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Autism: A "Critical Period" Disorder?

Jocelyn J. LeBlanc, Michela Fagiolini
2011 Neural Plasticity  
Cortical circuits in the brain are refined by experience during critical periods early in postnatal life. Critical periods are regulated by the balance of excitatory and inhibitory (E/I) neurotransmission in the brain during development. There is now increasing evidence of E/I imbalance in autism, a complex genetic neurodevelopmental disorder diagnosed by abnormal socialization, impaired communication, and repetitive behaviors or restricted interests. The underlying cause is still largely
more » ... n and there is no fully effective treatment or cure. We propose that alteration of the expression and/or timing of critical period circuit refinement in primary sensory brain areas may significantly contribute to autistic phenotypes, including cognitive and behavioral impairments. Dissection of the cellular and molecular mechanisms governing well-established critical periods represents a powerful tool to identify new potential therapeutic targets to restore normal plasticity and function in affected neuronal circuits.
doi:10.1155/2011/921680 pmid:21826280 pmcid:PMC3150222 fatcat:omimiy5aybbg3hbhoksgjvgrq4

Cortical Feedback Regulates Feedforward Retinogeniculate Refinement

Andrew D. Thompson, Nathalie Picard, Lia Min, Michela Fagiolini, Chinfei Chen
2016 Neuron  
note here that the experience-dependent phase of retinogeniculate development overlaps with critical periods in primary visual cortex (V1), which also requires visual experience to develop normally (Fagiolini  ...  model also provides an explanation for our previous observation that mice dark-reared from birth prune retinogeniculate inputs effectively, as chronic deprivation delays maturation of visual cortex (Fagiolini  ... 
doi:10.1016/j.neuron.2016.07.040 pmid:27545712 pmcid:PMC5156570 fatcat:4tfqscdyvrgmjnz5snq6ccvz4m

Anatomical Correlates of Functional Plasticity in Mouse Visual Cortex

Antonella Antonini, Michela Fagiolini, Michael P. Stryker
1999 Journal of Neuroscience  
., 1980; rat: Fagiolini et al., 1994) .  ...  Some of these results have been presented in abstract (Fagiolini et al., 1997) .  ... 
doi:10.1523/jneurosci.19-11-04388.1999 pmid:10341241 pmcid:PMC2452998 fatcat:euamqz7xnjgkzlyq7w5slz6r5a

Epigenetic influences on brain development and plasticity

Michela Fagiolini, Catherine L Jensen, Frances A Champagne
2009 Current Opinion in Neurobiology  
Current Opinion inNeurobiology 2009, Please cite this article in press as: Fagiolini M, et al.  ...  References and recommended reading Papers of particular interest, published within the period of review, have been highlighted as: of special interest of outstanding interest this article in press as: Fagiolini  ... 
doi:10.1016/j.conb.2009.05.009 pmid:19545993 pmcid:PMC2745597 fatcat:2kuyvomwgbbobj63zpeysbpmcq

Optimization of Somatic Inhibition at Critical Period Onset in Mouse Visual Cortex

Hiroyuki Katagiri, Michela Fagiolini, Takao K. Hensch
2007 Neuron  
Natural CP timing can similarly be accelerated in immature wild-type mice (Fagiolini and Hensch, 2000; Fagiolini et al., 2004) .  ...  Dark rearing from birth delays both the onset of the CP (Mower, 1991; Fagiolini et al., 1994; Hensch and Fagiolini, 2005) and the functional maturation of inhibition onto pyramidal cells (Benevento  ... 
doi:10.1016/j.neuron.2007.02.026 pmid:17359916 fatcat:eqsrfxhmdrduzoppmekqixfz54

Rapid Critical Period Induction by Tonic Inhibition in Visual Cortex

Youichi Iwai, Michela Fagiolini, Kunihiko Obata, Takao K. Hensch
2003 Journal of Neuroscience  
Typically plasticity is absent at eye opening, peaks at ϳ4 weeks, and gradually declines over weeks (rodents: Fagiolini et al., 1994; Gordon and Stryker, 1996; Fagiolini and Hensch, 2000) to months (  ...  Prolonged infusion of diazepam mimics a critical period to abolish latent plasticity in GAD65 KO mice (Fagiolini and Hensch, 2000) .  ... 
doi:10.1523/jneurosci.23-17-06695.2003 pmid:12890762 fatcat:5qgy27qxffdt7ivz7zjyxg6v3e

