Altered auditory processing in a mouse model of fragile X syndrome

Rotschafer, Sarah E.; Razak, Khaleel A.

doi:10.1016/j.brainres.2013.02.038

Cited by 119 publications

(144 citation statements)

References 80 publications

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“…Recent studies, both in vivo and ex vivo, have confirmed that the neocortex of Fmr1 −/y mice is hyperexcitable 11,[13][14][15] , suggesting that this is a suitable model for studying sensory hypersensitivity in FXS. A detailed cellular mechanism for neocortical hyperexcitability, however, has not yet been described.…”

Section: Discussionmentioning

confidence: 88%

“…8). Consistent with clinical studies, Fmr1 −/y mice (the mouse model for FXS) exhibit enhanced sensitivity to weak auditory stimuli 9-12 , and there is increasing evidence that the neocortex of Fmr1 −/y mice is hyperexcitable 11,[13][14][15] . Recent studies have suggested that circuits of the somatosensory cortex are altered under baseline conditions in Fmr1 −/y mice, pointing to a causative role for neocortical circuit defects in sensory hypersensitivity in FXS 13-15 .…”

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confidence: 76%

“…Although neocortical hyperexcitability under baseline conditions has been demonstrated in several procedures in Fmr1 −/y mice, sensory stimulus-evoked hyperexcitability has thus far been demonstrated only for auditory stimuli 11 . To investigate whether this phenomenon is more generally expressed in the sensory neocortex, we examined the neocortical responses to different tactile stimuli in anesthetized mice.…”

Section: S1 Of Fmr1 −/Y Mice Is Hyperexcited By Sensory Stimulusmentioning

confidence: 99%

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Dendritic channelopathies contribute to neocortical and sensory hyperexcitability in Fmr1−/y mice

et al. 2014

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Hypersensitivity in response to sensory stimuli and neocortical hyperexcitability are prominent features of Fragile X Syndrome (FXS) and autism spectrum disorders, but little is known about the dendritic mechanisms underlying these phenomena. We found that the primary somatosensory neocortex (S1) was hyperexcited in response to tactile sensory stimulation in Fmr1(-/y) mice. This correlated with neuronal and dendritic hyperexcitability of S1 pyramidal neurons, which affect all major aspects of neuronal computation, from the integration of synaptic input to the generation of action potential output. Using dendritic electrophysiological recordings, calcium imaging, pharmacology, biochemistry and a computer model, we found that this defect was, at least in part, attributable to the reduction and dysfunction of dendritic h- and BKCa channels. We pharmacologically rescued several core hyperexcitability phenomena by targeting BKCa channels. Our results provide strong evidence pointing to the utility of BKCa channel openers for the treatment of the sensory hypersensitivity aspects of FXS.

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Section: Discussionmentioning

confidence: 88%

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confidence: 76%

Section: S1 Of Fmr1 −/Y Mice Is Hyperexcited By Sensory Stimulusmentioning

confidence: 99%

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Dendritic channelopathies contribute to neocortical and sensory hyperexcitability in Fmr1−/y mice

et al. 2014

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“…50 Negative symptoms are also prominent in patients with autism, another disorder associated with the 22q11.2DS, and increased amplitude of AEPs have been reported in patients with autism-related syndromes, such as fragile X, 51 and in animal models of autism. 52,53 We have not assessed behavioural functions related to negative symptomatology in the present study. However, reports of a reduced progressive ratio response in Df(16)A+/-mice 54 supports negative symptom-like behaviour in these mice.…”

Section: J Psychiatry Neurosci 2017;42(1)mentioning

confidence: 98%

Persistent gating deficit and increased sensitivity to NMDA receptor antagonism after puberty in a new mouse model of the human 22q11.2 microdeletion syndrome: a study in male mice

