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 (GABAB) receptors, which are heterodimeric G-protein-coupled receptors constructed from R1a and R2 or R1b and R2 subunits. Via the activation of Gi/o, 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. GABAB receptors (GABABRs) exert powerful pre- and postsynaptic inhibitory effects on neurotransmission. R1a-containing GABABRs are believed to mediate presynaptic inhibition in principal neurons. In accordance with this result, deficits in the ability of GABABRs to suppress glutamate release were seen in Fmr1-KO mice. In contrast, the ability of GABABRs to suppress GABA release and induce postsynaptic hyperpolarization was unaffected. Significantly, this deficit contributes to the pathophysiology of FXS as the GABABR agonist (R)-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 GABABRs contribute to the pathophysiology of FXS.
Highlights
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
To address whether alterations in GABAB receptor signaling contribute to the pathophysiology of FXS, we used Fmr1-knock-out mice (KO) mice maintained on a C57BL/6 background [14]
Spontaneous EPSCs were recorded at Ϫ70 mV in the presence of 50 M picrotoxin, whereas spontaneous inhibitory postsynaptic currents were measured at the same potential in the presence of 50 M 2-amino-5-phosphonopentanoic acid and 10 M 6,7-dinitroquinoxaline-2,3-dione. sEPSC frequency was significantly lower in Fmr1-KO mice (Fig. 7A; WT ϭ 6.69 Ϯ 0.11 Hz and Fmr1-KO ϭ 6.04 Ϯ 0.10 Hz, Dunn’s post hoc test, p Ͻ 0.01, n ϭ 12–14 cells). This decrease in sEPSC frequency is consistent with the reductions in presynaptic GABAB receptors (GABABRs)-dependent modulation of evoked excitatory postsynaptic currents (eEPSCs) and increased paired pulse facilitation (PPF) seen in Fmr1-KO mice (Fig. 4)
Summary
Lectively, our results provided evidence that selective deficits in the activity of presynaptic GABABRs contribute to the pathophysiology of FXS. Increased mGluR1/5 signaling is believed to enhance the removal of ␣-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors from excitatory synapses This process leads to exaggerated long term depression, a well studied model of synaptic plasticity, which is believed to contribute to the deficits in dendritic morphology seen in FXS [9]. Slow prolonged synaptic inhibition in the brain is mediated by GABABRs, which are heterodimeric G-protein-coupled receptors composed of GABABR1 and GABABR2 subunits that activate Gi/o signaling pathways Their activation leads to diminished neurotransmitter release and increased neuronal hyperpolarization [23,24,25]. We demonstrate selective down-regulation of the GABABR1a isoform in Fmr1-KO mice and post-mortem hippocampi from FXS patients This deficit compromised the ability of (R)-baclofen to reduce excitatory neurotransmission without compromising its ability to modify GABAergic neurotransmission.
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