Differential acute impact of therapeutically effective and overdose concentrations of lithium on human neuronal single cell and network function

Abstract

Lithium salts are used as mood-balancing medication prescribed to patients suffering from neuropsychiatric disorders, such as bipolar disorder and major depressive disorder. Lithium salts cross the blood-brain barrier and reach the brain parenchyma within few hours after oral application, however, how lithium influences directly human neuronal function is unknown. We applied patch–clamp and microelectrode array technology on human induced pluripotent stem cell (iPSC)-derived cortical neurons acutely exposed to therapeutic (<1 mM) and overdose concentrations (>1 mM) of lithium chloride (LiCl) to assess how therapeutically effective and overdose concentrations of LiCl directly influence human neuronal electrophysiological function at the synapse, single-cell, and neuronal network level. We describe that human iPSC-cortical neurons exposed to lithium showed an increased neuronal activity under all tested concentrations. Furthermore, we reveal a lithium-induced, concentration-dependent, transition of regular synchronous neuronal network activity using therapeutically effective concentration (<1 mM LiCl) to epileptiform-like neuronal discharges using overdose concentration (>1 mM LiCl). The overdose concentration lithium-induced epileptiform-like activity was similar to the epileptiform-like activity caused by the GABAA-receptor antagonist. Patch–clamp recordings reveal that lithium reduces action potential threshold at all concentrations, however, only overdose concentration causes increased frequency of spontaneous AMPA-receptor mediated transmission. By applying the AMPA-receptor antagonist and anti-epileptic drug Perampanel, we demonstrate that Perampanel suppresses lithium-induced epileptiform-like activity in human cortical neurons. We provide insights in how therapeutically effective and overdose concentration of lithium directly influences human neuronal function at synapse, a single neuron, and neuronal network levels. Furthermore, we provide evidence that Perampanel suppresses pathological neuronal discharges caused by overdose concentrations of lithium in human neurons.

Ontogeny of oscillatory slow-wave and neuronal population activity in human iPSC-3D cortical circuits

“…video 1, ( 22 )) and oligodendroglial cells (suppl. video 1, ( 22, 25 )). Cortical neurons in 3D neural aggregates had mature synapses indicated by pre- and post-synaptic marker staining (fig.…”

“…Our experimental paradigm of adherently growing 3D neural aggregates has been utilized to assess the development and properties of synchronous mouse ( 27 ) and human pluripotent stem cell-derived neuronal population bursting ( 23 ), to evaluate effects of clinically relevant compounds on human neuronal network function ( 28 ), and to provide insights into the cellular neural ontogeny ( 29 ) and corticogenesis ( 30 ). For instance, Edri et al presented the cellular ontogeny of neuroepithelial cells and radial glia cells within neural rosettes ( 29 ).…”

“…Depending on the type of electrode and its relative position to the cellular source, such electrodes can record electrical signals in the form of spikes (corresponding to action potentials) or oscillatory slow-wave activity, local field potentials (LFPs). Since Hans Berger's first electroencephalogram (EEG) recordings in adult humans using extracranial scalp electrodes in 1929 (1), oscillatory slow-wave activity has been analyzed in traditional frequency bands like slow-oscillatory (< 1 Hz), delta (1-4 Hz), theta (4)(5)(6)(7)(8)(9)(10)(11), beta (11)(12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25)(26)(27)(28)(29)(30), gamma and high gamma (55-100 Hz). Sensorimotor function, speech, memory, perception, cognition and behavior-all brain information processing is accompanied by characteristic brain wave activity, reflected in the composition, power, and duration of neuronal local field potentials in these frequency bands.…”

Actionable Genomics in Clinical Practice: Paradigmatic Case Reports of Clinical and Therapeutic Strategies Based upon Genetic Testing

“…In fact, several studies were already indicating that by elevating δ-catenin, lithium could influence the clustering of AMPA receptors in the post-synaptic element of glutamatergic synapses, actively modulating neuronal activity [33]. More recently, lithium has been convincingly shown to enhance regular syncronous neuronal activity at therapeutic doses, whereas it produces epileptiform burst-like activity at overdose concentrations: both these effects are AMPA receptor-mediated and indeed lithium-induced epileptiform discharges can be effectively blocked by the AMPA receptor antagonist perampanel [34]. Collectively these studies point toward lithium as a potentially beneficial drug for this patient.…”

Functional Characterization of Human Pluripotent Stem Cell-Derived Models of the Brain with Microelectrode Arrays

“…However, the neurodevelopmental effects of the opioid-replacement drug methadone, for example, were shown to include disruption of neuronal growth and a dose-dependent (transient or permanent) reduction in firing in a cortical organoid model of MEA [ 227 ]. On a similar note, lithium salts used as mood stabilizers were shown to cause increased neuronal activity in 3D neural aggregates on MEA, and high concentrations were shown to elicit epileptiform activity [ 228 ]. hiPSC-derived cerebral organoids have been used to model certain psychiatric disorders and neurodegenerative diseases, and the studies are listed in Table 2 .…”