scholarly journals Hippocampal circuit abnormalities in MeCP2+/- mouse model of Rett syndrome

2015 ◽  
Author(s):  
Julia Chartove ◽  
Wenlin Liao ◽  
Aniqa Hassan ◽  
Mary McMullen ◽  
Rachel White ◽  
...  
Keyword(s):  
Rett Syndrome ◽  
Hippocampal Slices ◽  
Period Change ◽  
Childhood And Adolescence ◽  
Developmental Arrest ◽  
Developmental Regression ◽  
Stratum Oriens ◽  
Local Functional ◽  
Inhibitory Components ◽  
Evoked Activity

Rett syndrome (RTT) has a complex developmental course over childhood and adolescence. Patients with RTT often have a pre-symptomatic period with no or little outward signs of the disorder, followed by developmental arrest and regression. Following regression, the individual's condition is not static, as they often progress into defined stages with unique neurological symptoms. Similarly, the progression of RTT-like symptoms in female mice heterozygous for a null-mutation has a prodromal and symptomatic period. Change in functional local circuit connectivity was studied using hippocampal slices, assaying Schaffer evoked activity in area CA1 using fast voltage sensitive dye imaging. With this technique the local functional interactions between the excitatory and inhibitory components of the circuit can be characterized. The prodromal period was associated with a shift in extent of excitation into the stratum oriens of the hippocampus and reduced sensitivity to changes in divalent cation concentration. These data suggest that hyperexcitability of the hippocampus at the circuit level may contribute to the prodromal reduction in cognitive performance and the onset of developmental regression.

Rett syndrome and developmental regression

2019 ◽  
Vol 104 ◽  
pp. 100-101
Author(s):  
Eric E. Smeets ◽  
Gillian S. Townend ◽  
Leopold M.G. Curfs
Keyword(s):  
Rett Syndrome ◽  
Developmental Regression

Long-Term Depression of Temporoammonic-CA1 Hippocampal Synaptic Transmission

1999 ◽  
Vol 81 (3) ◽  
pp. 1036-1044 ◽  
Author(s):  
Hannah Dvorak-Carbone ◽  
Erin M. Schuman
Keyword(s):  
Synaptic Transmission ◽  
Calcium Influx ◽  
Hippocampal Slices ◽  
Low Frequency ◽  
Nmda Receptor Antagonist ◽  
Long Term Depression ◽  
Field Recordings ◽  
Old Rats ◽  
Inhibitory Components

Long-term depression of temporoammonic-CA1 hippocampal synaptic transmission. The temporoammonic pathway, the direct projection from layer III of the entorhinal cortex to area CA1 of the hippocampus, includes both excitatory and inhibitory components that are positioned to be an important source of modulation of the hippocampal output. However, little is known about synaptic plasticity in this pathway. We used field recordings in hippocampal slices prepared from mature (6- to 8-wk old) rats to study long-term depression (LTD) in the temporoammonic pathway. Low-frequency (1 Hz) stimulation (LFS) for 10 min resulted in a depression of the field response that lasted for ≥1 h. This depression was saturable by multiple applications of LFS. LTD induction was unaffected by the blockade of either fast (GABAA) or slow (GABAB) inhibition. Temporoammonic LTD was inhibited by the presence of the N-methyl-d-aspartate (NMDA) receptor antagonist AP5, suggesting a dependence on calcium influx. Full recovery from depression could be induced by high-frequency (100 Hz) stimulation (HFS); in the presence of the GABAA antagonist bicuculline, HFS induced recovery above the original baseline level. Similarly, HFS or θ-burst stimulation (TBS) applied to naive slices caused little potentiation, whereas HFS or TBS applied in the presence of bicuculline resulted in significant potentiation of the temporoammonic response. Our results show that, unlike the Schaffer collateral input to CA1, the temporoammonic input in mature animals is easy to depress but difficult to potentiate.

Enhanced Hypoxia Susceptibility in Hippocampal Slices From a Mouse Model of Rett Syndrome

2009 ◽  
Vol 101 (2) ◽  
pp. 1016-1032 ◽  
Author(s):  
Marc Fischer ◽  
Julia Reuter ◽  
Florian J. Gerich ◽  
Belinda Hildebrandt ◽  
Sonja Hägele ◽  
...  
Keyword(s):  
Rett Syndrome ◽  
Molecular Mechanisms ◽  
Pyramidal Neurons ◽  
Neurodevelopmental Disorder ◽  
Hippocampal Slices ◽  
Field Potential ◽  
Synaptic Function ◽  
Cell Swelling ◽  
Arterial Oxygen ◽  
Ca1 Pyramidal Neurons

