AKAP150-anchored PKA activity is important for LTD during its induction phase

Area of Science:

• Neuroscience
• Molecular Biology
• Cellular Signaling

Background:

• Protein kinase A (PKA) is believed to tonically enhance postsynaptic AMPA receptor responses.
• PKA activity is regulated by its localization to postsynaptic sites via A kinase anchor protein 150 (AKAP150).
• Previous models suggested PKA's role in maintaining AMPA receptor activity, potentially occluding long-term depression (LTD) induction.

Purpose of the Study:

• To investigate the specific role of AKAP150-anchored PKA in the induction of long-term depression (LTD) at postsynaptic sites.
• To determine if PKA's primary function is in LTD induction or in maintaining basal AMPA receptor activity.

Main Methods:

• Utilized acute hippocampal slices from genetically modified mice (D36 mice) lacking the PKA binding site on AKAP150.
• Performed extracellular field excitatory postsynaptic potential (fEPSP) recordings and intracellular excitatory postsynaptic current (EPSC) recordings.
• Administered PKA inhibitors (H-89 and KT5720) to wild-type (WT) hippocampal slices.

Main Results:

• LTD induction was significantly impaired in D36 mice compared to WT mice.
• Basal postsynaptic AMPA and NMDA receptor activity remained unchanged in D36 mice.
• PKA inhibitors (H-89, KT5720) blocked LTD by over 70% in WT slices without affecting basal synaptic transmission or GluR1 phosphorylation.

Conclusions:

• AKAP150-anchored PKA activity is essential for the induction of LTD.
• The data refutes the hypothesis that PKA solely maintains a tonic level of AMPA receptor activity.
• PKA's critical role lies in the signaling pathways that trigger synaptic plasticity, specifically LTD.