Biology subjects

Mylonaki, K.

Publications and source records attributed to Mylonaki, K..

2 recordsLinked to original sources

bioRxiv2026

Persistent enhancement of intrinsic neuronal excitability induced by transient divalent cation depletion

Fluctuations in external calcium concentration [Ca2+]e occur during the wake and sleep cycle and during intense neuronal activity. However, the incidence of these fluctuations on neuronal excitability is not precisely known. We show here that reducing divalent cation (Ca2+ and Mg2+) concentrations from 1.3/0.8 to 0.6/0.4 mM during 15-30 minutes induces long-term potentiation of intrinsic excitability (LTP-IE) in CA1 pyramidal neurons. LTP-IE induced by low divalent cations is associated with a hyperpolarization of the action potential threshold and constitutes a positive feed-back of brain activity. This plasticity requires Ca2+-sensing receptor (CaSR), IP3 receptor (IP3R) and calcium-calmodulin kinase II (CaMKII). In fact, LTP-IE was occluded in the presence of the calcilytic NPS-2143 and absent in CRISPR CaSR neurons. In addition, inhibiting IP3R with 2-APB and CaMKII with kin considerably reduced LTP-IE magnitude. LTP-IE and synaptic potentiation (LTP) induced by spike-timing-dependent plasticity (STDP) protocol were also found to depend on CaSR as they were totally absent in CRISPR CaSR neurons. Spontaneous excitatory synaptic activity was found to be reduced by [~]35% following LTP induced by STDP. Importantly, this drop of spontaneous activity was not observed in CRISPR CaSR neurons. Taken together, these results show that CaSR plays a critical role in LTP-IE induced by low [Ca2+]e and [Mg2+]e and as well as in LTP of synaptic transmission and intrinsic excitability induced by STDP.

neuroscience↗

bioRxiv2025

Divalent cation depletion enhances neuronal excitability through CaSR-dependent modulation of threshold channels

External calcium ([Ca{superscript 2}]{square}) and magnesium ([Mg{superscript 2}]{square}) concentrations fluctuate across physiological and pathological brain states. For example, [Ca{superscript 2}]{square} decreases during intense neuronal activity and epilepsy, whereas it rises during sleep. Similarly, [Mg{superscript 2}]{square} varies with the sleep/wake cycle and is reduced in epilepsy. Lowering either [Ca2+]e or [Mg2+]e increases intrinsic excitability and hyperpolarizes the action potential (AP) threshold, yet the underlying mechanisms remain unclear. Here, we confirm that reducing [Ca2+]e or [Mg2+]e enhances intrinsic excitability and hyperpolarizes the AP threshold of CA1 pyramidal neurons. Physiological reductions in [Mg{superscript 2}]{square} (0.8 [->] 0.4 mM) have minimal effect, whereas decreases from supraphysiological levels (2.0 [->] 0.4 mM) robustly increase excitability. Using pharmacology and CRISPR/Cas9 gene editing, we identify the calcium-sensing receptor (CaSR) as a key mediator of these effects. The calcilytic NPS-2143 mimics and largely occludes both the intrinsic excitability increase and the AP-threshold hyperpolarization, while genetic reduction of CaSR produces similar outcomes. We further show that AP-threshold hyperpolarization induced by low divalent cations involves both Kv1 and Nav1.2 channels. Together, these findings reveal CaSR as a critical link between external divalent cation levels and intrinsic neuronal excitability through the modulation of Kv1 and Nav channels.

neuroscience↗