Sensory Integration in Mouse Insular Cortex Reflects GABA Circuit Maturation

Nadine Gogolla, Anne E. Takesian, Guoping Feng, Michela Fagiolini, Takao K. Hensch
2014 Neuron  
Establishment of proper E/I balance that outlasts early drug exposure has been shown in the primary visual cortex (Fagiolini and Hensch 2000; Iwai et al., 2003) .  ...  BTBR mice were treated for 14 days with benzodiazepine agonist, diazepam (20 mg/kg, i.p. daily) (Fagiolini and Hensch 2000) , during one of two time windows ( Figure 5A ).  ... 
doi:10.1016/j.neuron.2014.06.033 pmid:25088363 pmcid:PMC4177076 fatcat:zd3k4ld3knandgktiozafnquom

Brain mapping across 16 autism mouse models reveals a spectrum of functional connectivity subtypes [article]

Valerio Zerbi, Marco Pagani, Marija Markicevic, Michela Matteoli, Davide Pozzi, Michela Fagiolini, Yuri Bozzi, Alberto Galbusera, Maria Luisa Scattoni, Giovanni Provenzano, Abhishek Banerjee, Fritjof Helmchen (+6 others)
2020 bioRxiv   pre-print
Autism Spectrum Disorder (ASD) is characterized by substantial, yet highly heterogeneous abnormalities in functional brain connectivity. However, the origin and significance of this phenomenon remain unclear. To unravel ASD connectopathy and relate it to underlying etiological heterogeneity, we carried out a bi-center cross-etiological investigation of fMRI-based connectivity in the mouse, in which specific ASD-relevant mutations can be isolated and modelled minimizing environmental
more » ... s. By performing brain-wide connectivity mapping across 16 mouse mutants, we show that different ASD-associated etiologies cause a broad spectrum of connectional abnormalities in which diverse, often diverging, connectivity signatures are recognizable. Despite this heterogeneity, the identified connectivity alterations could be classified into four subtypes characterized by discrete signatures of network dysfunction. Our findings show that etiological variability is a key determinant of connectivity heterogeneity in ASD, hence reconciling conflicting findings in clinical populations. The identification of etiologically-relevant connectivity subtypes could improve diagnostic label accuracy in the non-syndromic ASD population and paves the way for personalized treatment approaches.
doi:10.1101/2020.10.15.340588 fatcat:i77avtyzdzgn3pgxrda6edsnpi

Trehalose-enhanced isolation of neuronal sub-types from adult mouse brain

Alka Saxena, Akiko Wagatsuma, Yukihiko Noro, Takenobu Kuji, Atsuko Asaka-Oba, Akira Watahiki, Cecile Gurnot, Michela Fagiolini, Takao Hensch, Piero Carninci
2012 BioTechniques  
Efficient isolation of specific, intact, living neurons from the adult brain is problematic due to the complex nature of the extracellular matrix consolidating the neuronal network. Here, we present significant improvements to the protocol for isolation of pure populations of neurons from mature postnatal mouse brain using fluorescence activated cell sorting (FACS). The 10-fold increase in cell yield enables cell-specific transcriptome analysis by protocols such as nano-CAGE and RNA seq. The
more » ... malian brain consists of a variety of projection neurons, local interneurons, glial cells and extracellular matrix factors entangled in a complex network. Mature neurons are severely damaged by enzymatic dissociation and mechanical trituration, causing extensive cell death thus hampering downstream analyses. Collection of pure neuronal subtypes for RNA extraction and expression profiling has, therefore, been challenging, especially in the case of adult brain tissue. Gene expression profiling of isolated neuronal sub-types has the power to provide a catalog of genes expressed in neuronal sub-populations. Such catalogs would not only provide the means to understand normal neuronal development and function, but also permit distinctions between healthy and diseased states, establish biomarkers for diagnostic and prognostic applications, and facilitate the design of targeted molecular therapies (1, 2).
doi:10.2144/0000113878 pmid:22668417 pmcid:PMC3696583 fatcat:yvnzkyfzuzdibi2bx7gjmsj4da

