Visual evoked potentials detect cortical processing deficits in <scp>R</scp>ett syndrome

LeBlanc, Jocelyn J.; DeGregorio, Geneva; Centofante, Eleonora; Vogel‐Farley, Vanessa; Barnes, Katherine; Kaufmann, Walter E.; Fagiolini, Michela; Nelson, Charles A.

doi:10.1002/ana.24513

Cited by 105 publications

(129 citation statements)

References 42 publications

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“…RTT is marked by arrested development of visual processing (33), atypical visually evoked cortical responses (34,35), deficits in visual attention and recognition, and unusual gaze intensity (36). In primary visual cortex (V1), "simple" stimuli, such as oriented gratings, and "complex" stimuli, such as natural scenes, activate local and distributed circuits that lead to well-defined responses from visual cortex neurons (37)(38)(39)(40)(41).…”

Section: Significancementioning

confidence: 99%

Jointly reduced inhibition and excitation underlies circuit-wide changes in cortical processing in Rett syndrome

Banerjee

Rikhye

Breton-Provencher

et al. 2016

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

154

202

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Rett syndrome (RTT) arises from loss-of-function mutations in methyl-CpG binding protein 2 gene (Mecp2), but fundamental aspects of its physiological mechanisms are unresolved. Here, by whole-cell recording of synaptic responses in MeCP2 mutant mice in vivo, we show that visually driven excitatory and inhibitory conductances are both reduced in cortical pyramidal neurons. The excitation-to-inhibition (E/I) ratio is increased in amplitude and prolonged in time course. These changes predict circuit-wide reductions in response reliability and selectivity of pyramidal neurons to visual stimuli, as confirmed by two-photon imaging. and increases KCC2 expression to normalize the KCC2/NKCC1 ratio. Thus, loss of MeCP2 in the brain alters both excitation and inhibition in brain circuits via multiple mechanisms. Loss of MeCP2 from a specific interneuron subtype contributes crucially to the cell-specific and circuit-wide deficits of RTT. The joint restoration of inhibition and excitation in cortical circuits is pivotal for functionally correcting the disorder.MeCP2 | E/I balance | parvalbumin neurons | IGF1 | chloride transporters S ynaptic excitation (E) and inhibition (I), along with the neuronal balance of excitation and inhibition (E/I), is key to the function of brain circuits, and is often disrupted in neurodevelopmental disorders, including autism spectrum disorders (ASDs) (1-3). Rett syndrome (RTT) is a severe neurodevelopmental and adult disorder that arises from sporadic loss-of-function mutations in the X-linked (Xq28) methyl-CpG binding protein 2 gene (Mecp2) encoding the protein MeCP2 (4-7). MeCP2 is a critical regulator of brain development and adult neural function (8), and arrested brain maturation due to synaptic dysfunction is one of the hallmarks of RTT (3). However, the effects of MeCP2 on excitatory and inhibitory synaptic mechanisms in vivo, and on neuronal and circuit function underlying RTT pathophysiology, are unknown.MeCP2 is ubiquitously expressed in multiple cell types and subregions of the brain (4, 6, 9), including inhibitory interneurons, and has cell-autonomous as well as non-cell-autonomous effects (10); thus, it has been particularly challenging to identify its role in cell-specific brain circuits. Anatomically diverse inhibitory interneuron subtypes with distinct physiological signatures influence different aspects of neocortical function and behavior (11,12). Soma-targeting parvalbumin-expressing (PV + ) and dendritetargeting somatostatin-expressing (SOM + ) interneurons are the two major nonoverlapping populations of interneurons in mice that target cortical pyramidal neurons (13). Inhibition by PV + and SOM + neurons powerfully influences neuronal responses and circuit computations in visual cortex (14-17). Deletion of MeCP2 from all forebrain GABAergic interneurons recapitulates key aspects of RTT (18), demonstrating that altered inhibitory function is an important facet of RTT pathophysiology. Indeed, a major phenotype of MeCP2 reduction in individuals with RTT and in mouse models is ...

