KHSRP loss increases neuronal growth and synaptic transmission and alters memory consolidation through RNA stabilization

Sarah L. Olguin, Priyanka Patel, Courtney N. Buchanan, Michela Dell’Orco, Amy S. Gardiner, Robert Cole, Lauren S. Vaughn, Anitha Sundararajan, Joann Mudge, Andrea M. Allan, Pavel Ortinski, Jonathan L. Brigman, Jeffery L. Twiss, Nora I. Perrone-Bizzozero

Research output: Contribution to journalArticlepeer-review

Abstract

The KH-type splicing regulatory protein (KHSRP) is an RNA-binding protein linked to decay of mRNAs with AU-rich elements. KHSRP was previously shown to destabilize Gap43 mRNA and decrease neurite growth in cultured embryonic neurons. Here, we have tested functions of KHSRP in vivo. We find upregulation of 1460 mRNAs in 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. Khsrp−/− mice show increased axon growth and dendritic spine density in vivo. Neuronal cultures from Khsrp−/− mice show increased axon and dendrite growth and elevated KHSRP-target mRNAs, including subcellularly localized mRNAs. Furthermore, neuron-specific knockout of Khsrp confirms these are from neuron-intrinsic roles of KHSRP. Consistent with this, neurons in the hippocampus and infralimbic cortex of Khsrp−/− mice show elevations in frequency of miniature excitatory postsynaptic currents. The Khsrp−/− mice have deficits in trace conditioning and attention set-shifting tasks compared Khsrp+/+ mice, indicating impaired prefrontal- and hippocampal-dependent memory consolidation with loss of KHSRP. Overall, these results indicate that deletion of KHSRP impairs neuronal development resulting in alterations in neuronal morphology and function by changing post-transcriptional control of neuronal gene expression.

Original languageEnglish
Article number672
JournalCommunications Biology
Volume5
Issue number1
DOIs
StatePublished - Dec 2022

Bibliographical note

Funding Information:
The authors thank the NM-INBRE Sequencing and Bioinformatics Core (SBC) at the National Center for Genome resources (NCGR) for providing pilot funding and expertise for the KHSRP RIP-seq studies and Ms. Gabriela Perales for her help determining axonal growth in hippocampal slices. This work was supported by grants awards from the following agencies: National Institutes of Health (R01-NS089663 to J.L.T. and N.P.B.; R01-DA041513 to P.I.O.; P20-GM103451 to A.S. and J.M.; T32-DA016176 to R.C.), Wings for Life Spinal Cord Injury Research Foundation (WFL-US-09/18 to PP), Dr. Miriam and Sheldon G. Adelson Medical Research Foundation (to JLT), and South Carolina NSF EPSCoR Stimulus Research Program (to J.L.T.).

Funding Information:
The authors thank the NM-INBRE Sequencing and Bioinformatics Core (SBC) at the National Center for Genome resources (NCGR) for providing pilot funding and expertise for the KHSRP RIP-seq studies and Ms. Gabriela Perales for her help determining axonal growth in hippocampal slices. This work was supported by grants awards from the following agencies: National Institutes of Health (R01-NS089663 to J.L.T. and N.P.B.; R01-DA041513 to P.I.O.; P20-GM103451 to A.S. and J.M.; T32-DA016176 to R.C.), Wings for Life Spinal Cord Injury Research Foundation (WFL-US-09/18 to PP), Dr. Miriam and Sheldon G. Adelson Medical Research Foundation (to JLT), and South Carolina NSF EPSCoR Stimulus Research Program (to J.L.T.).

Publisher Copyright:
© 2022, The Author(s).

ASJC Scopus subject areas

  • Medicine (miscellaneous)
  • Biochemistry, Genetics and Molecular Biology (all)
  • Agricultural and Biological Sciences (all)

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