In trans neuregulin3-Caspr3 interaction controls DA axonal bassoon cluster development

Area of Science:

• Neuroscience
• Molecular Biology
• Synaptic Plasticity

Background:

• Dopamine (DA) transmission is vital for motor control, motivation, and emotion.
• The developmental mechanisms of DA synapses are less understood compared to other neurotransmitter systems.
• Bassoon (BSN) clusters indicate synapse maturation and stability.

Purpose of the Study:

• To elucidate the molecular mechanisms governing dopamine synapse development.
• To identify novel proteins involved in the formation and elimination of DA synapses.
• To understand the role of Neuregulin 3 (NRG3) in DA synapse maturation.

Main Methods:

• Investigated BSN cluster dynamics in developing DA synapses.
• Utilized a DA neuron-specific knockout of NRG3 in mice.
• Performed an unbiased screen to identify NRG3 binding partners using its extracellular domain (ECD).
• Analyzed Caspr3 null mice and disrupted NRG3-Caspr3 interactions in vivo.

Main Results:

• NRG3 levels correlate with BSN cluster dynamics during DA synapse development.
• Ablation of NRG3 in DA neurons increased BSN clusters and impaired DA release and associated behaviors.
• Caspr3 was identified as a trans-acting binding partner of NRG3, enriched in striatal medium spiny neurons (MSNs).
• Caspr3 null mice exhibited phenotypes mirroring NRG3-deficient mice regarding BSN clusters and DA transmission.
• Disruption of the NRG3-Caspr3 interaction in vivo led to increased BSN clusters.

Conclusions:

• The NRG3-Caspr3 interaction is a critical regulator of DA synapse development and elimination.
• This trans-synaptic signaling pathway involving NRG3 and Caspr3 is essential for proper DA circuit wiring.
• Identified NRG3 and Caspr3 as novel cell adhesion molecules crucial for brain circuit formation.