Age-Dependent and Selective Impairment of Long-Term Potentiation in the Anterior Piriform Cortex of Mice Lacking the Fragile X Mental Retardation Protein

Larson, John; Jessen, Ruth E.; Kim, Daniel; Fine, Ananda Kriiya S; Hoffmann, Johann du

doi:10.1523/jneurosci.2638-05.2005

Cited by 121 publications

(123 citation statements)

References 62 publications

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“…Although it is consistently reported that LTD is exaggerated in hippocampus (Huber et al, 2002;Zhang et al, 2009) and cerebellum (Koekkoek et al, 2005), LTP impairment depends on the region of the brain as well as the induction protocols. Some reports find that LTP is not affected in the hippocampus (Bear et al, 2004;Godfraind et al, 1996;Paradee et al, 1999;Zhang et al, 2009), whereas others show that LTP is reduced in the hippocampus (Hu et al, 2008;Larson et al, 2005;Lauterborn et al, 2007;Lee et al, 2011;Shang et al, 2009). In the ACC, we reported that the early phase of LTP was impaired in cingulate pyramidal cells (Zhao et al, 2005a).…”

Section: Fmr1 Ko Mice Exhibited Reduced L-ltp In the Accmentioning

confidence: 63%

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

Chen

Song

et al. 2014

Neuropsychopharmacol

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Fragile X syndrome, caused by the mutation of the Fmr1 gene, is characterized by deficits of attention and learning ability. In the hippocampus of Fmr1 knockout mice (KO), long-term depression is enhanced whereas long-term potentiation (LTP) including late-phase LTP (L-LTP) is reduced or unaffected. Here we examined L-LTP in the anterior cingulate cortex (ACC) in Fmr1 KO mice by using a 64-electrode array recording system. In wild-type mice, theta-burst stimulation induced L-LTP that does not occur in all active electrodes/ channels within the cingulate circuit and is typically detected in B75% of active channels. Furthermore, L-LTP recruited new responses from previous inactive channels. Both L-LTP and the recruitment of inactive responses were blocked in the ACC slices of Fmr1 KO mice. Bath application of metabotropic glutamate receptor 5 (mGluR5) antagonist or glycogen synthase kinase-3 (GSK3) inhibitors rescued the L-LTP and network recruitment. Our results demonstrate that loss of FMRP will greatly impair L-LTP and recruitment of cortical network in the ACC that can be rescued by pharmacological inhibition of mGluR5 or GSK3. This study is the first report of the network properties of L-LTP in the ACC, and provides basic mechanisms for future treatment of cortex-related cognitive defects in fragile X patients.

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Section: Fmr1 Ko Mice Exhibited Reduced L-ltp In the Accmentioning

confidence: 63%

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

Chen

Song

et al. 2014

Neuropsychopharmacol

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“…2A). To further analyze this apparent contradiction of the mGluR theory in the amygdala, we took note of earlier findings from other brain areas of Fmr1 KO mice exhibiting deficient forms of LTP that are not necessarily dependent on mGluR5 (7,10,11,15,16). Because restoration of AMPARs to the surface could also be mediated by other nonmGluR plasticity mechanisms, we wanted to ensure that contributions from such mechanisms are not constrained by our use of the 30 Hz mGluR-LTP induction protocol alone.…”

Section: Resultsmentioning

confidence: 99%

“…The underlying basis for this enhanced hippocampal mGluR-LTD is abnormally high internalization of the AMPA receptor (AMPAR) subunit, GluR1, caused by the absence of the endpoint inhibition normally provided by FMRP (2,6). Interestingly, defective AMPAR-mediated plasticity has also emerged as a common phenotype in other brain areas in the Fmr1 KO mouse, including the cortex and cerebellum (7)(8)(9)(10)(11). However, such deficits are not limited to LTD, but are also frequently manifested as an impairment of long-term potentiation (LTP) (7,(12)(13)(14)(15).…”

mentioning

confidence: 99%

Characterization and reversal of synaptic defects in the amygdala in a mouse model of fragile X syndrome

