Abstracts

RATIONALE: Thalamic oscillatory responses play an important, if not essential, role in the genesis of spike-wave discharges underlying absence epilepsy. The specific neuronal circuitry and roles of ionotropic receptors (AMPA, NMDA and GABA[sub]A[/sub]) have been described in a series of experiments over the last decade. In contrast, with the exception of GABA[sub]B[/sub] IPSPs, little is known regarding the metabotropic receptor-mediated synaptic responses produced by endogenously released neurotransmitters. We tested for functional synaptic currents mediated by neuropeptide Y (NPY), a peptidergic neurotransmitter endogenous to the thalamus, and glutamate, which activates both ionotropic and metabotropic responses.
METHODS: Whole cell recordings were obtained from thalamic reticular neurons (RTN) in horizontal slices obtained from P13-18 rats. Stimulus trains were applied to the internal capsule to activate corticothalamic fibers and mimic the periodic activity of absence seizures. In some cases, excitability was increased by the addition of 10 [mu]M bicuculline. In other experiments, network oscillatory responses were recorded via extracellular multi-unit electrodes in slices maintained in an interface chamber.
RESULTS: 1) Brief trains of 4 extracellular stimuli applied to the corticothalamic tract resulted in a slow excitatory postsynaptic potential ( ~4 mV and 200 ms), which was abolished by the specific group I mGluR antagonist AIDA (1 mM). 2) Application of the group I mGluR agonist DHPG (100 [mu]M) mimicked this response and resulted in a decreased membrane conductance with an estimated reversal potential of [lt] -80 mV, suggesting that mGluR-I receptors are negatively coupled to K+ channels. 3) With 3 Hz repetitions of the brief stimulus train (to mimic spike-wave activity) there was the progressive appearance of a long lasting (up to 10 seconds) inhibitory synaptic potential, which was blocked by the Y1 receptor antagonist BIBP3126 (100 nM). 4) NPY knockout mice lacked a BIBP3226-sensitive IPSP. 5) Network oscillatory responses were prolonged by application of BIBP3226, while AIDA application had the opposite effect.
CONCLUSIONS: NPY release, presumably from RTN cells, is triggered by epileptiform thalamic activity and it serves to autoregulate such activity through its inhibitory actions in RTN. The long lasting effects of Y1 receptor activation provide an enduring (seconds-long) suppression of RTN excitability, as would be desired for an endogenous antiepileptic compound. By contrast, glutamate release, likely from corticothalamic terminals in RTN, activates group I mGluRs to cause an intermediate term ([lt] 1 sec) enhancement RTN excitability. We speculate that mGluR activation may play a facilitatory role in the genesis of absence seizures, while Y1 receptors may mediate their termination. Such effects would indicate the potential for new approaches in the pharmacotherapy of absences. Further, these results suggest that the release of endogenous neuroactive substances may be a common feature of epileptiform activity.