Cellular and synaptic phenotypes lead to disrupted information processing in Fmr1-KO mouse layer 4 barrel cortex

Aleksander P F Domanski,Peter C Kind,John T R Isaac,Sam A Booker,David J A Wyllie

doi:10.1038/s41467-019-12736-y

Abstract

Sensory hypersensitivity is a common and debilitating feature of neurodevelopmental disorders such as Fragile X Syndrome (FXS). How developmental changes in neuronal function culminate in network dysfunction that underlies sensory hypersensitivities is unknown. By systematically studying cellular and synaptic properties of layer 4 neurons combined with cellular and network simulations, we explored how the array of phenotypes in Fmr1-knockout (KO) mice produce circuit pathology during development. We show that many of the cellular and synaptic pathologies in Fmr1-KO mice are antagonistic, mitigating circuit dysfunction, and hence may be compensatory to the primary pathology. Overall, the layer 4 network in the Fmr1-KO exhibits significant alterations in spike output in response to thalamocortical input and distorted sensory encoding. This developmental loss of layer 4 sensory encoding precision would contribute to subsequent developmental alterations in layer 4-to-layer 2/3 connectivity and plasticity observed in Fmr1-KO mice, and circuit dysfunction underlying sensory hypersensitivity.

Highlights

Sensory hypersensitivity is a common and debilitating feature of neurodevelopmental disorders such as Fragile X Syndrome (FXS)
stellate cell (SC) in Fmr1-KOs had enhanced excitability with an increase in the number of action potentials elicited by 500 ms depolarising current steps (Fig. 1b); this increase in action potential number was associated with a decrease in action potential frequency during the early part of the depolarisation resulting in a reduction in action potential frequency adaptation, as assessed over a duration necessary to fire a standardised number of spikes (Fig. 1c)
We found that postsynaptic potential (PSP) full width at half-maximum amplitude is increased in the Fmr1-KO mice (Fig. 3d) suggesting a decrease in functional feed-forward inhibition (FFI), despite the increased feed-forward inhibitory synaptic input onto SCs

Summary

Results

Altered membrane properties and excitability in Fmr1-KO mice. Previous work has identified a number of cellular, synaptic and circuit changes in Fmr1-KO mouse barrel cortex[9,24,40]. We first investigated whether there were changes in passive membrane properties in layer 4 barrel cortex neurons in acute slices from P10/11 Fmr1-KO mice compared with wild-type (WT) littermates, using whole-cell patch-clamp recordings. SCs from Fmr1-KO mice exhibited an increased impedance between 0.5 and 4 Hz (Fig. S2a), consistent with predictions from the change in passive membrane properties (Fig. S3) This frequency-dependent response suggests that SCs in Fmr1-KO mice should exhibit alterations in action potential generation in response to membrane depolarisations of the same frequency range. We applied suprathreshold sinusoidal depolarisations at specific frequencies and found an increase in the number of action potentials elicited at low frequencies in Fmr1-KO compared with wild-type mice (0.5–4 Hz; Fig. S2B). Short-term synaptic plasticity is an important mechanism for information processing in cortical networks[61,62] including a Currents

50 Hz TC stim pattern

50 Hz stim

Discussion

Methods

Code availability