α4β2* nicotinic acetylcholine receptors drive human temporal glutamate/GABA balance toward inhibition

Heteromeric nicotinic acetylcholine nAChRs (nAChRs) containing the alpha 4 and beta 2 subunits (alpha 4 beta 2* nAChRs) modulate neurotransmitter release in several regions of the brain. In temporal lobe epilepsy, inhibitory GABAergic neurotransmission is altered, whereas no evidence of nicotinic dysfunction has been reported. Here, we investigated, in human epileptic cortical tissues, the ability of alpha 4 beta 2* nAChRs to modulate synaptic transmission. An increased expression of alpha 4 and beta 2 subunits was observed in the temporal cortex of epileptic patients. We then recorded excitatory and inhibitory postsynaptic currents from layer 5 pyramidal neurons in the cortex of temporal lobe epilepsy patients, before and during selective modulation of alpha 4 beta 2* nAChRs by desformylflustrabromine (a selective alpha 4 beta 2* positive allosteric modulator). We observed a decrease in both frequency and amplitude of spontaneous excitatory postsynaptic currents, along with an increase in spontaneous inhibitory postsynaptic current frequency. Both these effects were blocked by dihydro-beta-erythroidine, a selective alpha 4* antagonist. alpha 4 beta 2* activation enhanced the excitability of interneurons (but not of layer 5 pyramidal neurons) by lowering the action potential threshold. Moreover, upon block of action potential propagation by TTX, alpha 4 beta 2* activation did not alter miniature inhibitory postsynaptic currents recorded from pyramidal neurons, at the same time as reducing the release at glutamatergic synapses by a GABAB-dependent process. image