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

doi:10.1038/s42003-022-03594-4

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 journal › Article › peer-review

6 Scopus citations

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 language	English
Article number	672
Journal	Communications Biology
Volume	5
Issue number	1
DOIs	https://doi.org/10.1038/s42003-022-03594-4
State	Published - Dec 2022

Bibliographical note

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

Funding

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.). 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.).

Funders	Funder number
National Center for Genome Resources
National Institutes of Health (NIH)	T32-DA016176, R01-DA041513, P20-GM103451, R01-NS089663
Institute of Neurological Disorders and Stroke National Advisory Neurological Disorders and Stroke Council	R01NS089633
Dr. Miriam and Sheldon G. Adelson Medical Research Foundation
Wings for Life Spinal Cord Research Foundation	WFL-US-09/18
South Carolina EPSCoR

ASJC Scopus subject areas

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

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Olguin, S. L., Patel, P., Buchanan, C. N., Dell’Orco, M., Gardiner, A. S., Cole, R., Vaughn, L. S., Sundararajan, A., Mudge, J., Allan, A. M., Ortinski, P., Brigman, J. L., Twiss, J. L., & Perrone-Bizzozero, N. I. (2022). KHSRP loss increases neuronal growth and synaptic transmission and alters memory consolidation through RNA stabilization. Communications Biology, 5(1), Article 672. https://doi.org/10.1038/s42003-022-03594-4

@article{f4456875554d4ba885af8c31834ebadb,

title = "KHSRP loss 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 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.",

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

note = "Publisher Copyright: {\textcopyright} 2022, The Author(s).",

year = "2022",

month = dec,

doi = "10.1038/s42003-022-03594-4",

language = "English",

volume = "5",

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Olguin, SL, Patel, P, Buchanan, CN, Dell’Orco, M, Gardiner, AS, Cole, R, Vaughn, LS, Sundararajan, A, Mudge, J, Allan, AM, Ortinski, P, Brigman, JL, Twiss, JL & Perrone-Bizzozero, NI 2022, 'KHSRP loss increases neuronal growth and synaptic transmission and alters memory consolidation through RNA stabilization', Communications Biology, vol. 5, no. 1, 672. https://doi.org/10.1038/s42003-022-03594-4

TY - JOUR

T1 - KHSRP loss increases neuronal growth and synaptic transmission and alters memory consolidation through RNA stabilization

AU - Olguin, Sarah L.

AU - Patel, Priyanka

AU - Buchanan, Courtney N.

AU - Dell’Orco, Michela

AU - Gardiner, Amy S.

AU - Cole, Robert

AU - Vaughn, Lauren S.

AU - Sundararajan, Anitha

AU - Mudge, Joann

AU - Allan, Andrea M.

AU - Ortinski, Pavel

AU - Brigman, Jonathan L.

AU - Twiss, Jeffery L.

AU - Perrone-Bizzozero, Nora I.

PY - 2022/12

Y1 - 2022/12

N2 - 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.

AB - 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.

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JO - Communications Biology

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ER -

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

Abstract

Bibliographical note

Funding

ASJC Scopus subject areas

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