Disruption of GpI mGluR-Dependent Cav2.3 Translation in a Mouse Model of Fragile X Syndrome

Abstract

Fragile X syndrome (FXS) is an inherited intellectual impairment that results from the loss of fragile X mental retardation protein (FMRP), an mRNA binding protein that regulates mRNA translation at synapses. The absence of FMRP leads to neuronal and circuit-level hyperexcitability that is thought to arise from the aberrant expression and activity of voltage-gated ion channels, although the identification and characterization of these ion channels have been limited. Here, we show that FMRP binds the mRNA of the R-type voltagegated calcium channel Cav2.3 in mouse brain synaptoneurosomes and represses Cav2.3 translation under basal conditions. Consequently, in hippocampal neurons from male and female FMRP KO mice, we find enhanced Cav2.3 protein expression by western blotting and abnormally large R currents in whole-cell voltage-clamp recordings. In agreement with previous studies showing that FMRP couples Group I metabotropic glutamate receptor (GpI mGluR) signaling to protein translation, we find that GpI mGluR stimulation results in increased Cav2.3 translation and R current in hippocampal neurons which is disrupted in FMRP KO mice. Thus, FMRP serves as a key translational regulator of Cav2.3 expression under basal conditions and in response to GpI mGluR stimulation. Loss of regulated Cav2.3 expression could underlie the neuronal hyperactivity and aberrant calcium spiking in FMRP KO mice and contribute to FXS, potentially serving as a novel target for future therapeutic strategies.

Calcium channelopathies and intellectual disability: a systematic review

“…Nifedipine can block Cav1.2 current [ 146 ] Oxidative stress pathway for affective disorders [ 156 ] Apoptotic pathway in Timothy syndrome [ 153 ] Apoptotic pathway in dilated cardiomyopathy [ 154 ] CACNA1D Calcium voltage-gated channel subunit alpha1 D Cav1.3 L-type None Zebrafish larvae for schizophrenia [ 251 ]. Animal model of epilepsy [ 252 ] None Oxidative stress pathway in hearing loss [ 157 ] CACNA1E Calcium voltage-gated channel subunit alpha1 E Cav2.3 R-type Mouse model of Fragile X Syndrome [ 253 ] Sprague–Dawley rats for epilepsy [ 254 ]. Cancer pain mouse model [ 255 ].…”

Altered A-type potassium channel function impairs dendritic spike initiation and temporammonic long-term potentiation in Fragile X syndrome

“…Recordings of isolated dendritic Ca 2+ spikes suggest that CA1 dendritic voltage-gated Ca 2+ channels are not different between wild type and fmr1 KO neurons. Previous studies have shown that changes in voltage-gated Ca 2+ channels in fmr1 KO mice occur in a brain region and cell type specific manner [33][34][35] . Our results further illustrate that changes in ion channel function and expression in FXS are not conserved across brain regions.…”

Synaptic NMDA receptor signalling controls R‐type calcium channel recruitment

“…The mechanistic aspects of the connection between synaptic NMDARs and R‐VGCCs will warrant further investigation. Potential involvement of translational regulation (Figure 1h) is especially relevant in the light of the recent studies showing the link between postsynaptic mGluR activation and R‐VGCC translation (Gray et al., 2019; Park et al., 2010), given the primarily postsynaptic localization of NMDARs (Paoletti et al., 2013). Also, recent findings have demonstrated considerable abundance of Ca V 2.3 mRNA in the presynaptic compartment compared to other Ca V 2‐containing VGCCs (Hafner et al., 2019), suggesting that Ca V 2.3 translation may also occur at the presynaptic site.…”