Nicotinic receptors in circuit excitability and epilepsy

Neuronal nicotinic acetylcholine receptors belong to the family of excitatory ligand-gated channels and result from the assembly of five subunits. Functional heteromeric nictonic receptors are present in the hippocampus and neocortex, thalamus, mesolimbic dopamine system and brainstem motor nuclei, where they may play a role, respectively, in memory, sensory processing, addiction and motor control. Some forms of autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE) have been found to be associated with mutations in the genes coding for the alpha 4 or beta2 subunits of the nicotinic receptor. Mutant receptors display an increased acetylcholine sensitivity with respect to normal receptors. Since the thalamus and the cortex are strongly innervated by cholinergic neurons projecting from the brainstem and basal forebrain, an unbalance between excitation and inhibition, brought about by the presence of mutant receptors, could generate seizures by facilitating and synchronizing spontaneous oscillations in thalamo-cortical circuits.