Input-Output Relationship of CA1 Pyramidal Neurons Reveals Intact Homeostatic Mechanisms in a Mouse Model of Fragile X Syndrome
Sam A. Booker,
Laura Simões de Oliveira,
Natasha J. Anstey,
Zrinko Kozic,
Owen R. Dando,
Adam D. Jackson,
Paul S. Baxter,
Lori L. Isom,
Diane L. Sherman,
Giles E. Hardingham,
Peter J. Brophy,
David J.A. Wyllie,
Peter C. Kind
Affiliations
Sam A. Booker
Centre for Discovery Brain Sciences, University of Edinburgh, Edinburgh, UK; Simons Initiative for the Developing Brain, University of Edinburgh, Edinburgh, UK; Patrick Wild Centre for Autism Research, University of Edinburgh, Edinburgh, UK; Corresponding author
Laura Simões de Oliveira
Centre for Discovery Brain Sciences, University of Edinburgh, Edinburgh, UK; Simons Initiative for the Developing Brain, University of Edinburgh, Edinburgh, UK; Patrick Wild Centre for Autism Research, University of Edinburgh, Edinburgh, UK
Natasha J. Anstey
Centre for Discovery Brain Sciences, University of Edinburgh, Edinburgh, UK; Simons Initiative for the Developing Brain, University of Edinburgh, Edinburgh, UK; Patrick Wild Centre for Autism Research, University of Edinburgh, Edinburgh, UK; Centre for Brain Development and Repair, InStem, GKVK Campus, Bangalore 560065, India
Zrinko Kozic
Centre for Discovery Brain Sciences, University of Edinburgh, Edinburgh, UK; Simons Initiative for the Developing Brain, University of Edinburgh, Edinburgh, UK
Owen R. Dando
Centre for Discovery Brain Sciences, University of Edinburgh, Edinburgh, UK; Simons Initiative for the Developing Brain, University of Edinburgh, Edinburgh, UK; Patrick Wild Centre for Autism Research, University of Edinburgh, Edinburgh, UK; Dementia Research Institute, University of Edinburgh, Hugh Robson Building, George Square, Edinburgh EH8 9XD, UK; Centre for Brain Development and Repair, InStem, GKVK Campus, Bangalore 560065, India
Adam D. Jackson
Centre for Discovery Brain Sciences, University of Edinburgh, Edinburgh, UK; Simons Initiative for the Developing Brain, University of Edinburgh, Edinburgh, UK; Patrick Wild Centre for Autism Research, University of Edinburgh, Edinburgh, UK; Centre for Brain Development and Repair, InStem, GKVK Campus, Bangalore 560065, India
Paul S. Baxter
Centre for Discovery Brain Sciences, University of Edinburgh, Edinburgh, UK; Dementia Research Institute, University of Edinburgh, Hugh Robson Building, George Square, Edinburgh EH8 9XD, UK
Lori L. Isom
Department of Pharmacology, University of Michigan Medical School, Ann Arbor, MI 48109-5632, USA
Diane L. Sherman
Centre for Discovery Brain Sciences, University of Edinburgh, Edinburgh, UK
Giles E. Hardingham
Centre for Discovery Brain Sciences, University of Edinburgh, Edinburgh, UK; Dementia Research Institute, University of Edinburgh, Hugh Robson Building, George Square, Edinburgh EH8 9XD, UK
Peter J. Brophy
Centre for Discovery Brain Sciences, University of Edinburgh, Edinburgh, UK
David J.A. Wyllie
Centre for Discovery Brain Sciences, University of Edinburgh, Edinburgh, UK; Simons Initiative for the Developing Brain, University of Edinburgh, Edinburgh, UK; Patrick Wild Centre for Autism Research, University of Edinburgh, Edinburgh, UK; Centre for Brain Development and Repair, InStem, GKVK Campus, Bangalore 560065, India
Peter C. Kind
Centre for Discovery Brain Sciences, University of Edinburgh, Edinburgh, UK; Simons Initiative for the Developing Brain, University of Edinburgh, Edinburgh, UK; Patrick Wild Centre for Autism Research, University of Edinburgh, Edinburgh, UK; Centre for Brain Development and Repair, InStem, GKVK Campus, Bangalore 560065, India; Corresponding author
Summary: Cellular hyperexcitability is a salient feature of fragile X syndrome animal models. The cellular basis of hyperexcitability and how it responds to changing activity states is not fully understood. Here, we show increased axon initial segment length in CA1 of the Fmr1−/y mouse hippocampus, with increased cellular excitability. This change in length does not result from reduced AIS plasticity, as prolonged depolarization induces changes in AIS length independent of genotype. However, depolarization does reduce cellular excitability, the magnitude of which is greater in Fmr1−/y neurons. Finally, we observe reduced functional inputs from the entorhinal cortex, with no genotypic difference in the firing rates of CA1 pyramidal neurons. This suggests that AIS-dependent hyperexcitability in Fmr1−/y mice may result from adaptive or homeostatic regulation induced by reduced functional synaptic connectivity. Thus, while AIS length and intrinsic excitability contribute to cellular hyperexcitability, they may reflect a homeostatic mechanism for reduced synaptic input onto CA1 neurons.
