Skip to content
DraconiticResearch
Search Sources API
197,768 studies31 sourcesUpdated 2 min ago
Peer-reviewedCC BYNature

Procognitive restoration of PV neuron plasticity in neurodevelopmental disorders

  • Yu‐Tzu Shih1,2,3,4
  • Jason Bondoc Alipio1,2,3,4
  • Zin‐Juan Klaft5
  • Nathaniel Green1,2,3,4
  • Alok Nath Mohapatra1,2,3,4
  • Travis D. Goode1,2,3,4
  • Muthu Panchanatham1,2,3,4
  • Devesh Pathak2,3,4
  • Lai Ping Wong6
  • Ruslan I. Sadreyev6
  • Jung Ho Hyun7
  • Omar J. Ahmed8,9,10
2 more authors
  • Chris G. Dulla5
  • Amar Sahay11,12,13,14
14 affiliations
  1. 1BROAD Institute of MIT and Harvard, Cambridge, MA, USA
  2. 2Center for Regenerative Medicine, Massachusetts General Hospital, Boston, MA, USA
  3. 3Department of Psychiatry, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
  4. 4Harvard Stem Cell Institute, Cambridge, MA, USA
  5. 5Department of Neuroscience, Tufts University School of Medicine, Boston, MA, USA
  6. 6Department of Molecular Biology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
  7. 7Department of Brain Sciences, Daegu Gyeongbuk Institute of Science and Technology, Daegu, South Korea
  8. 8Department of Biomedical Engineering, University of Michigan, Ann Arbor, MI, USA
  9. 9Department of Psychology, University of Michigan, Ann Arbor, MI, USA
  10. 10Neuroscience Graduate Program, University of Michigan, Ann Arbor, MI, USA
  11. 11BROAD Institute of MIT and Harvard, Cambridge, MA, USA. [email protected]
  12. 12Center for Regenerative Medicine, Massachusetts General Hospital, Boston, MA, USA. [email protected]
  13. 13Department of Psychiatry, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA. [email protected]
  14. 14Harvard Stem Cell Institute, Cambridge, MA, USA. [email protected]
Open at sourceDOICite

Abstract

The hippocampus forms memories of our experiences by registering processed sensory information in coactive populations of excitatory principal cells or ensembles. Fast-spiking parvalbumin-expressing inhibitory neurons (PV INs) in the dentate gyrus (DG)-CA3/CA2 circuit contribute to memory encoding by exerting precise temporal control of excitatory principal cell activity through mossy fiber-dependent feed-forward inhibition. PV INs respond to input-specific information by coordinating changes in their intrinsic excitability, input-output synaptic-connectivity, synaptic-physiology and synaptic-plasticity, referred to here as experience-dependent PV IN plasticity, to influence hippocampal functions. PV IN impairments in early life, when neural circuitry is highly sensitive to experience-dependent refinement, are thought to result in imbalanced excitation and inhibition, impaired cognition, network hyperexcitability and seizures: hallmarks of neurodevelopmental disorders (NDDs) such as Autism Spectrum Disorder and epilepsy. Discovery of transcriptional regulators of experience-dependent PV IN plasticity in the adult hippocampus may permit reversal of these developmental impairments. Here, in a screen designed to capture the PV IN intrinsic program induced by increased mossy fiber inputs, a trigger for experience-dependent PV IN plasticity, we identify the homeobox gene Meis2 as a regulator of experience-dependent PV IN plasticity gene (XPG) in the adult DG-CA3/CA2 circuit. We found that a significant number of upregulated XPGs also exhibit haploinsufficiency in ASDs, epilepsies, and schizophrenia. We demonstrate that virally-mediated rescue of experience-dependent Meis2 upregulation in CA3/CA2 PV INs in a NDD risk mouse model in adulthood is sufficient to restore experience-dependent PV IN plasticity, spatial and social memory, ensemble specificity, suppression of network hyperexcitability and seizures. Together, these findings suggest that experience-dependent PV IN plasticity is a convergent mechanism for NDD risk genes that can be re-instated in adulthood to reverse developmental deficits in circuitry, network excitability and cognition.

