Heparan Sulfates Support Pyramidal Cell Excitability, Synaptic Plasticity, and Context Discrimination

Area of Science:

• Neuroscience
• Extracellular Matrix Biology
• Synaptic Plasticity

Background:

• Heparan sulfate (HS) proteoglycans are key extracellular matrix components vital for brain development.
• The role of HSs in the mature brain's function is not fully understood.
• Investigating HS function is crucial for understanding brain plasticity and learning.

Purpose of the Study:

• To elucidate the function of heparan sulfates (HSs) in the mature hippocampus.
• To determine how HSs support synaptic plasticity and learning in the brain.
• To characterize the impact of HS removal on neuronal excitability and network activity.

Main Methods:

• Acute enzymatic digestion of HS side chains using heparinase 1.
• In vitro electrophysiology to measure long-term potentiation (LTP) at CA3-CA1 Schaffer collateral synapses.
• In vivo fear conditioning and electrophysiological recordings of network activity.
• Assessment of neuronal excitability and subcellular structural changes (ankyrin G expression).

Main Results:

• Heparinase 1 digestion impaired LTP, reduced Ca2+ influx, and decreased CA1 pyramidal neuron excitability.
• HS removal led to reorganization of the distal axon initial segment, evidenced by reduced ankyrin G.
• In vivo, HS digestion impaired fear conditioning memory and theta band network oscillations.
• HSs are essential for maintaining neuronal excitability, synaptic plasticity, and learning.

Conclusions:

• Heparan sulfates are critical for maintaining neuronal excitability in the mature hippocampus.
• HSs support synaptic plasticity and are essential for learning and memory processes.
• Targeting HSs could offer new avenues for understanding and treating neurological disorders affecting cognition.