Perampanel is a newly approved anticonvulsant uniquely targeting AMPA receptors, which mediate the most abundant form of excitatory synaptic transmission in the brain. However, the network mechanism underlying the anti-epileptic effect of the AMPAergic inhibition remains to be explored.

Anticonvulsants targeting K+ channels have not been clinically available, although neuronal hyperexcitability in seizures could be suppressed by activation of K+ channels. Voltage-gated A-type K+ channel (A-channel) inhibitors may be prescribed for diseases of neuromuscular junction but could cause seizures. Consistently, genetic loss of function of A-channels may also cause seizures. It is unclear why inhibition of A-channels, compared with other types of K+ channels, is particularly prone to seizure induction. This hinders the development of relevant therapeutic interventions.

Epileptic seizures constitute a common neurological disease primarily diagnosed by characteristic rhythms or waves in the local field potentials (LFPs) of cerebral cortices or electroencephalograms. With a basolateral amygdala (BLA) kindling model, we found that the dominant frequency of BLA oscillations is in the delta range (1-5 Hz) in both normal and seizure conditions. Multi-unit discharges are increased with higher seizure staging but remain phase-locked to the delta waves in LFPs. Also, the change in synchrony precedes and outlasts the changes in discharging units as well as behavioral seizures. One short train of stimuli readily drives the pyramidal-inhibitory neuronal networks in BLA slices into prolonged reverberating activities, where the burst and interburst intervals may concurrently set a "natural wavelength" for delta frequencies. Seizures thus could be viewed as erroneous temporospatial continuums to normal oscillations in a system with a built-in synchronizing and resonating nature for information relay.

Parkinson's disease is characterized by both hypokinetic and hyperkinetic symptoms. While increased subthalamic burst discharges have a direct causal relationship with the hypokinetic manifestations (e.g., rigidity and bradykinesia), the origin of the hyperkinetic symptoms (e.g., resting tremor and propulsive gait) has remained obscure. Neuronal burst discharges are presumed to be autonomous or less responsive to synaptic input, thereby interrupting the information flow. We, however, demonstrate that subthalamic burst discharges are dependent on cortical glutamatergic synaptic input, which is enhanced by A-type K+ channel inhibition. Excessive top-down-triggered subthalamic burst discharges then drive highly correlative activities bottom-up in the motor cortices and skeletal muscles. This leads to hyperkinetic behaviors such as tremors, which are effectively ameliorated by inhibition of cortico-subthalamic AMPAergic synaptic transmission. We conclude that subthalamic burst discharges play an imperative role in cortico-subcortical information relay, and they critically contribute to the pathogenesis of both hypokinetic and hyperkinetic parkinsonian symptoms.

Epileptic seizures are automatic, excessive, and synchronized neuronal activities originating from many brain regions especially the amygdala, the allocortices and neocortices. This may reflect a shared principle for network organization and signaling in these telencephalic structures. In theory, the automaticity of epileptic discharges may stem from spontaneously active "oscillator" neurons equipped with intrinsic pacemaking conductances, or from a group of synaptically-connected collaborating "resonator" neurons. In the basolateral amygdalar (BLA) network of pyramidal-inhibitory (PN-IN) neuronal resonators, we demonstrated that rhythmogenic currents are provided by glutamatergic rather than the classic intrinsic or cellular pacemaking conductances (namely the h currents). The excitatory output of glutamatergic neurons such as PNs presumably propels a novel network-based "relay burst mode" of discharges especially in INs, which precondition PNs into a state prone to burst discharges and thus further glutamate release. Also, selective activation of unilateral PNs, but never INs, readily drives bilateral BLA networks into reverberating discharges which are fully synchronized with the behavioral manifestations of seizures (e.g. muscle contractions). Seizures originating in BLA and/or the other structures with similar PN-IN networks thus could be viewed as glutamate-triggered erroneous network oscillations that are normally responsible for information relay.

ERG K+ channels have long been known to play a crucial role in shaping cardiac action potentials and, thus, appropriate heart rhythms. The functional role of ERG channels in the central nervous system, however, remains elusive. We demonstrated that ERG channels exist in subthalamic neurons and have similar gating characteristics to those in the heart. ERG channels contribute crucially not only to the setting of membrane potential and, consequently, the firing modes, but also to the configuration of burst discharges and, consequently, the firing frequency and automaticity of the subthalamic neurons. Moreover, modulation of subthalamic discharges via ERG channels effectively modulates locomotor behaviors. ERG channel inhibitors ameliorate parkinsonian symptoms, whereas enhancers render normal animals hypokinetic. Thus, ERG K+ channels could be vital to the regulation of both cardiac and neuronal rhythms and may constitute an important pathophysiological basis and pharmacotherapeutic target for the growing list of neurological disorders related to "brain arrhythmias."