Impaired feedforward inhibition of the thalamocortical projection in epileptic Ca2+ channel mutant mice, tottering.
The tottering (tg) mice have a mutation in the CaV2.1 (P/Q-type) voltage-dependent Ca2+ channel alpha(1)2.1 subunit gene. tg mice show not only cerebellar ataxia but also absence epilepsy, which begins at approximately 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.
Sasaki
Sachie
S
Department of Information Physiology, National Institute for Physiological Sciences, The Graduate University for Advanced Studies, Okazaki 444-8787, Japan.
Huda
Kadrul
K
Inoue
Tsuyoshi
T
Miyata
Mariko
M
Imoto
Keiji
K
D018750:6-Cyano-7-nitroquinoxaline-2,3-dione / Q000494:pharmacology; D000344:Afferent Pathways / Q000187:drug effects / Q000503:physiopathology*; D000367:Age Factors; D000818:Animals; D002121:Calcium Channel Blockers / Q000494:pharmacology; D020864:Calcium Channels, N-Type / Q000172:deficiency* / Q000187:drug effects / Q000235:genetics; D004195:Disease Models, Animal; D004558:Electric Stimulation; D004569:Electroencephalography; D004832:Epilepsy, Absence / Q000235:genetics / Q000503:physiopathology*; D005071:Evoked Potentials / Q000187:drug effects / Q000502:physiology; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects / Q000502:physiology; D006706:Homeostasis / Q000502:physiology*; D008012:Lidocaine / Q000031:analogs & derivatives / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D008818:Mice, Neurologic Mutants; D018408:Patch-Clamp Techniques; D010852:Picrotoxin / Q000494:pharmacology; D017966:Pyramidal Cells / Q000187:drug effects / Q000502:physiology; D013003:Somatosensory Cortex / Q000503:physiopathology*; D009435:Synaptic Transmission / Q000187:drug effects / Q000502:physiology; D013787:Thalamic Nuclei / Q000503:physiopathology*; D014633:Valine / Q000031:analogs & derivatives / Q000494:pharmacology; D020867:omega-Agatoxin IVA / Q000494:pharmacology; D020866:omega-Conotoxin GVIA / Q000494:pharmacology
D018750:6-Cyano-7-nitroquinoxaline-2,3-dione; D002121:Calcium Channel Blockers; D020864:Calcium Channels, N-Type; D008012:Lidocaine; D010852:Picrotoxin; D014633:Valine; D020867:omega-Agatoxin IVA; D020866:omega-Conotoxin GVIA; C500963:Cacna1b protein, mouse; C012647:QX-314; C056639:2-amino-5-phosphopentanoic acid