Rett syndrome is a neurodevelopmental disorder caused by mutations in the X-chromosomal MECP2 gene encoding for the transcriptional regulator methyl CpG binding protein 2 (MeCP2). Rett patients suffer from episodic respiratory irregularities and reduced arterial oxygen levels. To elucidate whether such intermittent hypoxic episodes induce adaptation/preconditioning of the hypoxia-vulnerable hippocampal network, we analyzed its responses to severe hypoxia in adult Rett mice. The occurrence of hypoxia-induced spreading depression (HSD)—an experimental model for ischemic stroke—was hastened in Mecp2− /y males. The extracellular K+ rise during HSD was attenuated in Mecp2− /y males and the input resistance of CA1 pyramidal neurons decreased less before HSD onset. CA1 pyramidal neurons were smaller and more densely packed, but the cell swelling during HSD was unaffected. The intrinsic optical signal and the propagation of HSD were similar among the different genotypes. Basal synaptic function was intact, but Mecp2− /y males showed reduced paired-pulse facilitation and higher field potential/fiber volley ratios, but no increased seizure susceptibility. Synaptic failure during hypoxia was complete in all genotypes and the final degree of posthypoxic synaptic recovery indistinguishable. Cellular ATP content was normal in Mecp2− /y males, but their hematocrit was increased as was HIF-1α expression throughout the brain. This is the first study showing that in Rett syndrome, the susceptibility of telencephalic neuronal networks to hypoxia is increased; the underlying molecular mechanisms apparently involve disturbed K+ channel function. Such an increase in hypoxia susceptibility may potentially contribute to the vulnerability of male Rett patients who are either not viable or severely disabled.

scholarly journals MeCP2: The Genetic Driver of Rett Syndrome Epigenetics

2021 ◽  
Vol 12 ◽  
Author(s):  
Katrina V. Good ◽  
John B. Vincent ◽  
Juan Ausió
Keyword(s):  
Rett Syndrome ◽  
Neuronal Development ◽  
Neurodevelopmental Disorder ◽  
Epigenetic Mark ◽  
Initial Development ◽  
Genetic Ablation ◽  
Developmental Regression ◽  
The Stability ◽  
The Brain

Mutations in methyl CpG binding protein 2 (MeCP2) are the major cause of Rett syndrome (RTT), a rare neurodevelopmental disorder with a notable period of developmental regression following apparently normal initial development. Such MeCP2 alterations often result in changes to DNA binding and chromatin clustering ability, and in the stability of this protein. Among other functions, MeCP2 binds to methylated genomic DNA, which represents an important epigenetic mark with broad physiological implications, including neuronal development. In this review, we will summarize the genetic foundations behind RTT, and the variable degrees of protein stability exhibited by MeCP2 and its mutated versions. Also, past and emerging relationships that MeCP2 has with mRNA splicing, miRNA processing, and other non-coding RNAs (ncRNA) will be explored, and we suggest that these molecules could be missing links in understanding the epigenetic consequences incurred from genetic ablation of this important chromatin modifier. Importantly, although MeCP2 is highly expressed in the brain, where it has been most extensively studied, the role of this protein and its alterations in other tissues cannot be ignored and will also be discussed. Finally, the additional complexity to RTT pathology introduced by structural and functional implications of the two MeCP2 isoforms (MeCP2-E1 and MeCP2-E2) will be described. Epigenetic therapeutics are gaining clinical popularity, yet treatment for Rett syndrome is more complicated than would be anticipated for a purely epigenetic disorder, which should be taken into account in future clinical contexts.

Mechanisms of selective long-term potentiation of excitatory synapses in stratum oriens/alveus interneurons of rat hippocampal slices

1995 ◽  
Vol 73 (2) ◽  
pp. 810-819 ◽  
Author(s):  
M. Ouardouz ◽  
J. C. Lacaille
Keyword(s):  
Receptor Antagonist ◽  
Hippocampal Slices ◽  
Long Term Potentiation ◽  
Peak Amplitude ◽  
Excitatory Synapses ◽  
Metabotropic Glutamate ◽  
Stratum Oriens ◽  
Term Potentiation ◽  
The Mean

