The β2V287L nicotinic subunit linked to sleep-related epilepsy differently affects fast-spiking and regular spiking somatostatin-expressing neurons in murine prefrontal cortex. (July 2022)

• Record Type: Journal Article
• Authors: Meneghini, Simone; Modena, Debora; Colombo, Giulia; Coatti, Aurora; Milani, Niccolò; Madaschi, Laura; Amadeo, Alida; Becchetti, Andrea
• Is Part Of: Progress in neurobiology. Volume 214(2022)
• Publication Date: 2022-07
• Subjects: ACSF artificial cerebro-spinal fluid -- ADSHE autosomal dominant sleep-related hypermotor epilepsy -- AP action potential -- AP-5 D(-)− 2-amino-5-phosphono-pentanoic acid -- ChAT choline acetyltransferase -- CNQX 6-cyano-7-nitroquinoxaline-2, 3-dione -- DHβE dihydro-β-erythroidine -- EEG electroencephalography -- ECl equilibrium potential for Cl- -- EGABA reversal potential for GABAA currents -- EPSC excitatory post-synaptic current -- EPSP excitatory postsynaptic potential -- Fr2 frontal area 2 -- FS fast-spiking -- GAD67 glutamic acid decarboxylase 67 -- IPSC inhibitory post-synaptic current -- LDT laterodorsal tegmental nucleus -- NBM nucleus basalis magnocellularis -- nAChR nicotinic acetylcholine receptor -- NREM non-rapid eye movement -- PFC prefrontal cortex -- PPT pedunculopontine nucleus -- PV parvalbumin -- ROI region of interest -- RSNP regular spiking non pyramidal -- RT room temperature -- SOM somatostatin -- SS somatosensory cortex -- SYN synaptophysin -- tTA tetracycline-controlled transcriptional activator -- TTX tetrodotoxin -- VAChT vesicular ACh transporter -- VGAT vesicular GABA transporter -- VGLUT1 vesicular glutamate transporter 1 -- Vm membrane potential -- Vrest resting membrane potential; Autosomal dominant sleep-related hypermotor epilepsy -- CHRNB2 -- EPSC -- Nicotinic acetylcholine receptors -- Nocturnal frontal lobe epilepsy -- Synaptogenesis -- M2; Neurobiology -- Periodicals; Neurology -- Periodicals; Neurology -- Periodicals; Neurobiologie -- Périodiques; 612.8
• DOI: 10.1016/j.pneurobio.2022.102279
• Languages: English
• ISSNs: 0301-0082

Abstract

Abstract: Mutant subunits of the neuronal nicotinic ACh receptor (nAChR) can cause Autosomal Dominant Sleep-related Hypermotor Epilepsy (ADSHE), characterized by frontal seizures during non-rapid eye movement (NREM) sleep. We studied the cellular bases of the pathogenesis in brain slices from mice conditionally expressing the ADSHE-linked β2 V287L nAChR subunit. β2 V287L mice displayed minor structural alterations, except for a ~10% decrease of prefrontal cortex thickness. However, they showed a substantial decrease of the excitatory input to layer V fast-spiking (FS) interneurons, despite a concomitant increase in the number of glutamatergic terminals around the cell soma. Hence, prefrontal hyperexcitability may depend on a permanent impairment of surround inhibition. The effect disappeared when β2 V287L was silenced until postnatal day 15th, suggesting that the transgene selectively affects the maturation of glutamatergic synapses on FS neurons. The other main population of interneurons in layer V was constituted by somatostatin-expressing regular spiking cells. When tested with 10 µM nicotine, these displayed larger somatic nicotinic currents in transgenic mice. Thus, during wakefulness, activation of β2 V287L -containing nAChRs by the high cholinergic tone may counteract hyperexcitability by promoting local inhibition by somatostatin-expressing cells and decreasing the effect of glutamatergic deficit in FS neurons. This interpretation was tested in networks disinhibited by 2 μM bicuculline. Slices expressing β2 V287L were more susceptible to develop synchronized activity in the absence of nicotine. Addition of the drug boosted excitability in the controls, but had little effect in β2 V287L . Our findings suggest why NREM sleep favors ADSHE seizures and nicotine can be palliative in patients. Highlights: We studied mice carrying β2 V287L nAChR subunits linked to sleep-related epilepsy Expressing β2 V287L up to P15 permanently lowered glutamatergic input on FS neurons In β2 V287L mice, layer V SOM+ regular spiking neurons were more sensitive to nicotine Stimulation of nAChRs decreased hyperexcitability in PFC slices carrying β2 V287L Data suggest why seizures occur in sleep and nicotine can be protective in patients