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A new mode of corticothalamic transmission revealed in the Gria4−/− model of absence epilepsy

Nature Neuroscience volume 14, pages 1167–1173 (2011)Cite this article

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Abstract

Cortico-thalamo-cortical circuits mediate sensation and generate neural network oscillations associated with slow-wave sleep and various epilepsies. Cortical input to sensory thalamus is thought to mainly evoke feed-forward synaptic inhibition of thalamocortical (TC) cells via reticular thalamic nucleus (nRT) neurons, especially during oscillations. This relies on a stronger synaptic strength in the cortico-nRT pathway than in the cortico-TC pathway, allowing the feed-forward inhibition of TC cells to overcome direct cortico-TC excitation. We found a systemic and specific reduction in strength in GluA4-deficient (Gria4−/−) mice of one excitatory synapse of the rhythmogenic cortico-thalamo-cortical system, the cortico-nRT projection, and observed that the oscillations could still be initiated by cortical inputs via the cortico-TC-nRT-TC pathway. These results reveal a previously unknown mode of cortico-thalamo-cortical transmission, bypassing direct cortico-nRT excitation, and describe a mechanism for pathological oscillation generation. This mode could be active under other circumstances, representing a previously unknown channel of cortico-thalamo-cortical information processing.

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Figure 1: Gria4−/− mice display spontaneous SWDs.
Figure 2: Evoked oscillations are enhanced in thalamic slices from Gria4−/− mice.
Figure 3: Absence of AMPA receptor GluA4 alters synaptic excitation in thalamic reticular nucleus.
Figure 4: Selective optical stimulation of TC axons evokes similar EPSCs in nRT neurons from wild-type and Gria4−/− mice.
Figure 5: Selective optical stimulation of CT axons evokes smaller EPSCs in nRT neurons from Gria4−/− mice.
Figure 6: Selective optical stimulation of CT axons evokes similar EPSCs in TC neurons from wild-type and Gria4−/− mice.
Figure 7: Specific reduction in the synaptic strength of the CT-nRT pathway in Gria4−/− mice abolishes the feed-forward inhibition in the CT-nRT-TC pathway and results in a hyperactivation of TC cells by CT inputs.

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Acknowledgements

We thank I. Parada for her expert histology technical support and A. Herbert and S. Jin for their help with animal husbandry. We also thank T. Davidson for insightful discussions on the optogenetic approach and C. Lee for a generous help during virus injections. This work was supported by grants from the US National Institutes of Health and the National Institute of Neurological Disorders and Stroke (NS34774, NS06477 and NS031348), the DARPA REPAIR program and the Epilepsy Foundation.

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Authors and Affiliations

  1. Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, California, USA

    Jeanne T Paz, Astra S Bryant, Kathy Peng & John R Huguenard

  2. Department of Bioengineering, Stanford University School of Medicine, Stanford, California, USA

    Lief Fenno, Ofer Yizhar & Karl Deisseroth

  3. The Jackson Laboratory, Bar Harbor, Maine, USA

    Wayne N Frankel

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Contributions

J.T.P. and J.R.H. designed the experiments and wrote the manuscript. L.F., O.Y., K.D. and W.N.F. provided reagents and tools. J.T.P., A.S.B. and K.P. carried out the experiments. J.T.P., A.S.B., K.P. and J.R.H. analyzed the data.

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Correspondence to John R Huguenard.

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Paz, J., Bryant, A., Peng, K. et al. A new mode of corticothalamic transmission revealed in the Gria4−/− model of absence epilepsy. Nat Neurosci 14, 1167–1173 (2011). https://doi.org/10.1038/nn.2896

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