| First Author | Lin L | Year | 2020 |
| Journal | PLoS Genet | Volume | 16 |
| Issue | 1 | Pages | e1008587 |
| PubMed ID | 32004315 | Mgi Jnum | J:284936 |
| Mgi Id | MGI:6392417 | Doi | 10.1371/journal.pgen.1008587 |
| Citation | Lin L, et al. (2020) The epilepsy and intellectual disability-associated protein TBC1D24 regulates the maintenance of excitatory synapses and animal behaviors. PLoS Genet 16(1):e1008587 |
| abstractText | Perturbation of synapse development underlies many inherited neurodevelopmental disorders including intellectual disability (ID). Diverse mutations on the human TBC1D24 gene are strongly associated with epilepsy and ID. However, the physiological function of TBC1D24 in the brain is not well understood, and there is a lack of genetic mouse model that mimics TBC1D24 loss-of-function for the study of animal behaviors. Here we report that TBC1D24 is present at the postsynaptic sites of excitatory synapses, where it is required for the maintenance of dendritic spines through inhibition of the small GTPase ARF6. Mice subjected to viral-mediated knockdown of TBC1D24 in the adult hippocampus display dendritic spine loss, deficits in contextual fear memory, as well as abnormal behaviors including hyperactivity and increased anxiety. Interestingly, we show that the protein stability of TBC1D24 is diminished by the disease-associated missense mutation that leads to F251L amino acid substitution. We further generate the F251L knock-in mice, and the homozygous mutants show increased neuronal excitability, spontaneous seizure and pre-mature death. Moreover, the heterozygous F251L knock-in mice survive into adulthood but display dendritic spine defects and impaired memory. Our findings therefore uncover a previously uncharacterized postsynaptic function of TBC1D24, and suggest that impaired dendritic spine maintenance contributes to the pathophysiology of individuals harboring TBC1D24 gene mutations. The F251L knock-in mice represent a useful animal model for investigation of the mechanistic link between TBC1D24 loss-of-function and neurodevelopmental disorders. |
