Publications by authors named "Susanna B Mierau"

8 Publications

  • Page 1 of 1

Neuromodulation of Spike-Timing-Dependent Plasticity: Past, Present, and Future.

Neuron 2019 08;103(4):563-581

Department of Physiology, Development and Neuroscience, University of Cambridge, Cambridge CB2 3EG, UK. Electronic address:

Spike-timing-dependent synaptic plasticity (STDP) is a leading cellular model for behavioral learning and memory with rich computational properties. However, the relationship between the millisecond-precision spike timing required for STDP and the much slower timescales of behavioral learning is not well understood. Neuromodulation offers an attractive mechanism to connect these different timescales, and there is now strong experimental evidence that STDP is under neuromodulatory control by acetylcholine, monoamines, and other signaling molecules. Here, we review neuromodulation of STDP, the underlying mechanisms, functional implications, and possible involvement in brain disorders.
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http://dx.doi.org/10.1016/j.neuron.2019.05.041DOI Listing
August 2019

Metabolic interventions in Autism Spectrum Disorder.

Neurobiol Dis 2019 12 24;132:104544. Epub 2019 Jul 24.

Lurie Center for Autism, Massachusetts General Hospital, Lexington, MA, USA; Harvard Medical School, Boston, MA USA. Electronic address:

Metabolic interventions including special diets and supplements are commonly used in Autism Spectrum Disorder (ASD). Yet little is known about how these interventions, typically initiated by caregivers, may affect metabolic function or the core symptoms of ASD. This review examines possible direct and indirect roles for metabolism in the core symptoms of ASD as well as evidence for metabolic dysfunction and nutritional deficiencies. We also discuss some of the most popular diets and supplements used in our patient population and suggest strategies for discussing the utility of these interventions with patients, families, and caregivers.
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http://dx.doi.org/10.1016/j.nbd.2019.104544DOI Listing
December 2019

Cerebral organoids at the air-liquid interface generate diverse nerve tracts with functional output.

Nat Neurosci 2019 04 18;22(4):669-679. Epub 2019 Mar 18.

MRC Laboratory of Molecular Biology, Cambridge Biomedical Campus, Cambridge, UK.

Neural organoids have the potential to improve our understanding of human brain development and neurological disorders. However, it remains to be seen whether these tissues can model circuit formation with functional neuronal output. Here we have adapted air-liquid interface culture to cerebral organoids, leading to improved neuronal survival and axon outgrowth. The resulting thick axon tracts display various morphologies, including long-range projection within and away from the organoid, growth-cone turning, and decussation. Single-cell RNA sequencing reveals various cortical neuronal identities, and retrograde tracing demonstrates tract morphologies that match proper molecular identities. These cultures exhibit active neuronal networks, and subcortical projecting tracts can innervate mouse spinal cord explants and evoke contractions of adjacent muscle in a manner dependent on intact organoid-derived innervating tracts. Overall, these results reveal a remarkable self-organization of corticofugal and callosal tracts with a functional output, providing new opportunities to examine relevant aspects of human CNS development and disease.
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http://dx.doi.org/10.1038/s41593-019-0350-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6436729PMC
April 2019

MPX-004 and MPX-007: New Pharmacological Tools to Study the Physiology of NMDA Receptors Containing the GluN2A Subunit.

PLoS One 2016 1;11(2):e0148129. Epub 2016 Feb 1.

Mnemosyne Pharmaceuticals, Inc. (formerly Luc Therapeutics) 400 Technology Square, Cambridge, MA 02139, United States of America.

GluN2A is the most abundant of the GluN2 NMDA receptor subunits in the mammalian CNS. Physiological and genetic evidence implicate GluN2A-containing receptors in susceptibility to autism, schizophrenia, childhood epilepsy and neurodevelopmental disorders such as Rett Syndrome. However, GluN2A-selective pharmacological probes to explore the therapeutic potential of targeting these receptors have been lacking. Here we disclose a novel series of pyrazine-containing GluN2A antagonists exemplified by MPX-004 (5-(((3-chloro-4-fluorophenyl)sulfonamido)methyl)-N-((2-methylthiazol-5-yl)methyl)pyrazine-2-carboxamide) and MPX-007 (5-(((3-fluoro-4-fluorophenyl)sulfonamido)methyl)-N-((2-methylthiazol-5-yl)methyl)methylpyrazine-2-carboxamide). MPX-004 and MPX-007 inhibit GluN2A-containing NMDA receptors expressed in HEK cells with IC50s of 79 nM and 27 nM, respectively. In contrast, at concentrations that completely inhibited GluN2A activity these compounds have no inhibitory effect on GluN2B or GluN2D receptor-mediated responses in similar HEK cell-based assays. Potency and selectivity were confirmed in electrophysiology assays in Xenopus oocytes expressing GluN2A-D receptor subtypes. Maximal concentrations of MPX-004 and MPX-007 inhibited ~30% of the whole-cell current in rat pyramidal neurons in primary culture and MPX-004 inhibited ~60% of the total NMDA receptor-mediated EPSP in rat hippocampal slices. GluN2A-selectivity at native receptors was confirmed by the finding that MPX-004 had no inhibitory effect on NMDA receptor mediated synaptic currents in cortical slices from GRIN2A knock out mice. Thus, MPX-004 and MPX-007 offer highly selective pharmacological tools to probe GluN2A physiology and involvement in neuropsychiatric and developmental disorders.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0148129PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4734667PMC
July 2016

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

Biol Psychiatry 2016 May 5;79(9):746-754. Epub 2015 Jun 5.

