Muscarinic Induction of Synchronous Population Activity in the Entorhinal Cortex

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Abstract
Oscillation and synchronization of neural activity is important in normal brain function but is also relevant to epileptogenesis. One of the most frequent forms of epilepsy originates in temporal lobe circuitry of which the entorhinal cortex (EC) is crucial. Because muscarinic receptor activation promotes oscillatory dynamics in EC neurons, we investigated in a brain slice preparation the effects of carbachol (CCh) on oscillatory population activity in the EC. We found that CCh produced epileptiform activity in EC, which according to field profile and current source density analysis was usually driven by layer V. In addition, localized CCh application and surgical isolation experiments demonstrated that EC layer II, but not layer III, can also independently generate synchronous population activity. Intracellular recordings from EC principal cells during epileptiform activity demonstrated large-amplitude, synaptically driven depolarizing events and bursts of action potentials synchronized to the field spikes. In layer II neurons, the depolarizing events had a multiphasic reversal potential that suggested concurrent glutamatergic and GABAergic synaptic input. Interestingly, although the epileptiform activity required activation of AMPA but not NMDA receptors, small-amplitude field spikes persisted during block of fast excitatory neurotransmission. These field spikes were correlated to large-amplitude IPSPs in layer II neurons, and both activities were abolished by GABAA-receptor antagonism. Thus, in response to muscarinic activation, pools of EC interneurons discharge synchronously by a mechanism not necessarily involving principal cell activation. Given the differential projection pattern of EC layers V and II toward the neocortex and hippocampus, respectively, their robust epileptogenic character may be of major importance in temporal lobe epilepsy.