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FUNCTIONAL MANIPULATION OF CORTICAL INTERNEURONAL SUBTYPES


Determining the sequence of events by which specific cortical interneurons integrate into cortical circuitry is only the first step towards our larger goal of understanding how this circuitry is assembled. Genetic methods offer the possibility of beginning to address the logic by which particular interneurons become integrated onto cortical circuits. However, the promise of using developmental genetics to target and manipulate specific subsets of cortical interneurons cannot be realized until an efficient means of using genetics to produce appropriate genetic tools comes to fruition. We recently proposed what we refer to as the "ternary approach" to employing developmental genetics. As the name implies, this approach relies on three genetic components, which provide great specificity and maximal adaptability for targeting different cortical interneuronal subsets (and for that matter any particular subset of CNS neurons). This approach builds upon binary methods that use recombinase-expressing driver lines to recombine so called reporter lines. The difficulty in separating the recombination event from a desired manipulation or labeling of the desired population has encouraged us to create a three part system for manipulating cortical interneurons. We are presently producing both a conditional tTA reporter, that will allow us to express the doxacycline-repressible tetracycline transcriptional activator in targeted populations, as well as a series of "output" TRE effector lines for the 1) retrograde of neurons synapsing onto the target population 2) the light or ligand-induced activation of activity or suppression of neuronal activity 3) the targeting of genetically-encoded sensors of intrinsic activity or 4) the labeling of specific cellular components such as those contributing to pre- or postsynaptic complexes. The successful implementation of this method will provide an unprecedented ability to target and manipulate neurons, including specific subsets of cortical interneurons.


Related Publications


Miyoshi, G., Fishell, G. Directing neuron-specific transgene expression in the mouse CNS. Current Opinion in Neurobiology , 2006, 9:1086-1088.

Batista-Brito R and Fishell G. The developmental integration of cortical interneurons into a functional network.Curr Top Dev Biol. 2009;87:81-118.

Lee, S-H., Hjerling-Leffler, J., Zagha, E., Fishell, G. and Rudy, B. The largest group of superficial neocortical GABAergic interneurons expresses ionotropic serotonin receptors. Journal of Neuroscience, 2010, 30: 16796-16808.

De Marco-Garcia, N.V., Karayannis, T., and Fishell, G. Neuronal activity is required for the development of specific cortical interneuron subtypes. Nature, 2011 (epub ahead of print).

Fishell G. and Rudy, B. Mechanisms of Inhibition within the Telencephalon:
"Where the Wild Things Are". Annu. Rev. Neurosci. 2011; 34:535–567.