F.M. Kirby Neurobiology Center, Boston Children's Hospital, Harvard Medical School. Electronic address:

Background: Early postnatal experience shapes N-methyl-D-aspartate 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-layer-2/3 synapses onto pyramidal and green fluorescent protein labeled parvalbumin-positive (PV) interneurons in visual cortex at three developmental ages (15, 30, and 45 postnatal days) with array tomography three-dimensional 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 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.

Conclusions: 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-knockout mice, which prevents the decline in visual cortical function, also prevents the premature NMDAR maturation in PV cells. Thus, circuit-based therapies targeting NMDAR subunit composition on PV cells may provide novel treatments for Rett syndrome.
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http://dx.doi.org/10.1016/j.biopsych.2015.05.018DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4670611PMC
May 2016

Double dissociation of spike timing-dependent potentiation and depression by subunit-preferring NMDA receptor antagonists in mouse barrel cortex.

Cereb Cortex 2009 Dec 10;19(12):2959-69. Epub 2009 Apr 10.

The Neuronal Oscillations Group, Department of Physiology, Anatomy and Genetics, Oxford, OX1 3PT, UK.

Spike timing-dependent plasticity (STDP) is a strong candidate for an N-methyl-D-aspartate (NMDA) receptor-dependent form of synaptic plasticity that could underlie the development of receptive field properties in sensory neocortices. Whilst induction of timing-dependent long-term potentiation (t-LTP) requires postsynaptic NMDA receptors, timing-dependent long-term depression (t-LTD) requires the activation of presynaptic NMDA receptors at layer 4-to-layer 2/3 synapses in barrel cortex. Here we investigated the developmental profile of t-LTD at layer 4-to-layer 2/3 synapses of mouse barrel cortex and studied their NMDA receptor subunit dependence. Timing-dependent LTD emerged in the first postnatal week, was present during the second week and disappeared in the adult, whereas t-LTP persisted in adulthood. An antagonist at GluN2C/D subunit-containing NMDA receptors blocked t-LTD but not t-LTP. Conversely, a GluN2A subunit-preferring antagonist blocked t-LTP but not t-LTD. The GluN2C/D subunit requirement for t-LTD appears to be synapse specific, as GluN2C/D antagonists did not block t-LTD at horizontal cross-columnar layer 2/3-to-layer 2/3 synapses, which was blocked by a GluN2B antagonist instead. These data demonstrate an NMDA receptor subunit-dependent double dissociation of t-LTD and t-LTP mechanisms at layer 4-to-layer 2/3 synapses, and suggest that t-LTD is mediated by distinct molecular mechanisms at different synapses on the same postsynaptic neuron.
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http://dx.doi.org/10.1093/cercor/bhp067DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2774397PMC
December 2009

Dissociation of experience-dependent and -independent changes in excitatory synaptic transmission during development of barrel cortex.

Proc Natl Acad Sci U S A 2004 Oct 18;101(43):15518-23. Epub 2004 Oct 18.

University Laboratory of Physiology, University of Oxford, Parks Road, Oxford OX1 3PT, United Kingdom.

A fundamental problem in the study of cortical development is the extent to which the formation and refinement of synaptic circuitry depends upon sensory experience. The barrel cortex is a useful model system to study experience-dependent cortical development because there is a simple mapping of individual whiskers to the corresponding barrel columns in the cortex. We investigated experience-dependent and -independent changes in glutamatergic synaptic transmission in the barrel cortex during the second postnatal week by comparing synaptic responses from whisker-intact mice at postnatal day (P) 7 and P14 with those from whisker-deprived mice at P14. alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) and N-methyl-D-aspartate (NMDA)-receptor-mediated excitatory synaptic responses were recorded from layer 2/3 pyramidal cells in vitro during voltage-clamp in response to stimulation in layer 4. We observed that the ratio of synaptic AMPA- to NMDA-receptor-mediated current (A/N ratio) increased with developmental age. The development of the A/N ratio was unchanged by deprivation of the whisker input throughout the second postnatal week. In contrast, the NMDA-receptor current decay and sensitivity to the NMDA receptor 2B subunit-selective antagonist ifenprodil was affected strongly by such deprivation. These results demonstrate a concurrent dissociation between sensory experience-dependent and -independent changes of glutamatergic transmission in the barrel cortex during the second postnatal week. Furthermore, they suggest that the development of subunit composition of synaptic receptors is dependent on sensory experience, whereas maturation of the synaptic A/N ratio is independent of such experience. Thus, different components of synaptic development may be governed by different developmental rules.
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http://dx.doi.org/10.1073/pnas.0402916101DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC524435PMC
October 2004
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