Dysregulated Prefrontal Cortex Inhibition in Prepubescent and Adolescent Fragile X Mouse Model.

Ioannis Kramvis,Alex Loebel,Danai Riga,Sabine Spijker,Tim S Heistek,Rhodé Van Westen,Huibert D Mansvelder,Rhiannon M Meredith,Hanna C A Lammertse

doi:10.3389/fnmol.2020.00088

Abstract

Changes in excitation and inhibition are associated with the pathobiology of neurodevelopmental disorders of intellectual disability and autism and are widely described in Fragile X syndrome (FXS). In the prefrontal cortex (PFC), essential for cognitive processing, excitatory connectivity and plasticity are found altered in the FXS mouse model, however, little is known about the state of inhibition. To that end, we investigated GABAergic signaling in the Fragile X Mental Retardation 1 (FMR1) knock out (Fmr1-KO) mouse medial PFC (mPFC). We report changes at the molecular, and functional levels of inhibition at three (prepubescence) and six (adolescence) postnatal weeks. Functional changes were most prominent during early postnatal development, resulting in stronger inhibition, through increased synaptic inhibitory drive and amplitude, and reduction of inhibitory short-term synaptic depression. Noise analysis of prepubescent post-synaptic currents demonstrated an increased number of receptors opening during peak current in Fmr1-KO inhibitory synapses. During adolescence amplitudes and plasticity changes normalized, however, the inhibitory drive was now reduced in Fmr1-KO, while synaptic kinetics were prolonged. Finally, adolescent GABAA receptor subunit α2 and GABAB receptor subtype B1 expression levels were different in Fmr1-KOs than WT littermate controls. Together these results extend the degree of synaptic GABAergic alterations in FXS, now to the mPFC of Fmr1-KO mice, a behaviourally relevant brain region in neurodevelopmental disorder pathology.

Highlights

Deregulated excitatory/inhibitory balance is proposed to underlie neuronal dysfunction and cognitive impairments in neurodevelopmental disorders of autism and intellectual disability, including Fragile X syndrome (FXS; Rubenstein and Merzenich, 2003; Gibson et al, 2008; Lozano et al, 2014; Contractor et al, 2015)
Synaptosomal fractions were prepared from medial PFC (mPFC) enriched protein lysates and analyzed for the expression of several GABA subunits and auxiliary proteins (Figure 1, Supplementary Figure S3)
During adolescence, an expression of GABAA receptor α2 subunit was increased in the Fmr1-KO mPFC (Figure 1Bi, p = 0.04)

Summary

Introduction

Deregulated excitatory/inhibitory balance is proposed to underlie neuronal dysfunction and cognitive impairments in neurodevelopmental disorders of autism and intellectual disability, including Fragile X syndrome (FXS; Rubenstein and Merzenich, 2003; Gibson et al, 2008; Lozano et al, 2014; Contractor et al, 2015). Prefrontal Inhibitory Dysfunction in FXS of the Fragile X Mental Retardation 1 (FMR1) gene, FXS is characterized by intellectual disability with high concomitance for autism spectrum disorders, epilepsy, attentional, executive control and behavioral deficits (Munir et al, 2000a,b; Wilding et al, 2002; Sullivan et al, 2006; Lozano et al, 2014). Little is currently known about prefrontal inhibitory synaptic function and plasticity in FXS, during early postnatal and pre-adulthood periods

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