Low levels of vitamin D are prevalent among patients with schizophrenia and have been linked to the risk and outcome of the disorder. Vitamin D has a regulatory effect on the inflammatory system, which is dysfunctional in schizophrenia. We investigated the association between serum vitamin D levels, inflammatory status, and severity of schizophrenia symptoms. A total of 39 clozapine-treated schizophrenia patients were recruited to the study. Blood samples for biochemical analysis were collected from all participants. Serum levels of vitamin D and cytokines (IL-4, IL-6, IL-10, and TNF-α) were analyzed and the association between biochemical and clinical measures was assessed. Most of the sample (82%) had insufficient levels of vitamin D. There was a significant inverse correlation between serum vitamin D and IL-6 levels (Pearson’s r = −0.38, P < 0.05). Vitamin D levels correlated with the severity of positive symptoms (r = 0.39, P < 0.05). These results suggest that within clozapine-treated schizophrenia patients, high levels of vitamin D are associated with lower serum levels of the proinflammatory cytokine IL-6. This relationship may indicate an immunomodulatory effect of vitamin D in treatment-resistant patients with schizophrenia maintained on clozapine.

Mitochondrial Ca2+ efflux by NCLX is a critical rate-limiting step in mitochondria signaling. We previously showed that NCLX is phosphorylated at a putative Casein Kinase 2 (CKII) site, the serine 271 (S271). Here, we asked if NCLX is regulated by CKII and interrogated the physiological implications of this control. We found that CKII inhibitors down-regulated NCLX-dependent Ca2+ transport activity in SH-SY5Y neuronal cells and primary hippocampal neurons. Furthermore, we show that the CKII phosphomimetic mutants on NCLX inhibited (S271A) and constitutively activated (S271D) NCLX transport, respectively, rendering it insensitive to CKII inhibition. These phosphomimetic NCLX mutations also control the allosteric regulation of NCLX by mitochondrial membrane potential (ΔΨm). Since the omnipresent CKII is necessary for modulating the plasticity of the axon initial segment (AIS), we interrogated, in hippocampal neurons, if NCLX is required for this process. Similarly to WT neurons, NCLX-KO neurons can exhibit homeostatic plasticity following M-channel block. However, while WT neurons utilize a CKII-sensitive distal relocation of AIS Na+ and Kv7 channels to decrease their intrinsic excitability, we did not observe such translocation in NCLX-KO neurons. Thus, our results indicate that NCLX is regulated by CKII and is a crucial link between CKII signaling and fast neuronal plasticity.

A large body of studies has investigated bidirectional homeostatic plasticity both in vitro and in vivo using numerous pharmacological manipulations of activity or behavioral paradigms. However, these experiments rarely explored in the same cellular system the bidirectionality of the plasticity and simultaneously on excitatory and inhibitory neurons. M-channels are voltage-gated potassium channels that play a crucial role in regulating neuronal excitability and plasticity. In cultured hippocampal excitatory neurons, we previously showed that chronic exposure to the M-channel blocker XE991 leads to adaptative compensations, thereby triggering at different timescales intrinsic and synaptic homeostatic plasticity. This plastic adaptation barely occurs in hippocampal inhibitory neurons. In this study, we examined whether this homeostatic plasticity induced by M-channel inhibition was bidirectional by investigating the acute and chronic effects of the M-channel opener retigabine on hippocampal neuronal excitability. Acute retigabine exposure decreased excitability in both excitatory and inhibitory neurons. Chronic retigabine treatment triggered in excitatory neurons homeostatic adaptation of the threshold current and spontaneous firing rate at a time scale of 4–24 h. These plastic changes were accompanied by a substantial decrease in the M-current density and by a small, though significant, proximal relocation of Kv7.3-FGF14 segment along the axon initial segment. Thus, bidirectional homeostatic changes were observed in excitatory neurons though not symmetric in kinetics and mechanisms. Contrastingly, in inhibitory neurons, the compensatory changes in intrinsic excitability barely occurred after 48 h, while no homeostatic normalization of the spontaneous firing rate was observed. Our results indicate that excitatory and inhibitory hippocampal neurons differ in their adaptation to chronic alterations in neuronal excitability induced by M-channel bidirectional modulation.