Dynamic electrical synapses rewire brain networks for persistent oscillations and epileptogenesis.

One of the very fundamental attributes for telencephalic neural computation in mammals involves network activities oscillating beyond the initial trigger. The continuing and automated processing of transient inputs shall constitute the basis of cognition and intelligence but may lead to neuropsychiatric disorders such as epileptic seizures if carried so far as to engross part of or the whole telencephalic system. From a conventional view of the basic design of the telencephalic local circuitry, the GABAergic interneurons (INs) and glutamatergic pyramidal neurons (PNs) make negative feedback loops which would regulate the neural activities back to the original state. The drive for the most intriguing self-perpetuating telencephalic activities, then, has not been posed and characterized. We found activity-dependent deployment and delineated functional consequences of the electrical synapses directly linking INs and PNs in the amygdala, a prototypical telencephalic circuitry. These electrical synapses endow INs dual (a faster excitatory and a slower inhibitory) actions on PNs, providing a network-intrinsic excitatory drive that fuels the IN-PN interconnected circuitries and enables persistent oscillations with preservation of GABAergic negative feedback. Moreover, the entities of electrical synapses between INs and PNs are engaged in and disengaged from functioning in a highly dynamic way according to neural activities, which then determine the spatiotemporal scale of recruited oscillating networks. This study uncovers a special wide-range and context-dependent plasticity for wiring/rewiring of brain networks. Epileptogenesis or a wide spectrum of clinical disorders may ensue, however, from different scales of pathological extension of this unique form of telencephalic plasticity.

Pre-synaptic and post-synaptic A-type K+ channels regulate glutamatergic transmission and switching of the network into epileptiform oscillations.

BACKGROUND AND PURPOSE: 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. EXPERIMENTAL APPROACH: Mechanisms underlying epileptogenesis with A-channel inhibition and antiepileptic actions of A-channel activation were investigated with electrophysiological, pharmacological, optogenetic, and behavioral approaches. KEY RESULTS: Pre-synaptic KV 1.4 and post-synaptic KV 4.3 A-channels act synergistically to gate glutamatergic transmission and control rhythmogenesis in the amygdala. The interconnected neurons set into the oscillatory mode by A-channel inhibition would reverberate with regular paces and the same top frequency, demonstrating a spatio-temporally well-orchestrated system with built-in oscillatory rhythms normally curbed by A-channels. Accordingly, selective over-excitation of glutamatergic neurons or inhibition of A-channels can induce behavioural seizures, which may be ameliorated by A-channel activators (e.g. NS-5806) or AMPA receptor antagonists (e.g. perampanel). CONCLUSION AND IMPLICATIONS: Trans-synaptic voltage-dependent A-channels serve as a biophysical-biochemical transducer responsible for a novel form of synaptic plasticity. Such a network-level switch into and out of the oscillatory mode may underlie a wide scope of telencephalic information processing or, at its extreme, epileptic seizures. A-channels thus constitute a potential target of antiepileptic therapy.

Conveyance of cortical pacing for parkinsonian tremor-like hyperkinetic behavior by subthalamic dysrhythmia.

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.

Glutamate transmission rather than cellular pacemaking propels excitatory-inhibitory resonance for ictogenesis in amygdala.

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.

Delta-Frequency Augmentation and Synchronization in Seizure Discharges and Telencephalic Transmission.

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.

Perampanel reduces paroxysmal depolarizing shift and inhibitory synaptic input in excitatory neurons to inhibit epileptic network oscillations.

BACKGROUND AND PURPOSE: 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. EXPERIMENTAL APPROACH: The mechanism of perampanel action was studied with the basolateral amygdala network containing pyramidal-inhibitory neuronal resonators in seizure models of 4-aminopyridine (4-AP) and electrical kindling. KEY RESULTS: Application of either 4-AP or electrical kindling to the basolateral amygdala readily induces AMPAergic transmission-dependent reverberating activities between pyramidal-inhibitory neuronal resonators, which are chiefly characterized by burst discharges in inhibitory neurons and corresponding recurrent inhibitory postsynaptic potentials in pyramidal neurons. Perampanel reduces post-kindling "paroxysmal depolarizing shift" especially in pyramidal neurons and, counterintuitively, eliminates burst activities in inhibitory neurons and inhibitory synaptic inputs onto excitatory pyramidal neurons to result in prevention of epileptiform discharges and seizure behaviours. Intriguingly, similar effects can be obtained with not only the AMPA receptor antagonist CNQX but also the GABAA receptor antagonist bicuculline, which is usually considered as a proconvulsant. CONCLUSION AND IMPLICATIONS: Ictogenesis depends on the AMPA receptor-dependent recruitment of pyramidal-inhibitory neuronal network oscillations tuned by dynamic glutamatergic and GABAergic transmission. The anticonvulsant effect of perampanel then stems from disruption of the coordinated network activities rather than simply decreased neuronal excitability or excitatory transmission. Positive or negative modulation of epileptic network reverberations may be pro-ictogenic or anti-ictogenic, respectively, constituting a more applicable rationale for the therapy against seizures.

Antiarrhythmics cure brain arrhythmia: The imperativeness of subthalamic ERG K+ channels in parkinsonian discharges.

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."