Neuronal network alterations underlying cognitive deficits in Fragile X syndrome model, Fmr1(y/-) mice

Bhandari, Komal. Neuronal network alterations underlying cognitive deficits in Fragile X syndrome model, Fmr1(y/-) mice. 2021, Doctoral Thesis, University of Basel, Associated Institutions.

[img] PDF
Restricted to Repository staff only until 26 July 2025.


Official URL: https://edoc.unibas.ch/95355/

Downloads: Statistics Overview


Fragile X Syndrome (FXS) is the most common form of intellectual disability and autism spectrum disorder, caused by loss of FMRP which is normally expressed ubiquitously in the brain and has important role for synaptic function and plasticity. Whether the defects in FXS reflect ubiquitous loss of function or deficits specific to particular brain networks has remained unclear. Here we show using area-specific conditional knockout of FMRP (cKO), that area-specific loss in adult wildtype (WT) mice behaviorally mimics acute silencing of the same area. However, in Fmr1y/- mice despite the ubiquitous absence of FMRP, behavioral and immediate early gene (IEG) expression analyses, revealed that cognitive functions of most brain areas were unaffected by the absence of FMRP, with the exception of ventral hippocampus (vH) and prelimbic cortex (PreL). Using conditional restoration of FMRP in adult Fmr1y/-, we found that the specific behavioral deficits of adult Fmr1y/- mice can entirely be accounted for by absence of FMRP in a vH-PreL axis. Mechanistic investigations revealed that late-born Parvalbumin (PV) interneuron deficit across the vH-PreL axis specifically accounted for insufficient recruitment of memory ensemble and deficit in learning related-coherence along this axis. Rescuing the plasticity of PV interneurons by chemogenetic interventions along this axis, could completely ameliorate Fmr1y/- cognitive impairments and network synchrony, even in the absence of FMRP. Overall our findings reveal for the first time a specific dysfunction of the PV interneuron networks in the vH-PreL axis underlies cognitive impairments in Frm1y/- mice and encourage for adopting a network-based therapeutic interventions targeting vH-PreL network in FXS.
Advisors:Caroni, Pico
Committee Members:Arber, Silvia
Faculties and Departments:05 Faculty of Science > Departement Biozentrum > Neurobiology > Cell Biology (Arber)
09 Associated Institutions > Friedrich Miescher Institut FMI > Neurobiology > Plasticity of neuronal connections (Caroni)
UniBasel Contributors:Arber, Silvia
Item Type:Thesis
Thesis Subtype:Doctoral Thesis
Thesis no:15085
Thesis status:Complete
Number of Pages:128
Identification Number:
  • urn: urn:nbn:ch:bel-bau-diss150853
edoc DOI:
Last Modified:01 Sep 2023 04:30
Deposited On:31 Aug 2023 08:02

Repository Staff Only: item control page