Endogenous retrovirus activation disrupts postsynaptic organization in human glutamatergic neurons

Endogenous retroviruses (ERVs) comprise a substantial fraction of the human genome, yet whether their expression can directly alter human neuronal function remains unknown. Because glutamatergic signaling is fundamental to brain function and frequently disrupted in brain disorders, we asked whether activation of the primate-specific ERV-W group, associated with neurological disease, perturbs human glutamatergic neurons. We used CRISPR activation of the LTR17-ERV-W consensus sequence to examine its effects on neuronal and synaptic function, inducing transcription from multiple proviral loci, including five with intact open reading frames. Functionally, ERV-W activation selectively altered the postsynaptic compartment, reducing PSD-95 and NMDA receptor abundance. These changes were accompanied by altered excitatory synaptic transmission and reduced intrinsic excitability, whereas activation of ERVW-1/Syncytin-1 alone did not reproduce the phenotype. Our findings identify ERV-W activation as a modulator of human neuronal function with potential relevance to ERV-associated brain disorders.