Hyperexcitability of the local cortical circuit in mouse models of tuberous sclerosis complex

Jian-Ping Zhao,Akira Yoshii

doi:10.1186/s13041-019-0427-6

Abstract

Tuberous sclerosis complex (TSC) is a neurogenetic disorder associated with epilepsy, intellectual disabilities, and autistic behaviors. These neurological symptoms result from synaptic dysregulations, which shift a balance between excitation and inhibition. To decipher the synaptic substrate of hyperexcitability, we examined pan-neuronal Tsc1 knockout mouse and found a reduction in surface expression of a GABA receptor (GABAR) subunit but not AMPA receptor (AMPAR) subunit. Using electrophysiological recordings, we found a significant reduction in the frequency of GABAR-mediated miniature inhibitory postsynaptic currents (GABAR-mIPSCs) but not AMPAR-mediated miniature excitatory postsynaptic currents (AMPAR-mEPSCs) in layer 2/3 pyramidal neurons. To determine a subpopulation of interneurons that are especially vulnerable to the absence of TSC1 function, we also analyzed two strains of conditional knockout mice targeting two of the prominent interneuron subtypes that express parvalbumin (PV) or somatostatin (SST). Unlike pan-neuronal knockout mice, both interneuron-specific Tsc-1 knockout mice did not develop spontaneous seizures and grew into adults. Further, the properties of AMPAR-mEPSCs and GABAR-mIPSCs were normal in both Pv-Cre and Sst-Cre x Tsc1fl/fl knockout mice. These results indicate that removal of TSC1 from all neurons in a local cortical circuit results in hyperexcitability while connections between pyramidal neurons and interneurons expressing PV and SST are preserved in the layer 2/3 visual cortex. Our study suggests that another inhibitory cell type or a combination of multiple subtypes may be accountable for hyperexcitability in TSC.

Highlights

The connectivity between pyramidal cells and interneurons matures during development and is one of the key determinants of critical period plasticity [1,2,3,4,5,6]
We found comparable levels of GluA2 subunits in both control and Syn1-Cre x Tsc1fl/fl neurons (Fig. 2a and b: p = 0.87) and a significant reduction of GABAA R-α1subunit in Syn1-Cre x Tsc1fl/fl neurons as compared to control (Fig. 2a and c: p = 0.011)
In Syn1-Cre x Tsc1fl/fl mice, we have found a reduction in GABAergic synapse formation

Summary

Introduction

The connectivity between pyramidal cells and interneurons matures during development and is one of the key determinants of critical period plasticity [1,2,3,4,5,6]. The balance between excitation and inhibition (E/I balance) underlie normal neuronal circuit functions that underlie learning, memory, and sensory processing. The TSC-1 and -2 proteins form a complex that suppresses the mammalian target of rapamycin (mTOR) pathway, which regulates cell growth, protein synthesis, autophagy and transcription [14]. The mTOR pathway plays critical roles in synaptic functions [15, 16]. Hippocampal neurons that are suppressed with Tsc-1 and -2 using RNA interference have impaired α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) currents [18]. Tsc-1-deleted hippocampal neurons exhibit impaired long-term depression (LTD) mediated by a metabotropic glutamate receptor (mGluR) [19, 20]. An E/I balance is skewed to hyperexcitability in Tsc-1-deleted hippocampal neurons [21]

Methods

Results

Conclusion