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The Journal of Neuroscience, March 15, 2006, 26(11):3056-3065; doi:10.1523/JNEUROSCI.5422-05.2006

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Neurobiology of Disease
Impaired Feedforward Inhibition of the Thalamocortical Projection in Epileptic Ca²⁺ Channel Mutant Mice, tottering

Sachie Sasaki,^1,2 Kadrul Huda,¹ Tsuyoshi Inoue,^1,2 Mariko Miyata,^1,2 and Keiji Imoto^1,2

¹Department of Information Physiology, National Institute for Physiological Sciences, and ²School of Life Sciences, The Graduate University for Advanced Studies, Okazaki 444-8787, Japan

Correspondence should be addressed to Keiji Imoto, Department of Information Physiology, National Institute for Physiological Sciences, Myodaiji, Okazaki 444-8787, Japan. Email: keiji{at}nips.ac.jp

The tottering (tg) mice have a mutation in the Ca_V2.1 (P/Q-type) voltage-dependent Ca²⁺ channel ₁2.1 subunit gene. tg mice show not only cerebellar ataxia but also absence epilepsy, which begins at 3 weeks of age and persists throughout life. Similarities in EEG and sensitivity to antiepileptic drugs suggest that tg mice are a good model for human absence epilepsy. Although imbalance between excitatory and inhibitory activity in the thalamocortical network is thought to contribute to the pathogenesis of absence epilepsy, the effect of the mutation on thalamocortical synaptic responses remains unknown. Here we showed imbalanced impairment of inhibitory synaptic responses in tg mice using brain slice preparations. Somatosensory thalamocortical projection makes not only monosynaptic glutamatergic connections but also disynaptic GABAergic connections, which mediate feedforward inhibition, onto layer IV neurons. In tg mice, IPSC amplitudes recorded from layer IV pyramidal cells of the somatosensory cortex in response to thalamic stimulation became disproportionately reduced compared with EPSC amplitudes at later developmental stages (postnatal days 21–30). Similar results were obtained by local stimulation of layer IV pyramidal neurons. However, IPSC reduction was not seen in layer V pyramidal neurons of epileptic tg mice or in layer IV pyramidal neurons of younger tg mice before the onset of epilepsy (postnatal days 14–16). These results showed that the feedforward inhibition from the thalamus to layer IV neurons of the somatosensory cortex was severely impaired in tg mice and that the impairment of the inhibitory synaptic transmission was correlated to the onset of absence epilepsy.

Key words: absence seizure; thalamocortical projection; feedforward inhibition; synaptic transmission; Ca²⁺ channel; mutant mice

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Received Jan. 18, 2005; revised Jan. 29, 2006; accepted Jan. 30, 2006.

Correspondence should be addressed to Keiji Imoto, Department of Information Physiology, National Institute for Physiological Sciences, Myodaiji, Okazaki 444-8787, Japan. Email: keiji{at}nips.ac.jp

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