1. We investigated long-term potentiation (LTP) of synaptic transmission in different populations of interneurons in the CA1 region of rat hippocampal slices using whole cell recordings. We elicited excitatory postsynaptic currents (EPSCs) in interneurons located in stratum oriens near the alveus (O/A) or in stratum lacunosum-moleculare near the stratum radiatum border (L-M) by electrical stimulation of nearby axons in stratum oriens and radiatum, respectively. 2. High-frequency stimulation (100 Hz, 1 s) of axons in conjunction with postsynaptic depolarization (to -20 mV) increased the peak amplitude of test EPSCs elicited at -80 mV in O/A interneurons. The mean peak amplitude of EPSCs was significantly potentiated relative to the control period at 10 min (39 +/- 7% increase, mean +/- SE; n = 11 cells) and 30 min (30 +/- 1% increase; n = 5 cells) after tetanization. Similar stimulation did not produce potentiation of EPSCs in L-M interneurons (n = 7 cells). 3. This selective LTP in O/A interneurons was reversibly blocked by the N-methyl-D-aspartate receptor antagonist (+/-)2-amino-5-phosphonopentanoic acid (AP-5). Tetanization in the presence of 25 microM AP-5 did not increase the amplitude of EPSCs (8 cells). After washout of AP-5 (4 cells), a second tetanization resulted in long-term potentiation of EPSCs. 4. LTP was dependent on the activation of metabotropic glutamate receptors. The peak amplitude of EPSCs was not increased 5-10 or 15-20 min after tetanization during bath application of the metabotropic glutamate receptor antagonist (RS)-alpha-methyl-4-carboxyphenylglycine (500 microM) (n = 5 cells). 5. Inclusion of the Ca2+ chelator 1,2-bis(2-aminophenoxy)-ethane-N,N,N',N'-tetraacetic acid (BAPTA; 25 mM) in the patch pipette blocked LTP in O/A interneurons. In five cells recorded with BAPTA-containing electrodes, the mean peak amplitude was not significantly increased after tetanization. Thus a rise in postsynaptic intracellular Ca2+ appeared necessary for the induction of LTP in these interneurons. 6. Incubation of slices with the inhibitor of nitric oxide synthase N omega-nitro-L-arginine methyl ester (100 microM) before and throughout the recording session also blocked the increase in EPSC amplitude at 5-10 min (5 cells) and 15-20 min (3 cells) after tetanization. NO synthesis may therefore be necessary for LTP in O/A interneurons. 7. These results suggest that LTP of excitatory synapses is selectively produced in O/A but not L-M interneurons, and that this LTP shares similar characteristics with LTP in hippocampal CA1 pyramidal cells.(ABSTRACT TRUNCATED AT 400 WORDS)

scholarly journals Rett Syndrome: A Case report

1970 ◽  
Vol 28 (1) ◽  
pp. 17-19
Author(s):  
M Shrestha ◽  
A Rajbhandari
Keyword(s):  
Case Report ◽  
Rett Syndrome ◽  
Developmental Disorder ◽  
Hand Function ◽  
Hand Movements ◽  
Clonic Convulsion ◽  
Developmental Regression ◽  
Severe Intellectual Disability ◽  
The World ◽  
Key Words Rett Syndrome

Rett syndrome (RS) is a severe neuro-developmental disorder leading to severe intellectual disability in females all around the world. A four-year-old girl from Kathmandu presented with classic features of Rett syndrome (RS), including developmental regression with dementia, loss of acquired speech and hand function, and stereotypic hand movements along with generalized tonic clonic convulsion. Key words: Rett Syndrome, Developmental Regression   DOI = 10.3126/jnps.v28i1.1401   J. Nepal Paediatr. Soc. Vol.28(1) p.17-19

scholarly journals Deficits in Skilled Motor and Auditory Learning in a Rat Model of Rett Syndrome

2020 ◽  
Author(s):  
Katherine S. Adcock ◽  
Abigail E. Blount ◽  
Robert A. Morrison ◽  
Amanda Alvarez-Dieppa ◽  
Michael P. Kilgard ◽  
...  
Keyword(s):  
Rett Syndrome ◽  
Discrimination Task ◽  
Neurodevelopmental Disorder ◽  
Motor Task ◽  
Speech Discrimination ◽  
Auditory Learning ◽  
Reaching Task ◽  
Developmental Regression ◽  
Learning Rates ◽  
And Performance

Abstract Background: Rett Syndrome is an X-linked neurodevelopmental disorder caused by a mutation in the gene MECP2. Individuals with Rett Syndrome display developmental regression at an early age, and develop a range of motor, auditory, cognitive and social impairments. Several studies have successfully modeled some aspects of dysfunction and Rett Syndrome-like phenotypes in transgenic mouse and rat models bearing mutations in the MECP2 gene. Here, we sought to extend these findings and characterize skilled learning, a more complex behavior known to be altered in Rett syndrome. Methods: We evaluated the acquisition and performance of auditory and motor function on two complex tasks in heterozygous female Mecp2 rats. Animals were trained to perform a speech discrimination task or a skilled forelimb reaching task. Results: Our results reveal that Mecp2 rats display slower acquisition and reduced performance on an auditory discrimination task than wild-type (WT) littermates. Similarly, Mecp2 rats exhibit impaired learning rates and worse performance on a skilled forelimb motor task compared to WT. Conclusions: Together, these findings illustrate novel deficits in skilled learning consistent with clinical manifestation of Rett syndrome and provide a framework for development of therapeutic strategies to improve these complex behaviors.

