this process, much less is known about the involvement of ion transporters. In this study we demonstrate that N-methyl-D-aspartate (NMDA) receptor activation causes recruitment of the brain-enriched Na(+)/H(+) exchanger NHE5 from endosomes to the plasma membrane. Concomitantly, real-time imaging of green fluorescent protein-tagged NHE5 revealed that NMDA receptor activation triggers redistribution of NHE5 to the spine head. We further show that neuronal activation causes alkalinization of dendritic spines following the initial acidification, and suppression of NHE5 significantly retards the activity-induced alkalinization. Perturbation of NHE5 function induces spontaneous spine growth, which is reversed by inhibition of NMDA receptors. In contrast, overexpression of NHE5 inhibits spine growth in response to neuronal activity. We propose that NHE5 constrains activity-dependent dendritic spine growth via a novel, pH-based negative-feedback mechanism.
Molecular biology of the cell 05/2011; 22(13):2246-57. DOI:10.1091/mbc.E11-01-0066 · 4.47 Impact Factor