cAMP Response Element-Binding Protein Deficiency Allows for Increased Neurogenesis and a Rapid Onset of Antidepressant Response

cAMP response element-binding protein (CREB) has been implicated in the molecular and cellular mechanisms of chronic antidepressant (AD) treatment, although its role in the behavioral response is unclear. CREB-deficient (CREBαΔ mutant) mice demonstrate an antidepressant phenotype in the tail suspension test (TST) and forced-swim test. Here, we show that, at baseline, CREBαΔ mutant mice exhibited increased hippocampal cell proliferation and neurogenesis compared with wild-type (WT) controls, effects similar to those observed in WT mice after chronic desipramine (DMI) administration. Neurogenesis was not further augmented by chronic DMI treatment in CREBαΔ mutant mice. Serotonin depletion decreased neurogenesis in CREBαΔ mutant mice toWTlevels, which correlated with a reversal of the antidepressant phenotype in the TST. This effect was specific for the reversal of the antidepressant phenotype in these mice, because serotonin depletion did not alter a baseline anxiety-like behavior in CREB mutant mice. The response to chronic AD treatment in the novelty-induced hypophagia (NIH) test may rely on neurogenesis. Therefore, we used this paradigm to evaluate chronic AD treatment in CREB mutant mice to determine whether the increased neurogenesis in these mice alters their response in the NIH paradigm. Whereas both WT and CREBαΔ mutant mice responded to chronic AD treatment in the NIH paradigm, only CREBαΔ mutant mice responded to acute AD treatment. However, in the elevated zero maze, DMI did not reverse anxiety behavior in mutant mice. Together, these data show that increased hippocampal neurogenesis allows for an antidepressant phenotype as well as a rapid onset of behavioral responses to AD treatment

Clinical phenotypes of infantile onset CACNA1A-related disorder

BACKGROUND: CACNA1A-related disorders present with persistent progressive and non-progressive cerebellar ataxia and paroxysmal events: epileptic seizures and non-epileptic attacks. These phenotypes overlap and co-exist in the majority of patients. OBJECTIVE: To describe phenotypes in infantile onset CACNA1A-related disorder and to explore intra-familial variations and genotype-phenotype correlations. MATERIAL AND METHODS: This study was a multicenter international collaboration. A retrospective chart review of CACNA1A patients was performed. Clinical, radiological, and genetic data were collected and analyzed in 47 patients with infantile-onset disorder. RESULTS: Paroxysmal non-epileptic events (PNEE) were observed in 68% of infants, with paroxysmal tonic upward gaze (PTU) noticed in 47% of infants. Congenital cerebellar ataxia (CCA) was diagnosed in 51% of patients including four patients with developmental delay and only one neurological sign. PNEEs were found in 63% of patients at follow-up, with episodic ataxia (EA) in 40% of the sample. Cerebellar ataxia was found in 58% of the patients at follow-up. Four patients had epilepsy in infancy and nine in childhood. Seven infants had febrile convulsions, three of which developed epilepsy later; all three patients had CCA. Cognitive difficulties were demonstrated in 70% of the children. Cerebellar atrophy was found in only one infant but was depicted in 64% of MRIs after age two. CONCLUSIONS: Nearly all of the infants had CCA, PNEE or both. Cognitive difficulties were frequent and appeared to be associated with CCA. Epilepsy was more frequent after age two. Febrile convulsions in association with CCA may indicate risk of epilepsy in later childhood. Brain MRI was normal in infancy. There were no genotype-phenotype correlations found

The role of CREB family transcription factors in depression, anxiety, and antidepressant response

Antidepressant (AD) treatment is used to treat both anxiety and depressive disorders. cAMP response clement binding (CREB) transcription factors are a possible common substrate for both these disorders and their treatment. In the present studies it was revealed that at baseline. CREBαΔ mutant mice exhibited increased hippocampal neurogenesis compared to wild-type (WT) controls. Furthermore, serotonin (5HT) depletion decreased neurogenesis in CREBαΔ mutant mice to WT levels, concurrent with a reversal of the antidepressant phenotype in the tail suspension test (TST). While both WT and CREBαΔ mutant mice responded to chronic AD treatment in the novelty-induced hypophagia (NIH) paradigm, only CREBαΔ mutant mice responded to acute AD treatment, suggesting that increased hippocampal neurogenesis allows for an antidepressant phenotype as well as a rapid onset of behavioral responses to AD treatment. Examination of CREBαΔ mutant mice demonstrated increased levels of the repressor inducible cAMP early repressor (ICER) in brain regions implicated in the modulation of anxiety, which correlated significantly with greater anxiety in the elevated zero maze (EZM). In mice lacking ICER, anxiety behavior in the EZM was decreased. 5HT depletion did not alter baseline anxiety-like behavior in CREBαΔ mutant mice or elevated ICER levels, providing evidence for a role of ICER in mediating the pro-anxiety phenotype found in CREBαΔ mutant mice. The role of CREB in anxiolytic responses to selective serotonin reuptake inhibitor (SSRIs) was examined. WT mice have an anxiolytic response to acute citalopram (CIT), in the NIH. Acute treatment with CIT also had an anxiolytic effect in WT mice in the EZM. Depletion of 5HT prevented the anxiolytic response to CIT, suggesting that the action of 5HT is required. The anxiolytic effect of CIT was concomitant with increased CREB phosphorylation in the hippocampus. Finally, CREB-deficient animals did not have an anxiolytic response to CIT in the EZM, suggesting that CREB is required for the anxiolytic effects of this SSRI treatment

Fast Image-Guided Stratification Using Anti-Programmed Death Ligand 1 Gold Nanoparticles for Cancer Immunotherapy

Cancer immunotherapy has made enormous progress in offering safer and more effective treatments for the disease. Specifically, programmed death ligand 1 antibody (αPDL1), designed to perform immune checkpoint blockade (ICB), is now considered a pillar in cancer immunotherapy. However, due to the complexity and heterogeneity of tumors, as well as the diversity in patient response, ICB therapy only has a 30% success rate, at most; moreover, the efficacy of ICB can be evaluated only two months after start of treatment. Therefore, early identification of potential responders and nonresponders to therapy, using noninvasive means, is crucial for improving treatment decisions. Here, we report a straightforward approach for fast, image-guided prediction of therapeutic response to ICB. In a colon cancer mouse model, we demonstrate that the combination of computed tomography imaging and gold nanoparticles conjugated to αPDL1 allowed prediction of therapeutic response, as early as 48 h after treatment. This was achieved by noninvasive measurement of nanoparticle accumulation levels within the tumors. Moreover, we show that the nanoparticles efficiently prevented tumor growth with only a fifth of the standard dosage of clinical care. This technology may be developed into a powerful tool for early and noninvasive patient stratification as responders or nonresponders