Temporal Aspects of Contrast Visual Evoked Potentials in the Pigmented Rat: Effect of Dark Rearing

1997 Vision Research  
Cortical visual evoked potentials (VEPS) in response to gratings temporally modulated in counterphase were recorded in normal and dark-reared pigmented rats. Temporal modulation was either sinusoidal (0.25-15 Hz, steady state condition) or abrupt (0.5 Hz, transient condition). In normals, the amplitude spectrum of contrast VEPShas two peaks (at about 0.5 and 4 Hz) and a high temporal frequency cut-off of the order of 11 Hz. The VEP phase lags with temporal frequency, showing two different
more » ... slopes for separate frequency ranges (0.25-1 Hz and 1-7 Hz) centred on the peaks of the curve. The different slopes correspond to apparent latencies of 500 and 136 msec, respectively. Dark rearing reduced the cut-off frequency by about 3 Hz and increased apparent Iatencies by about 42 msec in the low temporal frequency range and 30 msec in the high temporal frequency range. The latency of the first peak of transient VEPS was increased by about 47 msec. Results indicate that the frequency response of rat contrast VEPSis qualitatively similar to that of other mammals (including human), albeit shifted to a lower range of temporal frequencies. Dark rearing significantly alters the VEP temporal characteristics, suggesting that visual experience is necessary for their correct development.
doi:10.1016/s0042-6989(96)00172-1 pmid:9156170 fatcat:ceog7jpyrvf65cinfdxv44trjy

Cell-Specific Regulation of N-Methyl-D-Aspartate Receptor Maturation by Mecp2 in Cortical Circuits

Susanna B. Mierau, Annarita Patrizi, Takao K. Hensch, Michela Fagiolini
2016 Biological Psychiatry  
Background-Early postnatal experience shapes NMDA receptor (NMDAR) subunit composition and kinetics at excitatory synapses onto pyramidal cells; however, little is known about NMDAR maturation onto inhibitory interneurons. Methods-We combined whole-cell patch clamp recordings (n=440) of NMDAR-mediated currents from layer 4-to-2/3 synapses onto pyramidal and GFP-labeled parvalbumin-positive (PV) interneurons in visual cortex at three developmental ages (15, 30 & 45 postnatal days) with array
more » ... graphy 3-D reconstructions of NMDAR subunits GluN2A-and GluN2B-positive synapses onto PV cells. Results-We show that the trajectory of the NMDAR subunit switch is slower in parvalbuminpositive (PV) interneurons than in excitatory pyramidal cells in visual cortex. Notably, this differential time course is reversed in the absence of methyl-CpG-binding protein, MeCP2, the molecular basis for cognitive decline in Rett syndrome and some cases of autism. Additional genetic reduction of GluN2A subunits, which prevents regression of vision in Mecp2-knockout mice, specifically rescues the accelerated NMDAR maturation in PV cells. Conclusion-We demonstrate: (1) the time course of NMDAR maturation is cell-type specific and (2) a new cell-type specific role for Mecp2 in the development of NMDAR subunit composition. Reducing GluN2A expression in Mecp2-deficient mice, which prevents the decline in visual cortical function, also prevents the premature NMDAR maturation in PV cells. Thus,
doi:10.1016/j.biopsych.2015.05.018 pmid:26185009 pmcid:PMC4670611 fatcat:nm6infseffhghdpigmjtr4kyvm

NMDA 2A receptors in parvalbumin cells mediate sex-specific rapid ketamine response on cortical activity

