Abl2 Kinase Differentially Regulates iGluRs Current Activity and Synaptic Localization

Abstract

Abelson non-receptor tyrosine kinases (Abl1 and Abl2) are established cellular signaling proteins, implicated in cytoskeletal reorganization essential for modulation of cell morphology and motility. During development of the central nervous system, Abl kinases play fundamental roles in neurulation and neurite outgrowth, relaying information from axon guidance cues and growth factor receptors to promote cytoskeletal rearrangements. In mature neurons, Abl kinases localize to pre- and postsynaptic compartments and are involved in regulation of synaptic stability and plasticity. Although emerging evidence indicates interchangeability of these isoforms in managing of cellular functions, in healthy adult neurons, Abl1 contribution is less elucidated, while Abl2 is required for optimal synaptic functioning. Our previous study demonstrated compartmentalization of Abl1 to the presynapse and Abl2 to the postsynapse and characterized their modulatory effect on spontaneous excitatory synaptic transmission. Here, we further delineate the role of Abl2 on regulation of the postsynaptic component of miniature excitatory postsynaptic current (mEPSC). Our findings show that both acute and prolonged activation of Abl2, in line with reduction of mEPSC amplitude, also decrease AMPA and NMDA current amplitudes. In contrast with the current-detrimental effect, prolonged Abl2 activity stabilizes spines, particularly contributing to maintenance of active synapses at distal (perhaps apical) segments of dendrites. Hence, we propose that attenuation of ion currents via ionotropic glutamatergic receptors by Abl2 kinase derives from either reduction of the receptor sensitivity for glutamate or is due to alteration of channel gating mechanisms. Abl2 and excitatory postsynapses: Abl2 expression level affects active excitatory synapse density on distal dendrites, while Abl2 activity impacts current density through AMPA and NMDA receptors.

Keywords: AMPA; Abelson non-receptor tyrosine kinase (Abl); Miniature excitatory post synaptic currents (mEPSC); NMDA; Spontaneous synaptic activity.