Role of Acetylcholine and GABAergic Inhibition in Seizure Generation in Neural Networks Integrating the Neocortex, Hippocampus, Basal Ganglia, and Thalamus
We have analyzed the influence of acetylcholine and GABAergic inhibition on the functioning of parallel, topically organized neural circuits of the cortico-basal ganglia-thalamo-cortical loop including prefrontal and sensory areas of the cortex and hippocampus-basal ganglia-thalamus-hippocampus loop. Abnormal changes in the acetylcholine concentration as well as in the efficiency of excitation and inhibition in these circuits may lead to various types of epilepsy. Epileptiform activity may develop with the participation of long-range GABAergic cells which subserve the synchronization of discharges of excitatory neurons in different structures. We discuss the role of GABAergic interactions between the nuclei of the basal ganglia; GABAergic inputs from hippocampal field CA1 to the medial septum and retrosplenial cortex; from the neocortex to the striatum; from the external segment of the globus pallidus to the striatum and neocortex. We hypothesize that epileptiform activity is self-limited due to the functioning of several negative feedback loops. These loops are under the influence of GABAergic inputs from the pedunculopontine nucleus into the basal forebrain, thalamus, striatum, basal ganglia outputs, and external segment of the globus pallidus. The influence of acetylcholine is complex because different types of cholinoreceptors are present on excitatory and inhibitory neurons in all structures, and different types of receptors show different affinity for acetylcholine. Our analysis suggests that epileptiform activity may be suppressed by reinforcing the negative feedback loop that is formed by the inhibitory input from the external segment of the globus pallidus to the neocortex. This requires a reduction in the activity of GABAergic spiny cells of the striatum which project to the neurons of the external segment of the globus pallidus. This reduction may be promoted by M1 muscarinic receptor antagonists, therefore, they may be used to suppress epileptiform activity. We discuss possible side effects of targeting muscarinic receptors in the treatment of various diseases including neurodegenerative disorders. In order to reduce side effects caused by M1 receptor antagonists and other antiepileptic drugs, it was suggested to lower their dosage and use adenosine A2A receptor antagonists. Our conclusions are consistent with the known results of experimental and clinical studies, which means that they may be used in a targeted search for drugs alleviating the symptoms of various types of epilepsy.