Synaptic circuit abnormalities of motor-frontal layer 2/3 pyramidal neurons in a mutant mouse model of Rett syndrome
Section snippets
MeCP2−/y mice
Male wild type (WT) and hemizygous MeCP2−/y littermates were obtained from colonies of heterozygous mutant females and WT males (MeCP2tm1.1Bird, Jackson Laboratories) (Guy et al., 2001). Experiments involving MeCP2−/y mice were performed with the experimenter blind to genotype. Tail samples were collected at the time of recordings, and genotyped according to the vendor's PCR protocol (http://jaxmice.jax.org). Primers were MeCP2-common (5′-ggT AAA gAC CCA TgT gAC CC-3), MeCP2 wild type (5′-ggC
Reduced cortical thickness in MeCP2−/y mice
We prepared brain slices from 3 to 4 week old mice, using an off-sagittal angle to obtain slices with M1 and adjacent somatosensory (S1) cortex (Weiler et al., 2008) (Figs. 1 A, B). M1 was identified as agranular cortex anterior to somatosensory ‘barrel’ cortex. Because cortical thickness has been shown to be reduced in older MeCP2-null mice (Fukuda et al., 2005, Kishi and Macklis, 2004), we examined M1 cortical thickness in these slices prepared from WT (Fig. 1A) and mutant (Fig. 1B) mice.
Discussion
In this study we examined neocortical synaptic circuits in presymptomatic hemizygous male MeCP2tm1.1Bird mice (“Bird” strain, in which exons 3 and 4 of the MeCP2 gene are deleted), a model of RTT (Guy et al., 2001). We used LSPS to map local sources of excitatory input to L2/3 pyramidal neurons in the motor-frontal area of WT and MeCP2−/y mice. We observed a reduction in excitatory synaptic input, extending previous observations of generally decreased excitation onto cortical neurons (Chao et
Acknowledgments
We thank M. Bevan, A. Contractor, M. Hooks, G. Maccaferri, and M. Tresch for valuable input. We are especially grateful to N. Weiler for experimental efforts in the early stages of this work and for comments on earlier drafts. We thank M. Hooks for statistical advice and comments on a draft. Support: Simons Foundation, Rett Syndrome Research Foundation (International Rett Syndrome Foundation), and National Institutes of Health (NS061534 to LW; NS061963 to GS).
References (35)
Precise development of functional and anatomical columns in the neocortex
Neuron
(2004)Photochemical and pharmacological evaluation of 7-nitroindolinyl-and 4-methoxy-7-nitroindolinyl-amino acids as novel, fast caged neurotransmitters
J. Neurosci. Methods
(2001)- et al.
The story of Rett syndrome: from clinic to neurobiology
Neuron
(2007) MeCP2 controls excitatory synaptic strength by regulating glutamatergic synapse number
Neuron
(2007)- et al.
MECP2 is progressively expressed in post-migratory neurons and is involved in neuronal maturation rather than cell fate decisions
Mol. Cell. Neurosci.
(2004) - et al.
MeCP2 dysfunction in Rett syndrome and related disorders
Curr. Opin. Genet. Dev.
(2006) Rett syndrome. Current status and new vistas
Neurol. Clin.
(2002)Mice with truncated MeCP2 recapitulate many Rett syndrome features and display hyperacetylation of histone H3
Neuron
(2002)Circuit analysis of experience-dependent plasticity in the developing rat barrel cortex
Neuron
(2003)Homeostatic signaling: the positive side of negative feedback
Curr. Opin. Neurobiol.
(2007)
Rett syndrome is caused by mutations in X-linked MECP2, encoding methyl-CpG-binding protein 2
Nat. Genet.
Robust short-latency perisomatic inhibition onto neocortical pyramidal cells detected by laser-scanning photostimulation
J. Neurosci.
Interdigitated paralemniscal and lemniscal pathways in the mouse barrel cortex
PLoS Biol.
Circuit and plasticity defects in the developing somatosensory cortex of FMR1 knock-out mice
J. Neurosci.
Deficiency of methyl-CpG binding protein-2 in CNS neurons results in a Rett-like phenotype in mice
Nat. Genet.
Communication between the synapse and the nucleus in neuronal development, plasticity, and disease
Annu. Rev. Cell Dev. Biol.
Mild overexpression of MeCP2 causes a progressive neurological disorder in mice
Hum. Mol. Genet.
Cited by (46)
Critical periods and Autism Spectrum Disorders, a role for sleep
2023, Neurobiology of Sleep and Circadian RhythmsRett Syndrome: A Timely Review From Recognition to Current Clinical Approaches and Clinical Study Updates
2021, Seminars in Pediatric NeurologySensory evoked potentials in patients with Rett syndrome through the lens of animal studies: Systematic review
2020, Clinical NeurophysiologyCitation Excerpt :Taken together, these findings suggest a distinct role for Mecp2 deficiency in the regulation of evoked excitatory neurotransmission compared with its role in spontaneous synaptic activity in auditory cortex. Moreover, given opposite changes in evoked excitation following an Mecp2 knockout in neural assemblies of auditory and visual cortex of RTT animal models (see Section 3.2.2 below), the consequences of Mecp2 deficiency for E/I transmission balance are highly region-specific and may differ even between cortical layers within the same cortical region (Wood et al., 2009; Wood and Shepherd, 2010). A profound reduction of the cortical neuronal responses following stimulus repetition is called auditory forward masking (also termed forward suppression).
Altered trajectories of neurodevelopment and behavior in mouse models of Rett syndrome
2019, Neurobiology of Learning and Memory