Suvrathan

Hoeffer

Wong

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

126

108

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Fragile X syndrome (FXS), a common inherited form of mental impairment and autism, is caused by transcriptional silencing of the fragile X mental retardation 1 (FMR1) gene. Earlier studies have identified a role for aberrant synaptic plasticity mediated by the metabotropic glutamate receptors (mGluRs) in FXS. However, many of these observations are derived primarily from studies in the hippocampus. The strong emotional symptoms of FXS, on the other hand, are likely to involve the amygdala. Unfortunately, little is known about how exactly FXS affects synaptic function in the amygdala. Here, using whole-cell recordings in brain slices from adult Fmr1 knockout mice, we find mGluR-dependent long-term potentiation to be impaired at thalamic inputs to principal neurons in the lateral amygdala. Consistent with this long-term potentiation deficit, surface expression of the AMPA receptor subunit, GluR1, is reduced in the lateral amygdala of knockout mice. In addition to these postsynaptic deficits, lower presynaptic release was manifested by a decrease in the frequency of spontaneous miniature excitatory postsynaptic currents (mEPSCs), increased pairedpulse ratio, and slower use-dependent block of NMDA receptor currents. Strikingly, pharmacological inactivation of mGluR5 with 2-methyl-6-phenylethynyl-pyridine (MPEP) fails to rescue either the deficit in long-term potentiation or surface GluR1. However, the same acute MPEP treatment reverses the decrease in mEPSC frequency, a finding of potential therapeutic relevance. Therefore, our results suggest that synaptic defects in the amygdala of knockout mice are still amenable to pharmacological interventions against mGluR5, albeit in a manner not envisioned in the original hippocampal framework.autism | long-term potentiation | synaptic plasticity | metabotropic glutamate receptor

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“…Several studies have also shown impaired long-term potentiation (LTP) in different cortical areas of Fmr1 KO mice Zhao et al, 2005;Desai et al, 2006). In contrast, LTP appeared to be normal in the Fmr1 KO hippocampus (Paradee et al, 1999;Li et al, 2002;Larson et al, 2005). However, a defect in hippocampal LTP could be detected at lower levels of stimulation (Lauterborn et al, 2007), which was in line with another study showing that spike-timing-dependent LTP in the Fmr1 KO cortex was normal after a strong stimulus, but impaired when using a threshold induction paradigm (Meredith et al, 2007).…”

Section: Altered Synaptic Plasticity In Fmr1 Ko Micementioning

confidence: 99%

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

Groß

Berry‐Kravis

Bassell

2011

Neuropsychopharmacol

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Fragile X syndrome (FXS) is an inherited neurodevelopmental disease caused by loss of function of the fragile X mental retardation protein (FMRP). In the absence of FMRP, signaling through group 1 metabotropic glutamate receptors is elevated and insensitive to stimulation, which may underlie many of the neurological and neuropsychiatric features of FXS. Treatment of FXS animal models with negative allosteric modulators of these receptors and preliminary clinical trials in human patients support the hypothesis that metabotropic glutamate receptor signaling is a valuable therapeutic target in FXS. However, recent research has also shown that FMRP may regulate diverse aspects of neuronal signaling downstream of several cell surface receptors, suggesting a possible new route to more direct disease-targeted therapies. Here, we summarize promising recent advances in basic research identifying and testing novel therapeutic strategies in FXS models, and evaluate their potential therapeutic benefits. We provide an overview of recent and ongoing clinical trials motivated by some of these findings, and discuss the challenges for both basic science and clinical applications in the continued development of effective disease mechanism-targeted therapies for FXS.

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Age-Dependent and Selective Impairment of Long-Term Potentiation in the Anterior Piriform Cortex of Mice Lacking the Fragile X Mental Retardation Protein

Cited by 121 publications

References 62 publications

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

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

Characterization and reversal of synaptic defects in the amygdala in a mouse model of fragile X syndrome

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

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