Modulation of extracellular pH by glutamate and GABA in rat hippocampal slices

1992 ◽  
Vol 67 (1) ◽  
pp. 29-36 ◽  
Author(s):  
J. C. Chen ◽  
M. Chesler
Keyword(s):  
Hippocampal Slices ◽  
Extracellular Ph ◽  
Gamma Aminobutyric Acid ◽  
Local Pressure ◽  
Schaffer Collateral ◽  
Ca1 Region ◽  
Stratum Oriens ◽  
Alkaline Shift ◽  
Similar Appearance ◽  
Stimulation Of

1. Alkaline extracellular pH transients evoked by afferent stimulation, and local pressure ejection of glutamate and gamma-aminobutyric acid (GABA), were studied in the CA1 region of rat hippocampal slices. Amino acid-evoked responses were obtained by use of a dual micromanipulator, with the tip of a double-barreled pH-sensitive microelectrode positioned 50 microns from a pressure ejection pipette. 2. At 31 degrees C, in Ringer solutions buffered with 26 mM HCO3- and 5% CO2, mean extracellular pH in submerged 300-microns slices was 7.15 +/- 0.12 (n = 27 slices), at a tissue depth of approximately 150 microns. In Ringer buffered with 35 mM HCO3- and 5% CO2, extracellular pH was 7.29 +/- 0.10 (n = 19 slices). 3. Repetitive stimulation of the Schaffer collaterals caused an extracellular alkaline shift in stratum oriens, pyramidale, and radiatum, averaging 0.05 +/- 0.03 pH units among all regions (n = 138), with a maximum response of 0.16 pH units. Alkaline transients of similar appearance were obtained by local ejection of glutamate (0.01-0.12 pH units, n = 110) and GABA (0.01-0.18 pH units, n = 137). Control ejection of these amino acids into dilute agar caused only small acid shifts. 4. Superfusion of 100 microM picrotoxin abolished the GABA-evoked alkaline shift but failed to inhibit the Schaffer collateral- and glutamate-evoked alkalinizations. 5. Superfusion of 10(-5)-10(-3) M acetazolamide acidified the baseline by 0.05-0.10 pH units and amplified the Schaffer collateral- and glutamate-evoked alkaline shifts.(ABSTRACT TRUNCATED AT 250 WORDS)

scholarly journals Deficits in skilled motor and auditory learning in a rat model of Rett syndrome

2020 ◽  
Vol 12 (1) ◽  
Author(s):  
Katherine S. Adcock ◽  
Abigail E. Blount ◽  
Robert A. Morrison ◽  
Amanda Alvarez-Dieppa ◽  
Michael P. Kilgard ◽  
...  
Keyword(s):  
Rett Syndrome ◽  
Discrimination Task ◽  
Neurodevelopmental Disorder ◽  
Motor Task ◽  
Speech Discrimination ◽  
Auditory Learning ◽  
Reaching Task ◽  
Developmental Regression ◽  
Learning Rates ◽  
And Performance

Abstract Background Rett syndrome is an X-linked neurodevelopmental disorder caused by a mutation in the gene MECP2. Individuals with Rett syndrome display developmental regression at an early age, and develop a range of motor, auditory, cognitive, and social impairments. Several studies have successfully modeled some aspects of dysfunction and Rett syndrome-like phenotypes in transgenic mouse and rat models bearing mutations in the MECP2 gene. Here, we sought to extend these findings and characterize skilled learning, a more complex behavior known to be altered in Rett syndrome. Methods We evaluated the acquisition and performance of auditory and motor function on two complex tasks in heterozygous female Mecp2 rats. Animals were trained to perform a speech discrimination task or a skilled forelimb reaching task. Results Our results reveal that Mecp2 rats display slower acquisition and reduced performance on an auditory discrimination task than wild-type (WT) littermates. Similarly, Mecp2 rats exhibit impaired learning rates and worse performance on a skilled forelimb motor task compared to WT. Conclusions Together, these findings illustrate novel deficits in skilled learning consistent with clinical manifestation of Rett syndrome and provide a framework for development of therapeutic strategies to improve these complex behaviors.

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