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Section: Significancementioning

confidence: 99%

Jointly reduced inhibition and excitation underlies circuit-wide changes in cortical processing in Rett syndrome

Banerjee

Rikhye

Breton-Provencher

et al. 2016

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

154

202

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“…Consequently, it is critical to develop methods for detecting the stages of RTT and monitoring neuronal and glial abnormalities in a noninvasive manner. These biomarkers are becoming available; examples include blood-based assays of monocyte/microglia glutamate release [59] and neurophysiologic indices of disease progression [79]. However, more work needs to be done in this area in order to more accurately match pathophysiology and treatment in RTT.…”

Section: Genetics Neurobiology and Bases For New Treatmentsmentioning

confidence: 99%

“…enhanced NMDA receptor activity and regression), whether a particular individual is experiencing such an abnormality in neurotransmission is unclear. Data from mouse models are not easy to translate to patient populations; availability of biomarkers reflecting neurotransmitter or synaptic abnormalities is essential and some progress has been made in this area [59,79]. Another challenge is to determine which neurotransmitter(s) to target when more than one is presumably involved.…”

Section: Drugs Tested In Rtt Trialsmentioning

confidence: 99%

“…There is great interest in developing biomarkers that can detect drug effects and, consequently, be used as endpoints. Although some progress has been made in this area in FXS and autism spectrum disorder [123,124], limited efforts have been reported in RTT [25,59,79]. Objective outcome measures may not only impact clinical trial design but also clinical care.…”

Section: Outcome Measures and Biomarkers In Rtt Trialsmentioning

confidence: 99%

“…Nevertheless, if efficacy is demonstrated at older ages (i.e. using 12 months after the loss of the last skill as the operational definition of post-regression) [79], optimizing dosage and administration may demonstrate unquestionably a drug’s positive effects. Similarly, although the decline at the other end of the age spectrum is less pronounced, strategies applied to neurodegenerative disorders could assist with trial design and analysis for studies of adults with RTT.…”

Section: Expert Opinion: the Unique And Common Challenges In Developimentioning

confidence: 99%

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Neurobiologically-based treatments in Rett syndrome: opportunities and challenges

Kaufmann

Stallworth

Everman

et al. 2016

Expert Opinion on Orphan Drugs

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Introduction: Rett syndrome (RTT) is an X-linked neurodevelopmental disorder that primarily affects females, typically resulting in a period of developmental regression in early childhood followed by stabilization and severe chronic cognitive, behavioral, and physical disability. No known treatment exists beyond symptomatic management, and while insights into the genetic cause, pathophysiology, neurobiology, and natural history of RTT have been gained, many challenges remain. Areas covered: Based on a comprehensive survey of the primary literature on RTT, this article describes and comments upon the general and unique features of the disorder, genetic and neurobiological bases of drug development, and the history of clinical trials in RTT, with an emphasis on drug trial design, outcome measures, and implementation. Expert opinion: Neurobiologically based drug trials are the ultimate goal in RTT, and due to the complexity and global nature of the disorder, drugs targeting both general mechanisms (e.g., growth factors) and specific systems (e.g., glutamate modulators) could be effective. Trial design should optimize data on safety and efficacy, but selection of outcome measures with adequate measurement properties, as well as innovative strategies, such as those enhancing synaptic plasticity and use of biomarkers, are essential for progress in RTT and other neurodevelopmental disorders.

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Behavioral and transcriptomic analyses of mecp2 function in zebrafish

Santistevan,

Ford,

Gilsdorf

et al. 2024

American J of Med Genetics Pt B

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Rett syndrome (RTT), a human neurodevelopmental disorder characterized by severe cognitive and motor impairments, is caused by dysfunction of the conserved transcriptional regulator Methyl‐CpG‐binding protein 2 (MECP2). Genetic analyses in mouse Mecp2 mutants, which exhibit key features of human RTT, have been essential for deciphering the mechanisms of MeCP2 function; nonetheless, our understanding of these complex mechanisms is incomplete. Zebrafish mecp2 mutants exhibit mild behavioral deficits but have not been analyzed in depth. Here, we combine transcriptomic and behavioral assays to assess baseline and stimulus‐evoked motor responses and sensory filtering in zebrafish mecp2 mutants from 5 to 7 days post‐fertilization (dpf). We show that zebrafish mecp2 function is required for normal thigmotaxis but is dispensable for gross movement, acoustic startle response, and sensory filtering (habituation and sensorimotor gating), and reveal a previously unknown role for mecp2 in behavioral responses to visual stimuli. RNA‐seq analysis identified a large gene set that requires mecp2 function for correct transcription at 4 dpf, and pathway analysis revealed several pathways that require MeCP2 function in both zebrafish and mammals. These findings show that MeCP2's function as a transcriptional regulator is conserved across vertebrates and supports using zebrafish to complement mouse modeling in elucidating these conserved mechanisms.

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Visual evoked potentials detect cortical processing deficits in Rett syndrome

Cited by 105 publications

References 42 publications

Jointly reduced inhibition and excitation underlies circuit-wide changes in cortical processing in Rett syndrome

Jointly reduced inhibition and excitation underlies circuit-wide changes in cortical processing in Rett syndrome

Neurobiologically-based treatments in Rett syndrome: opportunities and challenges

Behavioral and transcriptomic analyses of mecp2 function in zebrafish

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