Enhanced Asynchronous Ca2+ Oscillations Associated with Impaired Glutamate Transport in Cortical Astrocytes Expressing Fmr1 Gene Premutation Expansion

Abstract

Background: FMR1 CGG expansion repeats in the premutation range have not been linked to astrocyte pathophysiology. Results: Premutation cortical astrocytes display decreased Glu transporter expression/activity and enhanced asynchronous Ca 2ϩ oscillations. Conclusion: Glu transport and Ca 2ϩ signaling defects in premutation astrocytes could contribute to FXTAS neuropathology. Significance: Premutation astrocytes may have an etiological role in FXTAS neuropathology.

Reduced excitatory amino acid transporter 1 and metabotropic glutamate receptor 5 expression in the cerebellum of fragile X mental retardation gene 1 premutation carriers with fragile X-associated tremor/ataxia syndrome

“…Alterations in Glu uptake kinetics and augmented group I metabotropic Glu receptors (Gp1 mGluRs: mGluR1 and mGluR5) activity observed in preCGG neurons suggests that a defect in Glu transport and signaling in astrocytes could also contribute to PM pathology (Cao et al 2012), and is consistent with results from a more recent study indicating that astrocytic cultures from frontal cortex of preCGG mice have altered asynchronous Ca 2+ oscillations and glutamatergic responses associated with modest reductions of both GLT1 and GLAST expression (Cao et al 2013). Moreover, these changes have been also observed in aged mice, which show 25–30% reduction in the expression of GLT1 and GLAST in preCGG mice compared to aged matched wild type mice (Cao et al 2013). Thus, neurons (Cao et al 2012) and astrocytes (Cao et al 2013) cultured from preCGG mice show significant sensitivity to Glu-triggered Ca 2+ signals that is primarily attributed to mGluR5 hyperactivity.…”

“…Moreover, these changes have been also observed in aged mice, which show 25–30% reduction in the expression of GLT1 and GLAST in preCGG mice compared to aged matched wild type mice (Cao et al 2013). Thus, neurons (Cao et al 2012) and astrocytes (Cao et al 2013) cultured from preCGG mice show significant sensitivity to Glu-triggered Ca 2+ signals that is primarily attributed to mGluR5 hyperactivity.…”

Fragile X-associated tremor/ataxia syndrome — features, mechanisms and management

“…In one study, allopregnanolone eliminated the spikes seen in cultured neurons with premutations 156 and has improved motor symptoms in the ageing knock-in mouse (R. Berman, personal communication). It has been used to treat traumatic brain injury 157 , status epilepticus 158 , and is currently being studied in patients with AD 159 .…”

Fragile X-associated tremor/ataxia syndrome

“…113 Premutation neuronal cultures have demonstrated that elements of RNA toxicity, such as upregulation of heat shock proteins and enhanced spike discharges from the neuron, are improved with the addition of allopregnanolone or even an mGluR5 antagonist, MPEP. 114 MPEP is neurotoxic in humans, but allopregnanolone is a natural neurosteroid that has neuroprotective features and stimulates neurogenesis; allopregnanolone is now being utilized in trials of traumatic brain injury and Alzheimer disease. 115,116 Treatment trials of allopregnanolone will likely begin in the near future for those with FXTAS.…”