An innate immune response to adeno-associated virus genomes decreases cortical dendritic complexity and disrupts synaptic transmission

• DOI: 10.1016/j.ymthe.2024.03.036
• Publication Date: 2024-04-01T15:23:12Z
• Authors: Christos M. Suriano; Neerav Kumar; Jessica L. Verpeut; Jie Ma; Caroline Jung; Connor E. Dunn; Brigett V. Carvajal; Ai Vy Nguyen; Lisa M. Boulanger
• Keywords: Adeno-associated virus; TLR9

Recombinant adeno-associated viruses (AAVs) allow rapid and efficient gene delivery to the nervous system, are widely used in neuroscience research, basis of FDA-approved neuron-targeting therapies. Here we find that an innate immune response AAV genome reduces dendritic length complexity disrupts synaptic transmission mouse somatosensory cortex. Dendritic loss is apparent 3 weeks after injection experimentally relevant viral titers, not restricted a particular capsid serotype, transgene, promoter, or production facility, cannot be explained by responses surgery transgene expression. AAV-associated accompanied decrease frequency amplitude miniature excitatory postsynaptic currents increase proportion GluA2-lacking, calcium-permeable AMPA receptors. The rich unmethylated CpG DNA, which recognized immunoreceptor Toll-like receptor 9 (TLR9), acutely blocking TLR9 preserves subunit composition AAV-injected mice. These results reveal unexpected impacts on neuronal structure function identify approaches improve safety efficacy AAV-mediated system.