Cognitive dysfunction and prefrontal synaptic abnormalities in a mouse model of fragile X syndrome

Abstract

Among the hallmark phenotypes reported in individuals with fragile X syndrome (FXS) are deficits in attentional function, inhibitory control, and cognitive flexibility, a set of cognitive skills thought to be associated with the prefrontal cortex (PFC). However, despite substantial clinical research into these core deficits, the PFC has received surprisingly little attention in preclinical research, particularly in animal models of FXS. In this study, we sought to investigate the molecular, cellular, and behavioral consequences of the loss of the fragile X mental retardation protein in the PFC of Fmr1 KO mice, a mouse model of FXS. We identify a robust cognitive impairment in these mice that may be related to the deficits in cognitive flexibility observed in individuals with FXS. In addition, we report that levels of proteins involved in synaptic function, including the NMDA receptor subunits NR1, NR2A, and NR2B; the scaffolding proteins PSD-95 and SAPAP3; and the plasticity-related gene Arc, are decreased in the prefrontal cortex of Fmr1 KO mice and are partly correlated with behavioral performance. Finally, we report that expression of c-Fos, a marker of neuronal activity, is decreased in the PFC of Fmr1 KO mice. Together, these data suggest that Fmr1 KO mice may represent a valuable animal model for the PFC-associated molecular, cellular, and behavioral abnormalities in FXS and that this model may be useful for testing the efficacy of therapeutic strategies aimed at treating the cognitive impairments in FXS.is the most common form of inherited mental retardation and a leading known cause of autism (1). It is caused by loss of the Fmr1 gene product fragile X mental retardation protein (FMRP), an mRNA-binding protein involved in translational regulation (2, 3). FMRP is thought to repress the synthesis of proteins required for protein synthesisdependent synaptic plasticity (4, 5). In FXS, the absence of FMRP is hypothesized to result in unrestricted synthesis of plasticity-related proteins (6, 7), impairing the ability of synapses to appropriately undergo plasticity in an activity-dependent and stimulus-specific manner. In support of this hypothesis, mice with a deletion in the Fmr1 gene (Fmr1 KO mice) display aberrant forms of plasticity (4) and an increase in immature dendritic spines that presumably reflects an abnormal synaptic connectivity (8). Together, these synaptic alterations are thought to underlie the cognitive and behavioral phenotypes that are the hallmark features of FXS.Among the most common symptoms reported in FXS are deficits in attentional function, inhibitory control, and cognitive flexibility (9), cognitive skills that have all been linked to the prefrontal cortex (PFC) and associated fronto-striatal networks (10, 11). Anatomical and imaging studies of individuals with FXS have identified structural alterations in PFC, and numerous fMRI studies have shown aberrant patterns of neural activity in fronto-striatal pathways during cognitive tasks (12). Together, all of these results suggest that...

Therapeutic Strategies in Fragile X Syndrome: Dysregulated mGluR Signaling and Beyond

“…However, in contrast to Zalfa et al (2003), another study reported reduced Arc/Arg3.1 protein levels in the orbital frontal cortex and medial prefrontal cortex of FXS mice (Krueger et al, 2011). Future experiments are needed to analyze whether FMRP regulates specific target mRNAs differently depending on the brain region.…”

“…Interestingly, a recent report has shown that prefrontal cortex-dependent forms of learning are altered in Fmr1 KO mice (Krueger et al, 2011), and patients with FXS are specifically impaired in several prefrontal cortex-dependent cognitive skills (Hoeft et al, 2007;Reiss and Hall, 2007;Mercaldo et al, 2009). This suggests that behavioral paradigms testing prefrontal cortical function in Fmr1 KO mice might be a better tool to assess therapeutic strategies for their potential to rescue cognitive impairment in FXS (Krueger et al, 2011).…”

“…Dysregulation of several FMRP targets might also contribute to aberrant network plasticity in FXS. Arc/Arg3.1, which was suggested to be an FMRP target (Zalfa et al, 2003;Krueger et al, 2011), was shown to be involved in neuronal network homeostasis (Shepherd et al, 2006;Peebles et al, 2010;Béïque et al, 2011). Moreover, lately, a few studies have reported that FMRP regulates potassium channels, which might also contribute to abnormal network activity in FXS.…”

Therapeutic Strategies in Fragile X Syndrome: From Bench to Bedside and Back

“…Of note, patients with FXS are mostly impaired in higher cognition, behavioral flexibility, and inhibitory control, which depend on the prefrontal cortex. To date, very few studies have reported defects in prefrontal cortex-dependent higherorder cognition in Fmr1 KO mice [215,237]. A recent study showed that defects in higher cognition in FXS mouse models were rescued by genetic reduction of the PI3K catalytic subunit p110β in the prefrontal cortex [237].…”

Modeling fragile X syndrome in the <i>Fmr1</i> knockout mouse

“…In light of clinical FXS symptomology (i.e., its comorbidity with ADHD), Fmr1 KO mice were evaluated in the five-choice serial reaction time task, considered the gold standard task for attention and impulsivity in rodents (118). Although Fmr1 KO mice were impaired in select phases of a visual-spatial discrimination task, they did not differ from wildtype controls in the five-choice serial reaction time task (119,120). Specifically, Krueger and colleagues found that Fmr1 KO mice took longer to reach criterion during the As a negative regulator of mRNA translation, FMRP influences protein synthesis and can therefore affect the synaptic components located in dendritic spines.…”