Nathalie Picard, Anne E. Takesian, Michela Fagiolini, Takao K. Hensch
2019 Molecular Psychiatry  
Ketamine has emerged as a widespread treatment for a variety of psychiatric disorders when used at sub-anesthetic doses, but the neural mechanisms underlying its acute action remain unclear. Here, we identified NMDA receptors containing the 2A subunit (GluN2A) on parvalbumin (PV)-expressing inhibitory interneurons as a pivotal target of low-dose ketamine. Genetically deleting GluN2A receptors globally or selectively from PV interneurons abolished the rapid enhancement of visual cortical
more » ... s and gamma-band oscillations by ketamine. Moreover, during the follicular phase of the estrous cycle in female mice, the ketamine response was transiently attenuated along with a concomitant decrease of grin2A mRNA expression within PV interneurons. Thus, GluN2A receptors on PV interneurons mediate the immediate actions of low-dose ketamine treatment, and fluctuations in receptor expression across the estrous cycle may underlie sex-differences in drug efficacy.
doi:10.1038/s41380-018-0341-9 pmid:30696941 pmcid:PMC6756203 fatcat:2p2wxmc7onekvourmmtwx6vjxi

A Resource for Transcriptomic Analysis in the Mouse Brain

Charles Plessy, Michela Fagiolini, Akiko Wagatsuma, Norihiro Harasawa, Takenobu Kuji, Atsuko Asaka-Oba, Yukari Kanzaki, Sayaka Fujishima, Kazunori Waki, Hiroyuki Nakahara, Takao K. Hensch, Piero Carninci (+1 others)
2008 PLoS ONE  
The transcriptome of the cerebral cortex is remarkably homogeneous, with variations being stronger between individuals than between areas. It is thought that due to the presence of many distinct cell types, differences within one cell population will be averaged with the noise from others. Studies of sorted cells expressing the same transgene have shown that cell populations can be distinguished according to their transcriptional profile. Methodology: We have prepared a low-redundancy set of
more » ... 209 full-length cDNA clones which represents the transcriptome of the mouse visual cortex in its coding and non-coding aspects. Using an independent tag-based approach, CAGE, we confirmed the cortical expression of 72% of the clones. Clones were amplified by PCR and spotted on glass slides, and we interrogated the microarrays with RNA from flow-sorted fluorescent cells from the cerebral cortex of parvalbuminegfp transgenic mice. Conclusions: We provide an annotated cDNA clone collection which is particularly suitable for transcriptomic analysis in the mouse brain. Spotting it on microarrays, we compared the transcriptome of EGFP positive and negative cells in a parvalbumin-egfp transgenic background and showed that more than 30% of clones are differentially expressed. Our clone collection will be a useful resource for the study of the transcriptome of single cell types in the cerebral cortex.
doi:10.1371/journal.pone.0003012 pmid:18714383 pmcid:PMC2507754 fatcat:lok3ww2kdjhbflwlhih5ye64na

Axonal Transport Blockade in the Neonatal Rat Optic Nerve Induces Limited Retinal Ganglion Cell Death

Michela Fagiolini, Matteo Caleo, Enrica Strettoi, Lamberto Maffei
1997 Journal of Neuroscience  
., September 15, 1997, 17(18):7045-7052 Fagiolini et al. • Axonal Transport Blockade Induces Limited RGC Death  ...  ., September 15, 1997, 17(18):7045-7052 Fagiolini et al. • Axonal Transport Blockade Induces Limited RGC Death J.  ... 
doi:10.1523/jneurosci.17-18-07045.1997 pmid:9278540 pmcid:PMC6573284 fatcat:56qya7bhhnczphvuceugxxmbmy

The Stage of the Estrus Cycle Is Critical for Interpretation of Female Mouse Social Interaction Behavior

Trishala Chari, Sophie Griswold, Nick A. Andrews, Michela Fagiolini
2020 Frontiers in Behavioral Neuroscience  
ACKNOWLEDGMENTS We wish to thank Nathalie Picard from the Fagiolini lab (Boston Children's Hospital, USA) for guiding us on how to evaluate the estrus cycle in mice.  ... 
doi:10.3389/fnbeh.2020.00113 pmid:32714163 pmcid:PMC7340104 fatcat:kygh7lxxufhqdotpzg5mipikdq
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