Deficits in Trace Fear Memory and Long-Term Potentiation in a Mouse Model for Fragile X Syndrome

Abstract

Trace fear memory requires the activity of the anterior cingulate cortex (ACC) and is sensitive to attention-distracting stimuli. Fragile X syndrome is the most common form of mental retardation with many patients exhibiting attention deficits. Previous studies in fragile X mental retardation 1 (FMR1) knock-out (KO) mice, a mouse model for fragile X, focused mainly on hippocampal-dependent plasticity and spatial memory. We demonstrate that FMR1 knock-out mice show a defect in trace fear memory without changes in locomotion, anxiety, and pain sensitivity. Whole-cell path-clamp recordings in the ACC show that long-term potentiation (LTP) was completely abolished. A similar decrease in LTP was found in the lateral amygdala, another structure implicated in fear memory. No significant changes were found in basal synaptic transmission. This suggests that synaptic plasticity in the ACC and amygdala of FMR1 KO mice plays an important role in the expression of behavioral phenotypes similar to the symptoms of fragile X syndrome.

Pharmacological Rescue of Cortical Synaptic and Network Potentiation in a Mouse Model for Fragile X Syndrome

“…Furthermore, L-LTP of the hippocampus was found to be normal in Fmr1 KO mice (Zhang et al, 2009). In the anterior cingulate cortex (ACC), we found that E-LTP induced by theta-burst stimulation (TBS) or the pairing training was impaired in Fmr1 KO mice (Zhao et al, 2005a). Similar findings have been made in other regions of the cortex (Li et al, 2002;Meredith et al, 2007;Wilson and Cox, 2007;Zhao et al, 2005a).…”

“…In our previous works, we already confirmed that Fmr1 KO mice have deficits in fear memory conditioning (Zhao et al, 2005a). To determine whether inhibition of the mGluR5 and GSK3 in the ACC can rescue the deficits in learning in the KO mice, we thus combined the microinjection of the MPEP, SB415286, or CT99021 with the trace fear conditioning paradigm.…”

“…Furthermore, we did not find any obvious recruitment of fEPSPs on any of the recorded slices from Fmr1 KO mice (n ¼ 7 slices/7 mice). Finally, there is no difference in the input-output curve in the ACC slices of Fmr1 KO and WT mice (F (1, 90) ¼ 0.0002, p ¼ 0.98; n ¼ 6 slices/6 mice in each group, two-way ANOVA; Figure 2m), suggesting that the basal synaptic transmission is not changed in Fmr1 KO mice (Zhao et al, 2005a). In sum, the results suggest that FMRP is important for the LTP of the activated fEPSPs and the recruitment of synaptic responses, but not the basal synaptic transmission in the ACC.…”

“…Trace fear conditioning was performed as reported previously (Wu et al, 2008;Zhao et al, 2005a). Briefly, the conditioned stimulus (CS) used was an 80-db white noise, delivered for 15 s, and the unconditioned stimulus (US) was a FMRP and cortical late-phase long-term potentiation T Chen et al 0.75-mA electric foot shock for 0.5 s. At 30 min after saline, MPEP, SB415286, or CT99021 microinjection into the ACC, mice were placed into the chamber and acclimated for 5 min, and were presented with 10 trials in the following order: CStrace-US-intertrial interval (ITI) (trace period ¼ 30 s, ITI ¼ 210 s).…”

The cyclic AMP phenotype of fragile X and autism

“…However, FMR1 knockouts (C57BL/6J) expressed reduced LTP in cortex relative to wild type, possibly due in part to significantly reduced cortical expression of the AMPA receptor GluR1 subunit (Li, Pelletier et al 2002). A recent patch clamp study of trace fear memory in the FMR1 knockout mouse (FVB.129P2-Fmr1 tm1CgR ) found reduced LTP in anterior cingulate cortex and lateral amygdala (Zhao, Toyoda et al 2005). Taken together, the differences in memory behavior and LTP among studies of knockout strains reflect characteristics of the experimental paradigm, brain region dependence, and could also reflect alterations in cAMP cascade function across brain regions.…”