Novel disinhibitory circuit identified for regulation of seizure in TLE

Epilepsy is one of the most pervasive neurological disorders, affecting 7.0‰ of the population in China. It is considered to be a circuit-level syndrome pathologically characterized by excessive or hypersynchronous discharges with enhanced neuronal excitability due to excitatory–inhibitory imbalance.

Temporal lobe epilepsy (TLE) is particularly challenging from a therapeutic perspective because of frequent resistance to anti-epileptic drugs (AEDs). Moreover, surgical resection of epileptic foci within the temporal lobe might still fail to control seizures. Thus, identification of the neuronal circuitry involved in the seizure of TLE is essential to developing precise and safe interventions to control TLE.

Clinical reports reveal that TLE patients have smaller structural volumes of substantia nigra (SN) and lower iron concentrations in the SN. Experimental studies have also reported structural and functional changes of substantia nigra pars reticulata (SNr) neurons among different types of epileptic models. In addition to those findings, lesion, pharmacological interference, or deep brain stimulation targeting the SNr can modulate the intensity of epileptic seizures, suggesting that the SNr plays a key role in seizure control. However, the cell types and neural circuits responsible for the SNr controlling of epilepsy are elusive.

 On February 17, the research team led by Prof. CHEN Zhong published their latest findings in the journal of Nature Communications. They identified a nigra-parafascicular disinhibitory circuit for regulation of seizure in TLE.   

 In their study, they found that optogenetic or chemogenetic activation of SNr parvalbumin+ (PV) GABAergic neurons amplified seizure activities in kindling- and kainic acid-induced TLE models, whereas selective inhibition of these neurons alleviated seizure activities. The severity of seizures was bi-directionally regulated by optogenetic manipulation of SNr PV fibers projecting to the parafascicular nucleus (PF). Electrophysiology combined with rabies virus-assisted circuit mapping showed that SNr PV neurons directly projected to and functionally inhibited posterior PF GABAergic neurons. The activity of these neurons also regulated seizure activities.

Their findings revealed that a long-range SNr-PF disinhibitory circuit participated in regulating seizures in TLE and that inactivation of this circuit could alleviate severity of epileptic seizures. This research provides a more insightful understanding of pathological changes from a circuit perspective and opens up an alternative approach to precisely controlling epilepsy.