NMDA receptor-targeted enrichment of CaMKIIα improves fear memory

Calcium/calmodulin-dependent protein kinase II alpha (CaMKII) is an essential player in long-term potentiation and memory formation. However, the establishment of effective molecular interventions with CaMKII to improve memory remains a long-standing challenge. Here we report a novel intrabody targeting GluN1, a subunit of N-methyl-D-aspartate receptors (NMDARs). We identify this anti-GluN1 intrabody (termed VHH Anti-GluN1; VHHAN1) by a synthetic phage display library selection and yeast-two-hybrid screenings. We validate specific targeting of VHHAN1 to GluN1 in heterologous cells and the mouse hippocampus. We further show that adeno-associated virus (AAV)-mediated expression of CaMKII fused with VHHAN1 is locally enriched at excitatory postsynaptic regions of the mouse hippocampus. We also find that the AAV- and VHHAN1-mediated postsynaptic enrichment of CaMKII in the hippocampus improves contextual fear memory in mice. This novel approach opens a new avenue to enhance memory ability in health and diseases.