The Neurexin1β Histidine-Rich Domain Is Involved in Excitatory Presynaptic Organization and Short-Term Plasticity

Area of Science:

• Neuroscience
• Molecular Biology
• Genetics

Background:

• Neurexins (Nrxns) are presynaptic cell adhesion molecules vital for synapse development and function.
• β-Nrxns possess a unique histidine-rich domain (HRD), whose physiological role is largely unknown.
• The HRD has been linked to pathological contexts, prompting investigation into its normal function.

Purpose of the Study:

• To elucidate the physiological role of the histidine-rich domain (HRD) in neurexin-1 beta (Nrxn1β).
• To characterize the impact of HRD deletion on synaptic function and behavior in mice.

Main Methods:

• Generated a novel mouse line using CRISPR-Cas9 to create an in-frame truncation of Nrxn1β, specifically lacking the HRD.
• Assessed mouse viability, gross brain development, and general behavior in both sexes.
• Investigated neuroligin-1-dependent presynaptic differentiation in primary neuronal cultures.
• Examined presynaptic short-term plasticity and basal synaptic transmission at hippocampal synapses.

Main Results:

• HRD deletion in Nrxn1β did not affect mouse viability, brain development, or general behavior.
• Loss of the HRD significantly altered neuroligin-1-dependent excitatory presynaptic differentiation.
• Presynaptic short-term plasticity, specifically paired pulse facilitation, was affected by HRD deletion.
• Basal synaptic transmission at hippocampal Schaffer collateral-CA1 synapses remained unchanged.

Conclusions:

• The Nrxn1β HRD is a key regulator of excitatory presynaptic organization and function.
• HRD deletion specifically impacts neuroligin-1-mediated excitatory synapse properties and short-term plasticity.
• These findings highlight the specialized roles of Nrxn isoforms in synaptic regulation.