| First Author | Jiang T | Year | 2019 |
| Journal | Dis Model Mech | Volume | 12 |
| Issue | 5 | PubMed ID | 31036551 |
| Mgi Jnum | J:276895 | Mgi Id | MGI:6315707 |
| Doi | 10.1242/dmm.038109 | Citation | Jiang T, et al. (2019) Amyotrophic lateral sclerosis mutant TDP-43 may cause synaptic dysfunction through altered dendritic spine function. Dis Model Mech 12(5):dmm038109 |
| abstractText | Altered cortical excitability and synapse dysfunction are early pathogenic events in amyotrophic lateral sclerosis (ALS) patients and animal models. Recent studies propose an important role for TAR DNA-binding protein 43 (TDP-43), the mislocalization and aggregation of which are key pathological features of ALS. However, the relationship between ALS-linked TDP-43 mutations, excitability and synaptic function is not fully understood. Here, we investigate the role of ALS-linked mutant TDP-43 in synapse formation by examining the morphological, immunocytochemical and excitability profile of transgenic mouse primary cortical pyramidal neurons that over-express human TDP-43(A315T) In TDP-43(A315T) cortical neurons, dendritic spine density was significantly reduced compared to wild-type controls. TDP-43(A315T) over-expression increased the total levels of the alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropinionic acid (AMPA) glutamate receptor subunit GluR1, yet the localization of GluR1 to the dendritic spine was reduced. These postsynaptic changes were coupled with a decrease in the amount of the presynaptic marker synaptophysin that colocalized with dendritic spines. Interestingly, action potential generation was reduced in TDP-43(A315T) pyramidal neurons. This work reveals a crucial effect of the over-expression mutation TDP-43(A315T) on the formation of synaptic structures and the recruitment of GluR1 to the synaptic membrane. This pathogenic effect may be mediated by cytoplasmic mislocalization of TDP-43(A315T) Loss of synaptic GluR1, and reduced excitability within pyramidal neurons, implicates hypoexcitability and attenuated synaptic function in the pathogenic decline of neuronal function in TDP-43-associated ALS. Further studies into the mechanisms underlying AMPA receptor-mediated excitability changes within the ALS cortical circuitry may yield novel therapeutic targets for treatment of this devastating disease. |
