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author:("mishell, G")
2.  CaV2.1 ablation in cortical interneurons selectively impairs fast-spiking basket cells and causes generalized seizures 
Annals of neurology  2013;74(2):209-222.
Both the neuronal populations and mechanisms responsible for generalized spike-wave absence seizures are poorly understood. In mutant mice carrying loss-of-function mutations in Cacna1a, which encodes the α1 pore-forming subunit of CaV2.1 (P/Q-type) voltage-gated Ca2+ channels, generalized spike-wave seizures have been suggested to result from excessive bursting of thalamocortical cells. However, other cellular populations including cortical inhibitory interneurons may contribute to this phenotype.
We investigated how different cortical interneuron subtypes are affected by the loss of CaV2.1 channel function and how this contributes to the onset of generalized epilepsy.
We designed genetic strategies to induce a selective Cacna1a LOF mutation in different cortical GABAergic and/or glutamatergic neuronal populations in mice. We assessed the cellular and network consequences of these mutations by combining immunohistochemical assays, in vitro physiology, optogenetics and in vivo video-EEG recordings.
We demonstrate that selective Cacna1a LOF from a subset of cortical interneurons, including parvalbumin (PV)- and somatostatin (SST)-positive interneurons, results in severe generalized epilepsy. Loss of CaV2.1 channel function compromises GABA release from PV-, but not SST-positive interneurons. Moreover, thalamocortical projection neurons do not show enhanced bursting in these mutants, suggesting that this feature is not essential for the development of generalized spike-wave seizures. Notably, the concurrent removal of CaV2.1 channels in cortical pyramidal cells and interneurons considerably lessens seizure severity by decreasing cortical excitability.
Our findings demonstrate that conditional ablation of CaV2.1 channel function from cortical PV interneurons alters GABA release from these cells, impairs their ability to constrain cortical pyramidal cell excitability and is sufficient to cause generalized seizures.
PMCID: PMC3849346  PMID: 23595603
3.  Dynamic changes in interneuron morpho-physiological properties mark the maturation of hippocampal network activity 
The Journal of Neuroscience  2012;32(19):6688-6698.
During early postnatal development, neuronal networks successively produce various forms of spontaneous patterned activity that provide key signals for circuit maturation. Initially, in both rodent hippocampus and neocortex, coordinated activity emerges in the form of Synchronous Plateau Assemblies (SPAs) that are initiated by sparse groups of gap-junction coupled oscillating neurons. Subsequently, SPAs are replaced by synapse-driven Giant Depolarizing Potentials (GDPs). Whether these sequential changes in mechanistically distinct network activities correlate with modifications in single-cell properties is unknown. To understand this, we have studied the morpho-physiological fate of single SPA-cells as a function of development. We focused on CA3 GABAergic interneurons, which are centrally involved in generating GDPs in the hippocampus. As the network matures, GABAergic neurons are engaged more in GDPs and less in SPAs. Using inducible genetic fate mapping, we show that the individual involvement of GABAergic neurons in SPAs is correlated to their temporal origin. In addition, we demonstrate that the SPA to GDP transition is paralleled by a remarkable maturation in the morpho-physiological properties of GABAergic neurons. Compared to those involved in GDPs, interneurons participating in SPAs possess immature intrinsic properties, receive synaptic inputs spanning a wide amplitude range, and display large somata as well as membrane protrusions. Thus, a developmental switch in the morpho-physiological properties of GABAergic interneurons as they progress from SPA to GDPs marks the emergence of synapse-driven network oscillations.
PMCID: PMC3371585  PMID: 22573691
4.  Pioneer GABA cells comprise a subpopulation of hub neurons in the developing hippocampus 
Neuron  2011;71(4):695-709.
Connectivity in the developing hippocampus displays a functional organization particularly effective in supporting network synchronization, as it includes superconnected hub neurons. We have previously shown that hub network function is supported by a subpopulation of GABA neurons. However it is unclear whether hub cells are only transiently present or later develop into distinctive subclasses of interneurons. These questions are difficult to assess given the heterogeneity of the GABA neurons and the poor early expression of markers. To circumvent this conundrum we used “genetic fate mapping” that allows for the selective labelling of GABA neurons based on their place and time of origin. We show that early generated GABA cells form a subpopulation of hub neurons, characterized by an exceptionally widespread axonal arborisation and the ability to single-handedly impact network dynamics when stimulated. Pioneer hub neurons remain into adulthood where they acquire the classical markers of long-range projecting GABA neurons.
PMCID: PMC3163067  PMID: 21867885
5.  Genes expressed in Atoh1 neuronal lineages arising from the r1/isthmus rhombic lip 
Gene expression patterns : GEP  2011;11(5-6):349-359.
During embryogenesis, the rhombic lip of the fourth ventricle is the germinal origin of a diverse collection of neuronal populations that ultimately reside in the brainstem and cerebellum. Rhombic lip neurogenesis requires the bHLH transcription factor Atoh1 (Math1), and commences shortly after neural tube closure (E9.5). Within the rhombomere 1 – isthmus region, the rhombic lip first produces brainstem and deep cerebellar neurons (E9.5-E12), followed by granule cell precursors after E12. While Atoh1 function is essential for all of these populations to be specified, the downstream genetic programs that confer specific properties to early and late born Atoh1 lineages are not well characterized. We have performed a comparative microarray analysis of gene expression within early and later born cohorts of Atoh1 expressing neural precursors purified from E14.5 embryos using a transgenic labeling strategy. We identify novel transcription factors, cell surface molecules, and cell cycle regulators within each pool of Atoh1 lineages that likely contribute to their distinct developmental trajectories and cell fates. In particular, our analysis reveals new insights into the genetic programs that regulate the specification and proliferation of granule cell precursors, the putative cell of origin for the majority of medulloblastomas.
PMCID: PMC3095718  PMID: 21440680
rhombic lip; Atoh1; Math1; cerebellum; neurogenesis; rhombomere 1

Results 1-5 (5)