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

Abstract

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.