A Late Phase of Long-Term Synaptic Depression in Cerebellar Purkinje Cells Requires Activation of MEF2

Area of Science:

• Neuroscience
• Molecular Biology
• Genetics

Background:

• Myocyte enhancer factor 2 (MEF2) transcription factors regulate excitatory synapse development.
• MEF2 pathway mutations are linked to autism spectrum disorders and cerebellar dysfunction.
• MEF2's role in long-term synaptic depression (LTD), a process involved in synapse elimination, is unknown.

Purpose of the Study:

• To investigate the role of postsynaptic MEF2 activation in cerebellar LTD.
• To determine if MEF2 is required for the late, transcription-dependent phase of LTD.

Main Methods:

• Purkinje cell cultures from MEF2A+MEF2D null mice.
• MEF2D knockdown experiments.
• Rescue experiments using MEF2D expression plasmids.
• Transfection with constitutively active MEF2.

Main Results:

• MEF2D knockdown suppressed the late phase of LTD in Purkinje cells.
• The late phase of LTD was abolished in MEF2A+MEF2D null Purkinje cells.
• MEF2D, but not a phosphatase-resistant mutant, rescued LTD.
• Constitutively active MEF2 did not alter synaptic strength.

Conclusions:

• Postsynaptic MEF2 activation, specifically dephosphorylation at S444, is necessary for the late phase of cerebellar LTD.
• MEF2 activation is not sufficient for inducing LTD.
• These findings link MEF2 function to synaptic plasticity and cerebellar development.