Critical period for activity-dependent synapse elimination in developing cerebellum

Area of Science:

• Neuroscience
• Developmental Biology
• Synaptic Plasticity

Background:

• Synapse elimination refines neural circuits during development.
• Climbing fiber innervation of Purkinje cells undergoes developmental elimination.
• NMDA receptors are implicated in synapse elimination processes.

Purpose of the Study:

• To identify the specific developmental period and mechanism of NMDA receptor-dependent climbing fiber synapse elimination.
• To investigate the role of NMDA receptors in refining cerebellar circuitry.

Main Methods:

• Administration of NMDA receptor antagonist MK-801 via intraperitoneal injection and local cerebellar application during specific postnatal days.
• Electrophysiological recordings of excitatory postsynaptic currents (EPSCs) at cerebellar synapses.
• Assessment of climbing fiber innervation patterns and motor coordination.

Main Results:

• MK-801 blockade during postnatal days 15-16, but not earlier or later, increased multiple climbing fiber innervation and caused motor coordination deficits.
• Synaptic function and cerebellar morphology remained unaffected by the MK-801 treatment.
• Large NMDA receptor-mediated EPSCs were observed at mossy fiber-granule cell synapses during this critical period.

Conclusions:

• A critical 2-day window (P15-P16) exists for NMDA receptor-dependent climbing fiber synapse elimination.
• NMDA receptors at mossy fiber-granule cell synapses likely mediate the elimination of surplus climbing fibers.
• Disruption of this NMDA receptor-dependent phase leads to permanent cerebellar dysfunction and motor impairment.