Excitability is increased in hippocampal CA1 pyramidal cells of Fmr1 knockout mice

Abstract

Fragile X syndrome (FXS) is caused by a failure of neuronal cells to express the gene encoding the fragile mental retardation protein (FMRP). Clinical features of the syndrome include intellectual disability, learning impairment, hyperactivity, seizures and anxiety. Fmr1 knockout (KO) mice do not express FMRP and, as a result, reproduce some FXS behavioral abnormalities. While intrinsic and synaptic properties of excitatory cells in various part of the brain have been studied in Fmr1 KO mice, a thorough analysis of action potential characteristics and input-output function of CA1 pyramidal cells in this model is lacking. With a view to determining the effects of the absence of FMRP on cell excitability, we studied rheobase, action potential duration, firing frequency–current intensity relationship and action potential after-hyperpolarization (AHP) in CA1 pyramidal cells of the hippocampus of wild type (WT) and Fmr1 KO male mice. Brain slices were prepared from 8- to 12-week-old mice and the electrophysiological properties of cells recorded. Cells from both groups had similar resting membrane potentials. In the absence of FMRP expression, cells had a significantly higher input resistance, while voltage threshold and depolarization voltage were similar in WT and Fmr1 KO cell groups. No changes were observed in rheobase. The action potential duration was longer in the Fmr1 KO cell group, and the action potential firing frequency evoked by current steps of the same intensity was higher. Moreover, the gain (slope) of the relationship between firing frequency and injected current was 1.25-fold higher in the Fmr1 KO cell group. Finally, AHP amplitude was significantly reduced in the Fmr1 KO cell group. According to these data, FMRP absence increases excitability in hippocampal CA1 pyramidal cells.

Cortical neurons derived from human pluripotent stem cells lacking FMRP display altered spontaneous firing patterns

“…Spontaneous network properties are influenced by active and passive membrane properties, and indeed, many studies have reported that in rodent models the loss of expression of FMRP leads to cortical hyperexcitability [9,[12][13][14]36]. It is becoming increasingly clear that FXS pathophysiology as assessed in rodent models shows complex diversity.…”

“…Given the distinct patterns of spontaneous burst firing in neurons lacking FMRP compared to control neurons, we sought to determine whether this was due to differences in either intrinsic or synaptic properties between cell lines. Indeed, rodent models of FXS have reported that some classes of principal neurons lacking FMRP display altered intrinsic excitability [9,[12][13][14]36] although others have not observed difference in these parameters [15,37] most likely reflecting the fact that where differences do occur these are cell-type specific, rather than a generalized alteration in intrinsic excitability due to the loss of expression of FMRP. However, human neurons lacking FMRP have been reported to exhibit a considerably compromised ability to generate trains of action potential firing in response to depolarizing current injections [21].…”

Of Men and Mice: Modeling the Fragile X Syndrome

“…For instance, while dendrites of hippocampal neurons from Fmr1 −/y mice display increased HCN1-channel 24 expression and reduced input resistance (Brager et al, 2012 ), dendrites of cortical layer 5 neurons show the opposite (Zhang Y. et al, 2014 ). The intrinsic membrane excitability of cortical layer 4 excitatory neurons is exaggerated (Gibson et al, 2008 ), while that of excitatory hippocampal neurons is normal (Deng et al, 2013 ; Luque et al, 2017 ). Hippocampal neurons demonstrate significantly longer action potential durations and higher firing frequencies in the absence of FMRP than under normal conditions (Luque et al, 2017 ), whereas layer 2/3 neurons in the prefontral cortex present significantly narrower and taller action potentials in Fmr1 −/y mice than in their wildtype litter mates (Routh et al, 2017 ).…”

“…The intrinsic membrane excitability of cortical layer 4 excitatory neurons is exaggerated (Gibson et al, 2008 ), while that of excitatory hippocampal neurons is normal (Deng et al, 2013 ; Luque et al, 2017 ). Hippocampal neurons demonstrate significantly longer action potential durations and higher firing frequencies in the absence of FMRP than under normal conditions (Luque et al, 2017 ), whereas layer 2/3 neurons in the prefontral cortex present significantly narrower and taller action potentials in Fmr1 −/y mice than in their wildtype litter mates (Routh et al, 2017 ). Although both alterations indicate enhanced excitability, the sharpened action potentials observed the cortex of Fmr1 −/y mice are in contrast with the broadened action potentials seen in the hippocampus.…”

Impaired reliability and precision of spiking in adults but not juveniles in a mouse model of Fragile X Syndrome

“…Multiple previous studies have found hyper excitability in hippocampus in FXS model mice (Deng and Klyachko, 2016;Luque et al, 2017). However, (Brager et al, 2012) found a lowering of Input Resistance for KO CA1 cells indicative of reduced excitability.…”