Mediodorsal thalamus plays a critical role in the development of limbic motor seizures

Abstract

Limbic motor seizures in animals, analogous to complex partial seizures in humans, result in a consistent activation of the mediodorsal thalamus (MD) and, with prolonged seizures, damage to MD. This study examined the functional role of MD in focally evoked limbic motor seizures in the rat. GABA- and glutamate (Glu)-mediated synaptic transmissions in MD were evaluated for an influence on seizures evoked from area tempestas (AT), a discrete epileptogenic site in the rostral piriform cortex. A GABAA receptor agonist, Glu receptor antagonists, or a GABA-elevating agent were focally microinfused into MD before evoking seizures by focal application of bicuculline methiodide into the ipsilateral AT. Focal pretreatment of MD with the GABAA agonist muscimol (190 pmol) protected against seizures evoked from AT. Seizure protection was also obtained with the focal application of 2, 3-dihydroxy-6-nitro-7-sulfamoyl-benzo(F)quinoxaline (NBQX) (500 pmol), an antagonist of the AMPA subtype of Glu receptors, into MD. In contrast, focal pretreatment of MD with a competitive antagonist of the NMDA receptor 2-amino-7-phosphonoheptanoic acid (500 pmol) did not attenuate seizures. The anticonvulsant effects achieved with intra-MD injections of muscimol and NBQX were site-specific, because no seizure protection was obtained with injections placed 2 mm ventral or lateral to MD. Prolonged seizure protection was obtained following GABA elevation in MD after the application of the GABA transaminase inhibitor vigabatrin (194 nmol). These results suggest the following: (1) MD is a critical participant in the generation of seizures elicited focally from piriform cortex; (2) transmission via AMPA receptors, but not NMDA receptors, in MD regulates limbic seizure propagation; and (3) a GABA-mediated system exists within MD, the enhancement of which protects against focally evoked limbic motor seizures.

Fig. 1.

Pictures of autoradiographs showing accumulation of 2DG (dark areas) in coronal sections of rat brain. Bicuculline methiodide was injected 15 min before the intraperitoneal injection of 2DG (18 mCi into 250 gm rats). Rats were anesthetized and perfused 1 hr after injection of bicuculline. Arrow inleft column, middle row, points to AT microinfusion site. Arrow in left column,bottom row, points to MD.

Fig. 2.

Sites of focal microinfusions. A, Coronal representation depicting area of microinfusions within AT (shaded area). B, Drawings of coronal sections depicting location of microinfusions of muscimol or NBQX within MD from which seizure protection was obtained (filled circles). Open circlesrepresent sites where no seizure protection was obtained from these two drugs. Numbers indicate anteroposterior distance from bregma in millimeters.

Fig. 3.

Effect of focal microinfusion of an AMPA receptor antagonist in MD. NBQX (500 pmol; n = 9) was unilaterally microinfused into MD 5 min before microinfusion of bicuculline (118 pmol) into the ipsilateral AT. Difference from controls, *p < 0.05 (t test).

Fig. 4.

Effect of injection of an NMDA receptor antagonist in MD. AP-7 (500 pmol; n = 7) was unilaterally microinfused into MD 5 min before microinfusion of bicuculline (118 pmol) into the ipsilateral AT. Neither seizure severity nor seizure frequency was modified by AP-7 in MD.

Fig. 5.

Effect of focal injection of GABA_Areceptor agonist in MD. Muscimol (190 pmol; n = 10) was microinjected into MD 5 min before microinjection of bicuculline (118 pmol) into the ipsilateral AT. Difference from controls, *p < 0.05 (t test).

Fig. 6.

Effect of focal application of a GABA transaminase inhibitor into MD. Vigabatrin (194 nmol) was unilaterally microinfused into MD 2.5, 24, or 48 hr before microinfusion of bicuculline into the ipsilateral AT. Seizure frequency (A) is shown as mean ± SE for four to six animals per group. Statistical comparisons using ANOVA were performed on the seizure frequency data shown in A. Difference from controls, *p < 0.05. Seizure incidence (percent of rats exhibiting bilateral clonic seizures) is shown in B for the same animals analyzed in A.