| First Author | Li Y | Year | 2017 |
| Journal | J Neurosci | Volume | 37 |
| Issue | 38 | Pages | 9259-9268 |
| PubMed ID | 28842416 | Mgi Jnum | J:252763 |
| Mgi Id | MGI:6094022 | Doi | 10.1523/JNEUROSCI.1051-17.2017 |
| Citation | Li Y, et al. (2017) Synaptic Adhesion Molecule Pcdh-gammaC5 Mediates Synaptic Dysfunction in Alzheimer's Disease. J Neurosci 37(38):9259-9268 |
| abstractText | Synaptic dysfunction and neuronal excitatory/inhibitory imbalance have been implicated in Alzheimer's disease (AD) pathogenesis. Although intensive studies have been focused on the excitatory synaptic system, much less is known concerning the mechanisms mediating inhibitory synaptic dysfunction in AD. We reported previously that protocadherin-gammaC5 (Pcdh-gammaC5), a member of clustered Pcdh-gamma subfamily of cadherin-type synaptic adhesion proteins, functions to promote GABAergic synaptic transmission. We reveal here that Pcdh-gammaC5 is enriched in vesicular GABA transporter-positive synaptic puncta and its expression levels are increased in neuronal hyperexcitation conditions, upon beta-amyloid (Abeta) treatment, and in amyloid precursor protein (APP)/presenilin-1 (PS1)-transgenic mice of both sexes. This is associated with elevated levels of GABAergic proteins and enhanced synaptic inhibition. Genetic knock-down experiments showed that Pcdh-gammaC5 modulates spontaneous synaptic currents and Abeta-induced synaptic alterations directly. Our results support a model in which Pcdh-gammaC5 senses neuronal hyperexcitation to augment GABAergic inhibition. This adaptive mechanism may be dysregulated under chronic excitation conditions such as AD, leading to aberrant Pcdh-gammaC5 expression and associated synaptic dysfunction.SIGNIFICANCE STATEMENT Synaptic dysfunction is causal for Alzheimer's disease (AD). Here, we reveal a novel pathway that contributes GABAergic synaptic dysfunction in AD mediated by protocadherin-gammaC5. Our study not only identifies a new mechanism mediating excitatory/inhibitory balance in AD, but may also offer a new target for potential therapeutic intervention. |
