Barron, J. C. | bioRxiv Science

bioRxiv2022

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.

neuroscience↗

bioRxiv2022

Asymmetric dysregulation of glutamate dynamics across the synaptic cleft in a mouse model of Alzheimer disease

Most research on glutamate spillover focuses on the deleterious consequences of postsynaptic glutamate receptor overactivation. However, two decades ago, it was noted that the glial coverage of hippocampal synapses is asymmetric: astrocytic coverage of postsynaptic sites exceeds coverage of presynaptic sites by a factor of four. The fundamental relevance of this glial asymmetry remains poorly understood. Here, we used the glutamate biosensor iGluSnFR, and restricted its expression to either CA3 or CA1 neurons to visualize glutamate dynamics at pre- and postsynaptic microenvironments, respectively. We demonstrate that inhibition of the primarily astrocytic glutamate transporter-1 (GLT-1) slows glutamate clearance to a greater extent at presynaptic compared to postsynaptic membranes. GLT-1 expression was reduced early in a mouse model of AD, resulting in slower glutamate clearance rates at presynaptic but not postsynaptic membranes that opposed presynaptic short-term plasticity. Overall, our data demonstrate that the presynapse is particularly vulnerable to GLT-1 dysfunction and may have implications for presynaptic impairments in a variety of brain diseases.

neuroscience↗