Abstracts

Rationale: Modification of local inhibitory networks in the dentate gyrus may contribute to the development of posttraumatic epilepsy after closed-head brain injury. However, little is known about these potentially pathogenic circuit changes. Enhanced excitatory innervation of dentate GABAergic interneurons has been proposed as a cellular mechanism associated with injury-induced epileptogenesis. We used transgenic mice which express enhanced green fluorescent protein (eGFP) in a subpopulation of somatostatin-positive GABA neurons. We tested whether surviving hilar eGFP neurons received increased excitatory inputs and whether synaptic inhibition of dentate granule cells is altered after experimental brain injury. Methods: Severe controlled cortical impact injury (1.0 mm impact depth) was administered to 7-8 wk old GIN mice. After 8-13 wks post-injury, coronal slices were prepared for cell attached and whole-cell patch-clamp recordings of hilar eGFP neurons and granule cells. Spontaneous and miniature EPSCs were recorded in eGFP neurons at -60 mV. Spontaneous and miniature IPSCs were recorded in granule cells at 0 mV. Glutamate photostimulation was applied focally to sites along the entire extent of the granule cell layer and in the CA3 region, and responses were examined in hilar eGFP neurons by voltage-clamp recordings. Paired electrical stimulation was applied to the hilus to examine whether a change in presynaptic function of GABAA receptor-mediated feedback inhibition could be detected in granule cells after TBI. Results: Cell attached and whole-cell voltage-clamp recordings revealed increased action potential and EPSC frequency in hilar GABA neurons from slices ipsilateral to the injury, versus slices contralateral to the injury or from control animals. An increase in evoked excitatory synaptic activity was detected in hilar GABA neurons ipsilateral to the injury after photostimulations applied to both the granule cell and CA3 pyramidal cell layers. Despite increased excitatory synaptic input to inhibitory neurons, whole-cell voltage-clamp recordings in granule cells revealed an overall reduction in spontaneous and miniature IPSC frequency. No change in the probability of GABA release was found in the dentate gyrus after paired electrical stimulation of the hilus. Conclusions: These findings suggest that excitatory drive to surviving hilar eGFP-positive neurons is enhanced, but synaptic inhibition of granule cells is not restored to control levels after injury. Rewiring patterns of specific inhibitory circuits after brain injury may be an important compensatory mechanism for controlling granule cell excitability in the posttraumatic dentate gyrus.