Synaptic Basis of Feature Selectivity in Hippocampal Neurons

Academic Background

A central question in neuroscience is how synaptic plasticity shapes the feature selectivity of neurons in behaving animals. Hippocampal CA1 pyramidal neurons (CA1PNs) exhibit one of the most striking forms of feature selectivity by forming spatially and contextually selective receptive fields called place fields (PFs), which serve as a model for studying the synaptic basis of learning and memory. Although various forms of synaptic plasticity have been proposed as cellular substrates for the emergence of PFs, our understanding of how synaptic plasticity underlies PF formation and memory encoding remains limited, largely due to the lack of tools and technical challenges associated with visualizing synaptic plasticity at single-neuron resolution in awake behaving animals.

To address this, researchers developed an all-optical approach to monitor the spatiotemporal tuning and synaptic weight changes of dendritic spines before and after the induction of PFs in single CA1PNs during spatial navigation. They identified a temporally asymmetric synaptic plasticity kernel resulting from bidirectional modifications of synaptic weights around the induction of PFs. Additionally, the study revealed compartment-specific differences in the magnitude and temporal expression of synaptic plasticity between basal and oblique dendrites. These results provide experimental evidence linking synaptic plasticity to the rapid emergence of spatial selectivity in hippocampal neurons, a critical prerequisite for episodic memory.

Paper Source

This paper was co-authored by Kevin C. Gonzalez, Adrian Negrean, Zhenrui Liao, Satoshi Terada, Guofeng Zhang, Sungmoo Lee, Katalin Ócsai, Balázs J. Rózsa, Michael Z. Lin, Franck Polleux, and Attila Losonczy. The authors are affiliated with multiple research institutions, including Columbia University, Stanford University, and the Budapest University of Technology and Economics. The paper was published online in Nature on October 31, 2024.

Research Process

1. Development and Use of Experimental Tools

To investigate the relationship between changes in synaptic weights (δw) and the emergence of PFs, researchers developed and deployed three tools at single-cell resolution:

1. Glutamate Release Sensor (sfVenus-iGluSnFR-A184S): Used to measure the spatial tuning of excitatory synaptic inputs received by dendritic spines and the timing of their activity.
2. Red Calcium Indicator (jRGECO1a): Used to monitor changes in functional synaptic strength in vivo before and after PF induction.
3. Red-Shifted Excitatory Optogenetic Tool (bReaChES): Used to induce PFs.

2. Single-Cell Electroporation and Imaging

Researchers used in vivo single-cell electroporation (SCE) to introduce plasmids into individual pyramidal neurons located in the dorsal CA1 region of the mouse hippocampus. Through a head-fixed spatial navigation task in a virtual reality (VR) environment, two-photon (2P) imaging was performed to monitor the synaptic activity dynamics of basal and oblique dendrites.

3. Measurement of Synaptic Plasticity

The experiments were divided into three phases: pre-induction, induction, and post-induction. In the pre-induction phase, the initial synaptic weights of dendritic spines were measured. In the induction phase, PFs were induced optogenetically. In the post-induction phase, the formation of PFs was confirmed, and the final synaptic weights of all spines were measured.

4. Data Analysis

Researchers analyzed changes in spine calcium signals to measure synaptic plasticity, excluding spine calcium events that co-occurred with globally detected dendritic calcium events to ensure that plasticity measurements were not contaminated by changes in somatic firing properties after PF formation.

Key Findings

1. Temporal Structure of Synaptic Plasticity: The study found that synaptic plasticity exhibited a highly structured temporal profile around PF induction, forming a temporally asymmetric synaptic plasticity kernel. Specifically, synaptic inputs active 1–2 seconds before optogenetic induction were potentiated, while inputs active outside this temporal window were depressed.

2. Spatial Distribution of Synaptic Plasticity: After PF formation, spines receiving inputs active before the induction site underwent significant potentiation, while spines receiving inputs active after the induction site were suppressed.

3. Compartment-Specific Differences: The study revealed significant differences in the expression of synaptic plasticity between oblique and basal dendrites. Oblique spines exhibited larger changes in synaptic weights and were more likely to undergo both potentiation and depression.

Conclusion

This study, using an all-optical approach, identified the synaptic plasticity rules underlying PF formation in hippocampal CA1PNs. The results demonstrate that synaptic plasticity exhibits temporal asymmetry around PF induction and that this plasticity is compartment-specific, differing between oblique and basal dendrites. These findings provide important insights into how synaptic plasticity supports spatial selectivity and episodic memory.

Research Highlights

1. Temporally Asymmetric Synaptic Plasticity Kernel: The study directly demonstrated the temporal asymmetry of synaptic plasticity around PF induction in vivo for the first time.
2. Compartment-Specific Differences: The study revealed significant differences in synaptic plasticity expression between oblique and basal dendrites.
3. Innovation in All-Optical Methods: The all-optical approach developed in this study provides a new framework for studying synaptic plasticity in behaving animals.

Research Significance

This study not only deepens our understanding of how synaptic plasticity supports learning and memory but also provides a new experimental framework for future research into the molecular mechanisms of synaptic plasticity. These findings are significant for understanding the function of neural circuits and developing therapeutic strategies for memory disorders.