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Updated: May 31, 2025
Combined Mechanical and Enzymatic Dissociation of Mouse Brain Hippocampal Tissue
Published on: October 21, 2021
Huntingtin plays an essential role in the adult hippocampus
Jessica C Barron1, Laura J Dawson2, Samantha J Carew1
1Division of Biomedical Sciences, Faculty of Medicine, Memorial University of Newfoundland, St. John's, NL, Canada.
Insights
Wild-type huntingtin (wtHTT) reduction in adult mouse brains causes severe hippocampal abnormalities and neuronal dysfunction. Despite temporary synapse recovery, long-term memory and behavior impairments persist, highlighting risks of non-selective therapies.
Area of Science:
- Neuroscience
- Genetics
- Molecular Biology
Background:
- Huntingtin (HTT) lowering therapies are in clinical trials, but many non-selectively reduce both mutant and wild-type HTT (wtHTT).
- The consequences of wtHTT reduction in the mature brain, particularly in the hippocampus, remain largely unknown.
Purpose of the Study:
- To investigate the role of wtHTT in adult hippocampal pyramidal neurons.
- To explore the implications of wtHTT loss in the mature brain.
Main Methods:
- Injected CaMKII-promoted AAV-Cre into the hippocampus of adult HTT floxed mice.
- Assessed hippocampal structure, gliosis, synaptic morphology, neuronal excitability, and long-term potentiation.
Main Results:
- wtHTT depletion caused macroscopic hippocampal abnormalities, reactive gliosis, and reduced presynaptic terminals.
- Synaptic changes included increased postsynaptic spine density and larger excitatory postsynaptic currents.
- Neuronal excitability and NMDA receptor-dependent long-term potentiation were significantly diminished.
- Synapse density normalized at 6-8 months, but morphological and behavioral deficits persisted.
Conclusions:
- wtHTT is crucial for maintaining hippocampal structure and function in the mature brain.
- Non-selective HTT reduction poses risks to the hippocampus, potentially leading to lasting cognitive impairments.
- The hippocampus may be particularly vulnerable to adverse effects of non-selective HTT-lowering therapies.
Abstract:
The consequences of non-pathogenic huntingtin (HTT) reduction in the mature brain are of substantial importance as clinical trials for numerous HTT-lowering therapies are underway; many of which are non-selective in that they reduce both mutant and wild type protein variants. In this study, we injected CaMKII-promoted AAV-Cre directly into the hippocampus of adult HTT floxed mice to explore the role of wild-type huntingtin (wtHTT) in adult hippocampal pyramidal neurons and the broader implications of its loss. Our findings reveal that wtHTT depletion results in profound macroscopic morphological abnormalities in hippocampal structure, accompanied by significant reactive gliosis. At the synaptic level, we identified a marked reduction in presynaptic terminals 1-2 months following wtHTT loss; this was contrasted by an increased density of postsynaptic mushroom spines and larger amplitudes of spontaneous excitatory postsynaptic currents, indicative of disrupted synaptic homeostasis. Furthermore, intrinsic neuronal excitability was significantly diminished in CA1 pyramidal neurons lacking wtHTT, and we observed a complete loss of NMDA receptor-dependent long-term potentiation. Unexpectedly, synapse density returned to control levels 6-8 months following wtHTT loss, despite the ongoing presence of macroscopic morphological abnormalities, altered anxiety-related behaviors and clear impairments in spatial learning and memory. Overall, these findings uncover a previously unrecognized role of wtHTT as a critical regulator of hippocampal function in the mature brain, and highlight the hippocampus as a potentially vulnerable region to the adverse effects of non-selective HTT reduction.
