A Kinase Anchor Protein 150 (AKAP150)-associated Protein Kinase A Limits Dendritic Spine Density

Steven H. Green,Eun Young Kim,Scott Schachtele,Yuan Lu,Duane D. Hall,Xiang-ming Zha,Michael E. Dailey,Dax A. Hoffman,Johannes W. Hell,Stefan Strack

doi:10.1074/jbc.m111.254912

Abstract

The A kinase anchor protein AKAP150 recruits the cAMP-dependent protein kinase (PKA) to dendritic spines. Here we show that in AKAP150 (AKAP5) knock-out (KO) mice frequency of miniature excitatory post-synaptic currents (mEPSC) and inhibitory post-synaptic currents (mIPSC) are elevated at 2 weeks and, more modestly, 4 weeks of age in the hippocampal CA1 area versus litter mate WT mice. Linear spine density and ratio of AMPAR to NMDAR EPSC amplitudes were also increased. Amplitude and decay time of mEPSCs, decay time of mIPSCs, and spine size were unaltered. Mice in which the PKA anchoring C-terminal 36 residues of AKAP150 are deleted (D36) showed similar changes. Furthermore, whereas acute stimulation of PKA (2-4 h) increases spine density, prolonged PKA stimulation (48 h) reduces spine density in apical dendrites of CA1 pyramidal neurons in organotypic slice cultures. The data from the AKAP150 mutant mice show that AKAP150-anchored PKA chronically limits the number of spines with functional AMPARs at 2-4 weeks of age. However, synaptic transmission and spine density was normal at 8 weeks in KO and D36 mice. Thus AKAP150-independent mechanisms correct the aberrantly high number of active spines in juvenile AKAP150 KO and D36 mice during development.

Highlights

Dendritic spines receive most of the excitatory input in mammalian neurons [1, 2] and compartmentalize signaling that regulates the synaptic response [3, 4]
More recently we found that LTP is not impaired in AKAP150 KO mice in contrast to D36 mice and that D36 but not KO mice have impaired reversal learning of operant conditioning [25]. Despite these different phenotypes we report that both mouse strains show an increase in miniature excitatory post-synaptic currents (mEPSC) frequency and linear spine density at 2– 4 but not 8 weeks of age, suggesting that protein kinase (PKA) anchoring is the most critical function of AKAP150 in controlling spine formation or maintenance
Increased mEPSC Frequency and Spine Density in AKAP150 KO Mice at 2 and 4 but Not 8 Weeks of Age—Earlier evidence suggests that PKA could regulate spine density [57]

Summary

Introduction

Dendritic spines receive most of the excitatory input in mammalian neurons [1, 2] and compartmentalize signaling that regulates the synaptic response [3, 4]. Overexpression of full-length AKAP79 (residues 1– 427), N terminus [1–153], and N- plus C terminus (⌬109 – 315 lacking the central region) had no effect but residues 1–361, which are only lacking the PKA binding site, increased spine density after 48 h (Fig. 7B).

Results

Conclusion