A Locus Coeruleus- dorsal CA1 dopaminergic circuit modulates memory linking

Individual memories are often linked so that the recall of one triggers the recall of another. For example, contextual memories acquired close in time can be linked, and this is known to depend on temporary increase in excitability that drive the overlap between dorsal CA1 (dCA1) hippocampal ensembles encoding the linked memories. Here, we show that the Locus Coeruleus (LC) cells projecting to dCA1 have a key permissive role in contextual memory linking, without affecting contextual memory formation, and that this effect is mediated by dopamine and not by noradrenaline. Additionally, we found that LC to dCA1 projecting neurons modulate the excitability of dCA1 neurons, and the extent of overlap between dCA1 memory ensembles, as well as the stability of coactivity patterns within these ensembles. This discovery of a neuromodulatory system that specifically affects memory linking without affecting memory formation, reveals a fundamental separation between the brain mechanisms that modulate these two distinct processes.

Superoxide dismutase, BDNF and cognitive improvement in drug-naive first episode patients with schizophrenia: a 12-week longitudinal study

Objective Cognitive improvement after antipsychotic agents in patients with schizophrenia (SCZ) appears to involve redox regulation through neurotrophins such as brain derived neurotropic factor (BDNF). This study examined whether cognitive improvement was associated with the increase in superoxide dismutase (SOD), and whether higher levels of BDNF could have a permissive role in allowing SOD to improve cognition. Methods We examined this hypothesis in 183 drug-naïve first episode (DNFE) SCZ patients taking risperidone monotherapy for 12 weeks. We measured total copper-zinc superoxide dismutase (CuZn-SOD), manganese superoxide dismutase (Mn-SOD) and SOD activities and BDNF levels in these patients and compared their levels to 152 healthy controls. We assessed cognitive functioning and clinical symptoms at baseline and 12-week follow-up. Results After treatment with risperidone, CuZn-SOD activity was significantly increased, and BDNF levels were slightly increased. Increased CuZn-SOD activity was associated with the cognitive effectiveness of risperidone monotherapy. The BDNF levels and SOD activities were correlated at baseline, but not correlated after 12-week treatment. Furthermore, baseline CuZn-SOD activity positively correlated with improvement on the delayed memory subscale of the RBANS only in high BDNF subgroup. Conclusions Our longitudinal study suggests that risperidone can enhance SOD activity and that in combination with higher baseline BDNF levels acting in a permissive role can improve cognitive impairments in SCZ. Greater baseline CuZn-SOD activity also may have predictive value for cognitive improvement of delayed memory in SCZ patients getting risperidone treatment.

Ectonucleotidase Modulation of Lymphocyte Function in Gut and Liver

Imbalance between regulatory and effector T lymphocytes contributes to loss of immunotolerance and plays a permissive role in the initiation, perpetuation, and progression of chronic inflammatory diseases and autoimmune disorders. Regulatory/effector cell balance is governed by the CD39 ectonucleotidase, the prototype member of the NTPDase family that hydrolyzes ATP and ADP into AMP, subsequently converted into adenosine by CD73. Generation of adenosine impacts T-cell function as it contributes to the mechanism of suppression of Tregs and confers regulatory properties to pathogenic Th17-cells. CD39 cell distribution, mechanism of regulation and impact on inflammatory and regulatory signaling pathways are also discussed here. Innovative therapeutic strategies to boost CD39 levels and activity by either administering soluble ADPases or interfering with CD39 inhibitory signals are reviewed. Restoration of CD39 levels and function has enormous translational and clinical implications and should be regarded as an additional form of treatment to be deployed in the chronic inflammatory setting. The key role of CD39 in immunoregulation in the context of Crohn's disease, one of the most frequent manifestations of inflammatory bowel disease, and autoimmune hepatitis, an autoimmune disorder of the liver, is reviewed and discussed here.

Transcription cofactor GRIP1 differentially affects myeloid cell–driven neuroinflammation and response to IFN-β therapy

Macrophages (MФ) and microglia (MG) are critical in the pathogenesis of multiple sclerosis (MS) and its mouse model, experimental autoimmune encephalomyelitis (EAE). Glucocorticoids (GCs) and interferon β (IFN-β) are frontline treatments for MS, and disrupting each pathway in mice aggravates EAE. Glucocorticoid receptor–interacting protein 1 (GRIP1) facilitates both GR and type I IFN transcriptional actions; hence, we evaluated the role of GRIP1 in neuroinflammation. Surprisingly, myeloid cell–specific loss of GRIP1 dramatically reduced EAE severity, immune cell infiltration of the CNS, and MG activation and demyelination specifically during the neuroinflammatory phase of the disease, yet also blunted therapeutic properties of IFN-β. MФ/MG transcriptome analyses at the bulk and single-cell levels revealed that GRIP1 deletion attenuated nuclear receptor, inflammatory and, interestingly, type I IFN pathways and promoted the persistence of a homeostatic MG signature. Together, these results uncover the multifaceted function of type I IFN in MS/EAE pathogenesis and therapy, and an unexpectedly permissive role of myeloid cell GRIP1 in neuroinflammation.