Disruption of inhibition in area CA1 of the hippocampus in a rat model of temporal lobe epilepsy

Previous studies have revealed a loss of neurons in layer III of the entorh inal cortex (EC) in patients with temporal lobe epilepsy. These neurons pro ject to the hippocampus and may activate inhibitory interneurons, so that t heir loss could disrupt inhibitory function in the hippocampus. The present study evaluates this hypothesis in a rat model in which layer III neurons were selectively destroyed by focal injections of the indirect excitotoxin, aminooxyacetic acid (AOAA). Inhibitory function in the hippocampus was ass essed by evaluating the discharge of CA1 neurons in response to stimulation of afferent pathways in vivo. In control animals, stimulation of the tempo roammonic pathway leads to heterosynaptic inhibition of population spikes g enerated by subsequent stimulation of the commissural projection to CA1. Th is heterosynaptic inhibition was substantially reduced in animals that had received AOAA injections 1 mo previously. Stimulation of the commissural pr ojection also elicited multiple population spikes in CA1 in AOAA-injected a nimals, and homosynaptic inhibition in response to paired-pulse stimulation of the commissural projection was dramatically diminished. These results s uggest a disruption of inhibitory function in CA1 in AOAA-injected animals. To determine whether the disruption of inhibition occurred selectively in CA1, we assessed paired-pulse inhibition in the dentate gyrus. Both homosyn aptic inhibition generated by paired-pulse stimulation of the perforant pat h, and heterosynaptic inhibition produced by activation of the commissural projection to the dentate gyrus appeared largely comparable in AOAA-injecte d and control animals; thus abnormalities in inhibitory function following AOAA injections occurred relatively selectively in CA1. Electrolytic lesion s of the EC did not cause the same loss of inhibition as seen in animals wi th AOAA injections, indicating that the loss of inhibition in CA1 is not du e to the loss of excitatory driving of inhibitory interneurons. Also, elect rolytic lesions of the EC in animals that had been injected previously with AOAA had little effect on the abnormal physiological responses in CA1, sug gesting that most alterations in inhibition in CA1 are not due to circuit a bnormalities within the EC. Comparisons of control and AOAA-injected animal s in a hippocampal kindling paradigm revealed that the duration of afterdis charges elicited by high-frequency stimulation of CA3, and the number of st imulations required to elicit kindled seizures were comparable. Taken toget her, our results reveal that the selective loss of layer III neurons induce d by AOAA disrupts inhibitory function in CA1, but this does not create a c ircuit that is more prone to at least one form of kindling.