Input-Output Relationship of CA1 Pyramidal Neurons Reveals Intact Homeostatic Mechanisms in a Mouse Model of Fragile X Syndrome

Abstract

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.

Altered A-type potassium channel function impairs dendritic spike initiation and temporammonic long-term potentiation in Fragile X syndrome

“…Two photon Ca 2+ imaging demonstrated that synaptically evoked dendritic Ca 2+ signals were consistently smaller in fmr1 KO neurons. In agreement with a previous study, we found that basal synaptic transmission at TA synapses was not different between wild type and fmr1 KO mice as has been described previously 10 (but see 11 ). There was no difference in the function of NMDARs, dendritic complex spikes, or isolated dendritic Ca 2+ spikes between wild type and fmr1 KO CA1 pyramidal neurons.…”

Brief Sensory Deprivation Triggers Cell Type-Specific Structural and Functional Plasticity in Olfactory Bulb Neurons

“…Importantly, while activity-dependent changes in both AIS position and length have been described in cultured neurons ( Grubb and Burrone, 2010 ; Evans et al, 2013 , 2015 ; Muir and Kittler, 2014 ; Chand et al, 2015 ; Horschitz et al, 2015 ; Wefelmeyer et al, 2015 ; Dumitrescu et al, 2016 ; Lezmy et al, 2017 ; Sohn et al, 2019 ; Booker et al, 2020 ), plasticity of AIS position without any accompanying length change has yet to be described in intact networks. Indeed, to date, all activity-dependent AIS plasticity described in vivo or in ex vivo acute slices seems to express itself as length changes ( Fig.…”

Selective vulnerability of inhibitory networks in multiple sclerosis

“…Slices containing LPC lesion and PBS control neurons were prepared from mice which had been implanted with cryogels overlaying the motor cortex (M1), as previously described [5,6]. Briefly, mice were sedated with isofluorane, decapitated and their brains rapidly removed and placed in ice-cold sucrose-modified artificial cerebrospinal fluid (sucrose-ACSF; in mM: 87 NaCl, 2.5 KCl, 25 , containing 500 nM tetrodotoxin,TTX) and bubbled with carbogen, at a rate of 4-6 mL.min −1 , recordings were maintained at 30 ± 1 °C with an inline Peltier heating device (Scientifica, Brighton, UK).…”