Thalamocortical circuits in generalized epilepsy: Pathophysiologic mechanisms and therapeutic targets

Abstract

Generalized epilepsy affects 24 million people globally; at least 25% of cases remain medically refractory. The thalamus, with widespread connections throughout the brain, plays a critical role in generalized epilepsy. The intrinsic properties of thalamic neurons and the synaptic connections between populations of neurons in the nucleus reticularis thalami and thalamocortical relay nuclei help generate different firing patterns that influence brain states. In particular, transitions from tonic firing to highly synchronized burst firing mode in thalamic neurons can cause seizures that rapidly generalize and cause altered awareness and unconsciousness. Here, we review the most recent advances in our understanding of how thalamic activity is regulated and discuss the gaps in our understanding of the mechanisms of generalized epilepsy syndromes. Elucidating the role of the thalamus in generalized epilepsy syndromes may lead to new opportunities to better treat pharmaco-resistant generalized epilepsy by thalamic modulation and dietary therapy.

Keywords: Absence epilepsy; Burst firing; Generalized spike-and-wave discharge; Genetic generalized epilepsy; Idiopathic generalized epilepsy; Oscillation; Thalamus.

Fig. 1.

Clinical differences and areas of overlap within GGE, between IGEs and generalized DEEs. CAE: childhood absence epilepsy, DEE: developmental and epileptic encephalopathy, GTCA: generalized tonic-clonic seizures alone, IGE: idiopathic generalized epilepsy, JAE: juvenile absence epilepsy, JME: juvenile myoclonic epilepsy. Blue: features associated with IGE, red: features associated with generalized DEEs.

Fig. 2.

Simplified diagram of the major thalamocortical circuit and schematic representation of burst-firing and tonic-firing modes regulating thalamocortical output. A. Feedforward axons from TC neurons target middle cortical layers (e.g., a VB TC neuron targeting cortical layer IV), while corticothalamic (CT) pyramidal neurons in layers V and VI project to the thalamus. Both projection neurons also synapse on inhibitory neurons in the nucleus reticularis thalami (nRT). Intra-nRT lateral inhibitory projections are omitted for clarity. B. Schematic of tonic firing mode. During alert wakefulness, under conditions of high acetylcholine and high norepinephrine tone, TASK channels close (inhibited by Gq-coupled signaling cascades), and cAMP-bound HCN channels open at higher voltages (downstream of Gs-coupled signaling cascades), resulting in a relatively depolarized TC membrane potential. Consequently, T-type Ca²⁺ channels remain inactivated. Under these conditions, TC neurons fire Na⁺-mediated action potentials in response to excitatory synaptic inputs. C. Schematic of burst firing observed when neurons are exposed to conditions of low acetylcholine and low norepinephrine tone: TASK channels are open, contributing to outward potassium “leak current,” and cAMP-unbound HCN channels require lower voltages to open; TC membrane potential is dynamically regulated around a relatively hyperpolarized set-point, and this relieves the inactivation of T-type Ca²⁺ channels. In these conditions, excitatory post-synaptic potentials (EPSPs) depolarize the membrane to the activation threshold of T-type Ca²⁺ channels, which elicits a low-threshold Ca²⁺ spike (LTS) and a burst of Na⁺ action potentials in nRT and variable responses in TC neurons, which can fire either bursts of action potentials or single action potentials during a SWD. An intrathalamic network oscillation is generated by interactions between bursting nRT and TC neurons: nRT neuron firing leads to GABA-mediated inhibitory post-synaptic potentials (IPSPs) in TC neurons, leading to activation of HCN channels, resulting in membrane depolarization to the activation threshold of T-type Ca²⁺ channels. A subsequent LTS and train of Na⁺ spikes lead to glutamate release from the TC neurons onto the nRT neurons and the next cycle of burst firing. In nRT, Ca²⁺ influx activates SK channels, resulting in afterhyperpolarization of nRT neurons which makes T-type Ca²⁺ available for another burst and perpetuates the cycle.

Fig. 3.

Simplified diagram of the major glutamatergic, GABAergic, and neuromodulatory inputs to the thalamus. Projections from the cortex, basal ganglia, cerebellum, and brainstem converge on TC neurons. BF: basal forebrain, GPe: globus pallidus externa, GPi: globus pallidus interna, LC: locus coeruleus, LDT: laterodorsal tegmentum, nRT: nucleus reticularis thalami, PBG: parabigeminal nucleus, PPT: pedunculopontine tegmentum, STN: subthalamic nucleus, SNc: substantia nigra pars compacta, SNr: substantia nigra pars reticulata.