Summary: Purpose:In limbic or mesial temporal lobe epilepsy, much attention has been given to specific regions or cell populations (e.g., the hippocampus or dentate granule cells). Epileptic seizures may involve broader changes in neural circuits, and evidence suggests that subcortical regions may play a role. In this study we examined the midline thalamic regions for involvement in limbic seizures, changes in anatomy and physiology, and the potential role for this region in limbic seizures and epilepsy Methods: Using two rat models for limbic epilepsy (hippocampal kindled and chronic spontaneous limbic epilepsy) we examined the midline thalamus for evidence of involvement in seizure activity, alterations in structure, changes in the basic in vitro physiology of the thalamic neurons. We also explored how this region may influence limbic seizures. Results:The midline thalamus was consistently involved with seizure activity from the onset, and there was significant neuronal loss in the medial dorsal and reuniens/rhomboid nuclei. In addition, thalamic neurons had changes in synaptically mediated and voltage-gated responses. Infusion of lidocaine into the midline thalamus significantly shortened afterdischarge duration.Conclusions: These observations suggest that this thalamic region is part of the neural circuitry of limbic epilepsy and may play a significant role in seizure modulation. Local neuronal changes can enhance the excitability of the thalamolimbic circuits.

SUMMARYPurpose: Studies have suggested that the medial dorsal nucleus of the thalamus plays a role in the behavioral expression of limbic seizures, but it is unclear whether this region is a key component for the primary seizure circuitry or a path for seizure spread from one region to another. This study was undertaken to determine the potential role of this region in limbic seizure activity. Methods: Adult male rats received kindling stimulation either under urethane anesthesia or while awake. Glutamate or its agonists or the GABA antagonist bicuculline or agonist muscimol were infused into the medial dorsal nucleus. In another series, kindling acquisition was compared among three thalamic sites as well as with the amygdala and hippocampus Results: Drugs that enhanced excitatory drive or blocked GABA resulted in significant prolongation of electrographic seizure activity compared to saline infused controls. Enhanced GABA activity resulted in a significant reduction of seizure duration. Infusion of the compounds lateral to the medial dorsal nucleus did not affect seizure duration.In the kindling studies the medial dorsal region is the only thalamic nucleus from which hippocampal seizures can be induced, but with an elevated afterdischarge threshold compared to the two limbic sites. However, the seizures generalized more rapidly from the medial dorsal region. Conclusions: This study demonstrates that the medial dorsal nucleus and other dorsal midline nuclei have a significant role in the primary seizure circuits of limbic seizures as well as in spread of seizure activity to other regions.

SUMMARYPurpose: The midline thalamus is an important component of the circuitry in limbic seizures, but it is unclear how synaptic modulation of the thalamus affects that circuitry. In this study, we wished to understand how synaptic modulation of the thalamus can affect interregional signaling and seizure spread in the limbic network. Methods: We examined the effect of c-aminobutyric acid (GABA) modulation of the mediodorsal (MD) region of the thalamus on responses in the prefrontal cortex (PFC) by stimulation of the subiculum (SB). Muscimol, a GABA A agonist, was injected into the MD, and the effect on local responses to subiculum stimulation was examined. Evoked potentials were induced in the MD and the PFC by low-frequency stimulation of the SB, and seizures were generated in the subiculum by repeated 20-Hz stimulations. The effect of muscimol in the MD on the evoked potentials and seizures was measured. Key Findings: Thalamic responses to stimulation of the subiculum were reduced in the presence of muscimol. Reduction of the amplitudes of evoked potentials in the MD resulted in an attenuation of the late, thalamic components of the responses in the PFC, as well as of seizure durations. Significance: Activation of GABA A receptors in the midline thalamus not only causes changes within the thalamus, but it has broader effects on the limbic network. This work provides further evidence that synaptic modulation within the midline thalamus alters system excitability more broadly and reduces seizure activity.

Introduction The midline thalamic nuclei are an important component of limbic seizures. Although the anatomic connections and excitatory influences of the midline thalamus are well known, its physiological role in limbic seizures is unclear. We examined the role of the midline thalamus on two circuits that are involved in limbic seizures: (a) the subiculum-prefrontal cortex (SB-PFC), and (b) the piriform cortex-entorhinal cortex (PC-EC). Methods Evoked field potentials for both circuits were obtained in anesthetized rats, and the likely direct monosynaptic and polysynaptic contributions to the responses were identified. Seizures were generated in both circuits by 20 Hz stimulus trains. Once stable seizures and evoked potentials were established, the midline thalamus was inactivated through an injection of the sodium channel blocker tetrodotoxin (TTX), and the effects on the evoked responses and seizures were analyzed. Results Inactivation of the midline thalamus suppressed seizures in both circuits. Seizure suppression was associated with a significant reduction in the late thalamic component but no significant change in the early direct monosynaptic component. Injections that did not suppress the seizures did not alter the evoked potentials. Conclusions Suppression of the late thalamic component of the evoked potential at the time of seizure suppression suggests that the thalamus facilitates seizure induction by extending the duration of excitatory drive through a divergent-convergent excitatory amplification system. This work may have broader implications for understanding signaling in the limbic system.