Molecular Mechanisms Underlying the Generation of Absence Seizures: Identification of Potential Targets for Therapeutic Intervention

Abstract

Understanding the molecular mechanisms underlying the generation of absence seizures is crucial for developing effective, patient-specific treatments for childhood absence epilepsy (CAE). Currently, one-third of patients remain refractive to the antiseizure medications (ASMs), previously called antiepileptic drugs (AEDs), available to treat CAE. Additionally, these ASMs often produce serious side effects and can even exacerbate symptoms in some patients. Determining the precise cellular and molecular mechanisms directly responsible for causing this type of epilepsy has proven challenging as they appear to be complex and multifactorial in patients with different genetic backgrounds. Aberrant neuronal activity in CAE may be caused by several mechanisms that are not fully understood. Thus, dissecting the causal factors that could be targeted in the development of precision medicines without side effects remains a high priority and the ultimate goal in this field of epilepsy research. The aim of this review is to highlight our current understanding of potential causative mechanisms for absence seizure generation, based on the latest research using cutting-edge technologies. This information will be important for identifying potential targets for future therapeutic intervention.

Keywords: AMPA receptors; GABA; absence seizures; antiseizure medications; calcium channels; cerebellum; channelopathies; feedforward inhibition; genetic generalized epilepsies; parvalbumin interneurons; personalized medicines; reticular thalamic nucleus; somatosensory cortex; spike-wave discharges; striatum; thalamocortical network; thalamus.

Figure 1

Simplified schematic of the normal cortico-thalamo-cortical (CTC) network in the rodent brain showing reciprocal connections between the pyramidal cells in the cortex (green triangles) and relay neurons in the VP thalamus (red triangles). PV+ inhibitory interneurons are strategically located to provide feedforward inhibition (FFI) to their target neurons. The PV+ inhibitory interneurons (black circles) in the reticular thalamic nucleus (RTN) project onto the relay neurons in the VP thalamus (black line) and provide fast feedforward inhibition (−). They are excited by corticothalamic projections onto their synapses (+), which contain GluA4-AMPA receptors. The CT-RTN pathway is stronger than the CT-VP relay neuron pathway. Normal physiological oscillations are generated when feedforward inhibition RTN-VP is followed by post-inhibitory rebound bursts of action potentials in VP relay neurons that in turn re-excite RTN interneurons and activate the feedback inhibitory pathway (FBI) from VP-RTN-VP. The PV+ inhibitory interneurons in the cortex (blue circle) are excited (+) by thalamocortical projections onto their synapses containing GluA4-AMPA receptors and provide fast feedforward inhibition (−) to pyramidal neurons (blue line).

Figure 2

Simplified schematic showing impaired feedforward microcircuits in the cortico-thalamocortical (CTC) network in the rodent brain. Loss of GluA4-AMPA receptors at PV+ interneurons synapses in the stargazer mouse model and the GRIA4 knockout mouse results in reduced activation of the inhibitory PV+ interneurons and thus impaired feedforward inhibition in CTC microcircuits leading to disinhibition (dashed lines and scissors symbol) and absence seizures. Impaired feedforward inhibition, through loss of excitation onto inhibitory neurons, may be one underlying mechanism for SWDs in a subpopulation of patients with absence epilepsy.