Didriksen

Fejgin

Nilsson

et al. 2017

JPN

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IntroductionThe 22q11.2 hemizygous microdeletion confers very high risk for neurodevelopmental disorders, including autism and schizophrenia (22q11.2 deletion syndrome [22q11.2DS]). The estimated prevalence is approximately 1 in 2000.1 The International Consortium on Brain and Behaviour in 22q11.2 has recently reported the cumulated prevalence of schizophrenia to be 24% in adolescence and 41% in adulthood.2 Studies of patients with schizophrenia find that 22q11.2 deletion accounts for approximately 0.3% of the cases. Despite massive efforts there is still no coherent understanding of the etiology of schizophrenia -a highly heritable heterogeneous disorder with strong environmental influence. 4,5 Several neurotransmitters are implicated in the disorder: glutamate, 6 γ-aminobutyric acid (GABA), 7 dopamine (DA) 8 and acetylcholine signalling 9 have all been highlighted in the disease etiology and manifestation. The cognitive impairment and negative symptomatology have been related to dysfunction in regulation of glutamate-GABA transmission leading to excitatory-inhibitory imbalances.7 Like in individuals with schizophrenia, 10,11 cognition 12 and information processing is disrupted in children with 22q11.2 deletion, in whom schizophrenia has not (yet) developed.13,14 Given the highly increased risk for schizophrenia and the phenotypic overlap between schizophrenia and the 22q11.2DS, studying the consequence of the 22q11.2 deletion provides a unique opportunity to add to the understanding of the Background: The hemizygous 22q11.2 microdeletion is a common copy number variant in humans. The deletion confers high risk for neuro developmental disorders, including autism and schizophrenia. Up to 41% of deletion carriers experience psychotic symptoms. Methods: We present a new mouse model (Df(h22q11)/+) of the deletion syndrome (22q11.2DS) and report on, to our knowledge, the most comprehensive study undertaken to date in 22q11.2DS models. The study was conducted in male mice. Results: We found elevated postpubertal N-methyl-d-aspartate (NMDA) receptor antagonist-induced hyperlocomotion, age-independent prepulse inhibition (PPI) deficits and increased acoustic startle response (ASR). The PPI deficit and increased ASR were resistant to antipsychotic treatment. The PPI deficit was not a consequence of impaired hearing measured by auditory brain stem responses. The Df(h22q11)/+ mice also displayed increased amplitude of loudness-dependent auditory evoked potentials. Prefrontal cortex and dorsal striatal elevations of the dopamine metabolite DOPAC and increased dorsal striatal expression of the AMPA receptor subunit GluR1 was found. The Df(h22q11)/+ mice did not deviate from wild-type mice in a wide range of other behavioural and biochemical assays. Limitations: The 22q11.2 microdeletion has incomplete penetrance in humans, and the severity of disease depends on the complete genetic makeup in concert with environmental factors. In order to obtain more marked phenotypes reflecting the severe conditions related to 22q11.2DS it...

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“…1A)(Chen and Toth, 2001; Musumeci et al, 2000; Yan et al, 2005). These seizures are possibly triggered by elevated responsiveness of neurons in the auditory cortex to sound (Rotschafer and Razak, 2013), providing another example of how increased neuronal excitability in sensory cortices underlies a behavioral phenotype. Similar increases in responses in the auditory cortex are observed in the event related brain potential (ERP) recorded in the EEG in humans with FXS (Castren et al, 2003), consistent with hyperexcitability of auditory circuits associated with loss of FMRP in both mice and humans.…”

Section: Symptoms In Fxs and Parallel Phenotypes In The Mouse Model Tmentioning

confidence: 99%

Altered Neuronal and Circuit Excitability in Fragile X Syndrome

Contractor

Klyachko

Portera‐Cailliau

2015

Neuron

359

365

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Fragile X syndrome (FXS) results from a genetic mutation in a single gene, yet produces a phenotypically complex disorder with a range of neurological and psychiatric problems. Efforts to decipher how perturbations in signaling pathways lead to the myriad alterations in synaptic and cellular functions have provided insights into the molecular underpinnings of this disorder. From this large body of data the theme of circuit hyperexcitability has emerged as a potential explanation for many of the neurological and psychiatric symptoms in FXS. The mechanisms for hyperexcitability range from alterations in the expression or activity of ion channels to changes in neurotransmitters and receptors. Contributions of these processes are often brain region- and cell type-specific, resulting in complex effects on circuit function that manifest as altered excitability. Here, we review the current state of knowledge of the molecular, synaptic and circuit-level mechanisms underlying hyperexcitability and their contributions to the FXS phenotypes.

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Altered auditory processing in a mouse model of fragile X syndrome

Cited by 119 publications

References 80 publications

Dendritic channelopathies contribute to neocortical and sensory hyperexcitability in Fmr1−/y mice

Dendritic channelopathies contribute to neocortical and sensory hyperexcitability in Fmr1−/y mice

Persistent gating deficit and increased sensitivity to NMDA receptor antagonism after puberty in a new mouse model of the human 22q11.2 microdeletion syndrome: a study in male mice

Altered Neuronal and Circuit Excitability in Fragile X Syndrome

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