Circuit Mechanisms Underlying Epileptogenesis in a Mouse Model of Focal Cortical Malformation

HighlightsEctopic interlaminar excitatory inputs from infragranular layers to layer 2/3 pyramidal neurons is a key component of the hyperexcitable circuitryDisrupted E/I balance was located far away from cortical malformationsDendritic inhibition from somatostatin interneurons play a key role in epileptogenesisClosed-loop optogenetic stimulation to activate remainder somatostatin interneurons irreversibly stops the spontaneous spike-wave discharges in vivo.In BriefYang et al. report abnormal synaptic reorganization in an epileptogenesis zone in a mouse model of cortical malformation. The authors further demonstrate that spontaneous spike-wave discharges can be curbed by selectively activating somatostatin interneurons using close-loop fiber optogenetic stimulation to a small cortical region away from the microgyrus.SummaryHow aberrant neural circuits contribute to chronic epilepsy remains unclear. Using a mouse model of focal cortical malformation with spontaneous seizures, we dissected the circuit mechanisms underlying epileptogenesis. Spontaneous and optogenetically induced hyperexcitable bursts in vivo were present in a cortical region distal to (> 1mm) freeze-lesion induced microgyrus, instead of a region near it. ChR2-assisted circuit mapping revealed ectopic interlaminar excitatory inputs from infragranular layers to layer 2/3 pyramidal neurons as a key component of the hyperexcitable circuitry. This disrupted balance between excitation and inhibition was prominent in the cortical region distal to the microgyrus. Consistently, the synapses of both parvalbumin-positive interneurons (PV) and somatostatin-positive interneurons (SOM) to pyramidal neurons were maladaptive in a layer- and site-specific fashion. Finally, closed-loop optogenetic stimulation of SOM, but not PV, terminated spontaneous spike-wave discharges. Together, these results demonstrate highly site- and cell-type specific synaptic reorganization underlying chronic cortical epilepsy and provide insights into potential treatment strategies for this devastating neurological disorder.

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Regenerating myofibers in tibialis anterior muscles of young ‘MDX’ mice

Proceedings, annual meeting, Electron Microscopy Society of America ◽

10.1017/s0424820100127943 ◽

1987 ◽

Vol 45 ◽

pp. 726-727

Author(s):

H. D. Geissinge ◽

L.D. Rhodes

Keyword(s):

Muscular Dystrophy ◽

Mouse Model ◽

Tibialis Anterior ◽

Physiological Activity ◽

Mdx Mice ◽

Mode Of Inheritance

A recently discovered mouse model (‘mdx’) for muscular dystrophy in man may be of considerable interest, since the disease in ‘mdx’ mice is inherited by the same mode of inheritance (X-linked) as the human Duchenne (DMD) muscular dystrophy. Unlike DMD, which results in a situation in which the continual muscle destruction cannot keep up with abortive regenerative attempts of the musculature, and the sufferers of the disease die early, the disease in ‘mdx’ mice appears to be transient, and the mice do not die as a result of it. In fact, it has been reported that the severely damaged Tibialis anterior (TA) muscles of ‘mdx’ mice seem to display exceptionally good regenerative powers at 4-6 weeks, so much so, that these muscles are able to regenerate spontaneously up to their previous levels of physiological activity.

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