Deficits in the activity of presynaptic γ-aminobutyric acid type B receptors contribute to altered neuronal excitability in fragile X syndrome

Abstract

The behavioral and anatomical deficits seen in fragile X syndrome (FXS) are widely believed to result from imbalances in the relative strengths of excitatory and inhibitory neurotransmission. Although modified neuronal excitability is thought to be of significance, the contribution that alterations in GABAergic inhibition play in the pathophysiology of FXS are ill defined. Slow sustained neuronal inhibition is mediated by γ-aminobutyric acid type B (GABA) receptors, which are heterodimeric G-protein-coupled receptors constructed from R1a and R2 or R1b and R2 subunits. Via the activation of G, they limit cAMP accumulation, diminish neurotransmitter release, and induce neuronal hyperpolarization. Here we reveal that selective deficits in R1a subunit expression are seen in Fmr1 knock-out mice (KO) mice, a widely used animal model of FXS, but the levels of the respective mRNAs were unaffected. Similar trends of R1a expression were seen in a subset of FXS patients. GABA receptors (GABARs) exert powerful pre- and postsynaptic inhibitory effects on neurotransmission. R1a-containing GABARs are believed to mediate presynaptic inhibition in principal neurons. In accordance with this result, deficits in the ability of GABARs to suppress glutamate release were seen in Fmr1-KO mice. In contrast, the ability of GABARs to suppress GABA release and induce postsynaptic hyperpolarization was unaffected. Significantly, this deficit contributes to the pathophysiology of FXS as the GABAR agonist ()-baclofen rescued the imbalances between excitatory and inhibitory neurotransmission evident in Fmr1-KO mice. Collectively, our results provided evidence that selective deficits in the activity of presynaptic GABARs contribute to the pathophysiology of FXS.

Multifarious Functions of the Fragile X Mental Retardation Protein

“…In the mouse FXS model, recent work shows FMRP loss changes cell differentiation kinetics for both neurons and glia (Table 1) [14], and astrocyte-specific FMRP knockout in mice increases neuronal dendritic spine density similar to the global FXS condition [15]. Within neurons in all model systems, the soma contains the vast majority of FMRP, yet the lion’s share of research and discussion focuses on local FMRP functions at the synapse [2,16–19]. Most study postsynaptic mechanisms, but there appears to be at least as many presynaptic mRNA targets and presynaptic defects in mutants [2,16,20,21].…”

“…For example, a GABA b R subunit (R1a) mediating presynaptic inhibition is reduced in FMR1 knockout mice [73]. Similarly, the Drosophila FXS model shows deficits in GABA b R suppression of presynaptic glutamate release [19]. This early delay in GABA signaling is followed by later overelaboration of GABAergic neurons in a Drosophila brain learning/memory center [27].…”

Imbalance of synaptic actin dynamics as a key to fragile X syndrome?

“…In some neurons FMRP has been shown to be present directly at the presynapse as well as in axon-restricted fragile X granules (FXGs), which can be observed especially during particularly plastic developmental stages (Christie et al 2009;Akins et al 2012). A presynaptic role has been suggested, as the absence of FMRP correlates with dysregulations in GABA release (Centonze et al 2008;Kang et al 2017), causing imbalances between inhibitory and excitatory neurotransmission. Additionally, several studies showed that FMRP is able to regulate presynaptic ion channel stability, trafficking, surface expression as well as sensitivity indicating a presynaptic role Strumbos et al 2010;Gross et al 2011;Lee et al 2011;Zhang et al 2012;Ferron et al 2014;Wang et al 2014;Deng & Klyachko, 2016).…”

“…; Kang et al . ), causing imbalances between inhibitory and excitatory neurotransmission. Additionally, several studies showed that FMRP is able to regulate presynaptic ion channel stability, trafficking, surface expression as well as sensitivity indicating a presynaptic role (Brown et al .…”

Activity‐dependent plasticity of presynaptic GABAB receptors at parallel fiber synapses

“…Several studies have shown that presynaptic GABA B R expression can be altered by pathophysiological conditions. For example, presynaptic GABA B R expression is reduced in fragile‐x syndrome (Kang et al ) and following seizures (Straessle, Loup, Arabadzisz, Ohning, & Fritschy, ; Thompson, Ayman, Woodhall, & Jones, ) or prolonged exposure to methamphetamine (Padgett et al, ). Presynaptic GABA B R expression is also reduced following long‐term activity blockade with tetrodotoxin (Laviv et al, ), suggesting homeostatic regulation of receptor expression.…”