Related

  1. An endocannabinoid-nitric oxide signaling switch triggers reciprocal inhibitory-excitatory plasticity at dopamine neuron inputs following prenatal cannabinoid exposure
    V. Serra, F. Brandalise, V. Miczan +2
    bioRxivPreprintAll rights reservedFull textNeurosciencebioRxiv
  2. SET Domain Genes in Neurodevelopmental Disorders
    Aki Ohguri, Tadashi Nakagawa, Makiko Nakagawa +1
    GenesPeer-reviewedCC BYFull textGenetics & genomicsEurope PMC
  3. Neurodevelopmental disorders in infants treated with anti-VEGF agents vs. laser photocoagulation or cryotherapy for ROP
    Inès Ben Ghezala, Caroline Bonnet, Caroline Conese +4
    Ophthalmology SciencePeer-reviewedLicence not statedZoology & animal behaviourHAL
  4. Parsing altered brain connectivity in neurodevelopmental disorders by integrating graph-based normative modeling and deep generative networks
    Rui Sherry Shen, Livia Rodrigues, Yusuf Osmanlıoğlu +6
    Communications MedicinePeer-reviewedCC BY-NC-ND 4.0Full text1 citedNeuroscienceCrossref
  5. Copy number variants (CNVs) interfere with human accelerated regions (HARs) in neurodevelopmental disorders: a large-scale cohort study
    Maria E. Iuditskaia, Ekaterina V. Semina, Elizaveta D. Pankratova +5
    Scientific ReportsPeer-reviewedCC BY-NC-ND 4.0Full textGenetics & genomicsCrossref

Cite

BibTeXRIS
BibTeX
@article{shih2026procognitive,
  title = {{Procognitive restoration of PV neuron plasticity in neurodevelopmental disorders}},
  author = {Yu‐Tzu Shih and Jason Bondoc Alipio and Zin‐Juan Klaft and Nathaniel Green and Alok Nath Mohapatra and Travis D. Goode and Muthu Panchanatham and Devesh Pathak and Lai Ping Wong and Ruslan I. Sadreyev and Jung Ho Hyun and Omar J. Ahmed and Chris G. Dulla and Amar Sahay},
  journal = {Nature},
  year = {2026},
  month = aug,
  doi = {10.1038/s41586-026-10907-8},
  url = {https://doi.org/10.1038/s41586-026-10907-8},
  note = {CC BY},
}
RIS
TY  - JOUR
TI  - Procognitive restoration of PV neuron plasticity in neurodevelopmental disorders
AU  - Yu‐Tzu Shih
AU  - Jason Bondoc Alipio
AU  - Zin‐Juan Klaft
AU  - Nathaniel Green
AU  - Alok Nath Mohapatra
AU  - Travis D. Goode
AU  - Muthu Panchanatham
AU  - Devesh Pathak
AU  - Lai Ping Wong
AU  - Ruslan I. Sadreyev
AU  - Jung Ho Hyun
AU  - Omar J. Ahmed
AU  - Chris G. Dulla
AU  - Amar Sahay
PY  - 2026
DA  - 2026/08/12
JO  - Nature
DO  - 10.1038/s41586-026-10907-8
UR  - https://doi.org/10.1038/s41586-026-10907-8
AB  - The hippocampus forms memories of our experiences by registering processed sensory information in coactive populations of excitatory principal cells or ensembles. Fast-spiking parvalbumin-expressing inhibitory neurons (PV INs) in the dentate gyrus (DG)-CA3/CA2 circuit contribute to memory encoding by exerting precise temporal control of excitatory principal cell activity through mossy fiber-dependent feed-forward inhibition. PV INs respond to input-specific information by coordinating changes in their intrinsic excitability, input-output synaptic-connectivity, synaptic-physiology and synaptic-plasticity, referred to here as experience-dependent PV IN plasticity, to influence hippocampal functions. PV IN impairments in early life, when neural circuitry is highly sensitive to experience-dependent refinement, are thought to result in imbalanced excitation and inhibition, impaired cognition, network hyperexcitability and seizures: hallmarks of neurodevelopmental disorders (NDDs) such as Autism Spectrum Disorder and epilepsy. Discovery of transcriptional regulators of experience-dependent PV IN plasticity in the adult hippocampus may permit reversal of these developmental impairments. Here, in a screen designed to capture the PV IN intrinsic program induced by increased mossy fiber inputs, a trigger for experience-dependent PV IN plasticity, we identify the homeobox gene Meis2 as a regulator of experience-dependent PV IN plasticity gene (XPG) in the adult DG-CA3/CA2 circuit. We found that a significant number of upregulated XPGs also exhibit haploinsufficiency in ASDs, epilepsies, and schizophrenia. We demonstrate that virally-mediated rescue of experience-dependent Meis2 upregulation in CA3/CA2 PV INs in a NDD risk mouse model in adulthood is sufficient to restore experience-dependent PV IN plasticity, spatial and social memory, ensemble specificity, suppression of network hyperexcitability and seizures. Together, these findings suggest that experience-dependent PV IN plasticity is a convergent mechanism for NDD risk genes that can be re-instated in adulthood to reverse developmental deficits in circuitry, network excitability and cognition.
SN  - 0028-0836
SN  - 1476-4687
ER  -