Loss of KHSRP Increases Neuronal Growth and Synaptic Transmission and Alters Memory Consolidation Through RNA Stabilization

Abstract

The KH-type splicing regulatory protein (KHSRP) is an RNA-binding protein linked to decay of AU-rich element containing mRNAs. We have previously shown that KHSRP destabilizes the mRNA encoding the growth-associated protein GAP-43 and decreases neurite growth in cultured embryonic neurons. In contrast, loss of KHSRP stabilizes Gap43 mRNA and increases neurite growth. Here, we have tested functions of neural KHSRP in vivo. We find upregulation of 1460 mRNAs in the neocortex of adult Khsrp-/- mice, of which 527 bind to KHSRP with high specificity. These KHSRP targets are involved in pathways for neuronal morphology, axon guidance, neurotransmission and long-term memory. Neocortical neurons show increased axon growth and dendritic spine density in Khsrp-/- mice. Analyses of neuronal cultures from embryonic Khsrp-/- mice point to a neuron-intrinsic alteration in axonal and dendritic growth and elevations in KHSRP-target mRNAs, including subcellularly localized mRNAs. Hippocampus and infralimbic cortex of Khsrp-/- mice show presynaptic elevations in neurotransmission. The Khsrp-/- mice have significant deficits in both trace conditioning and attention set-shifting tasks compared Khsrp+/+ mice, indicating impaired prefrontal- and hippocampal-dependent memory consolidation with loss of KHSRP. Overall, our results indicate that prenatal deletion of KHSRP impairs neuronal development resulting in alterations in neuronal morphology and function by changing post-transcriptional control of neuronal gene expression.