Huntingtin is essential for synaptic plasticity in the adult hippocampus

Huntingtin (HTT), an exceptionally large protein with hundreds of interacting partners within the central nervous system, has been extensively studied due to its role in Huntingtons disease (HD) pathology. HD is a monogenic disorder caused by a polyglutamine repeat expansion in the HTT gene, which results in the production of a pathogenic mutant huntingtin (mHTT) protein, and toxic effects of this mutant protein in the context of HD have been well-established. Less-established, however, is the role of wild type HTT (wtHTT) in the adult brain, particularly in areas outside the corticostriatal pathway. wtHTT has previously been suggested to play a vital role in cellular functions that promote synapse homeostasis, such as fast axonal transport of synaptic cargo, vesicle replenishment and receptor localization and stability. Synaptic dysfunction precedes and predicts cell death in many neurodegenerative diseases including HD (termed synaptopathies) and whether proper synaptic transmission can be maintained without wtHTT in extrastriatal brain areas such as the hippocampus remains unknown. Consequences of wtHTT reduction in the adult brain are of particular importance as clinical trials for many non-selective HTT-lowering therapies for HD are underway, which are unable to distinguish between mHTT and wtHTT, and therefore reduce levels of both proteins. We investigated the consequences of wtHTT loss of function in the CA3-CA1 pathway of the adult hippocampus using a conditional knockout mouse model and found that 1-2 month deletion of wtHTT in excitatory hippocampal neurons inhibits post-tetanic potentiation and completely abolishes NMDA receptor-dependent long-term potentiation in these animals. These data reveal a novel role of wtHTT as an essential regulator of short- and long-term plasticity in the adult hippocampus.