No abstract

Large-scale genome-wide association studies have consistently shown that genetic variation in CACNA1C, a gene that encodes calcium voltage-gated channel subunit alpha1C, increases risk for psychiatric disorders. CACNA1C encodes the Cav1.2 subunit of voltage-gated calcium channels, which themselves have been functionally implicated in a broad spectrum of neuropsychiatric syndromes. Research has concentrated on uncovering the underlying biological mechanisms that could be responsible for this increased risk. This review presents an overview of recent findings regarding Cacna1c variation in animal models, particularly focusing on behavioral phenotypes associated with neurodevelopmental disorders such as cognition, anxiety and depressive phenotypes, and fear conditioning. The impact of reduced gene dosage of Cacna1c on adult hippocampal neurogenesis is also assessed, including new data from a novel Cacna1c+/- rat model.

The biological basis of the increased risk for psychiatric disorders seen in 15q11.2 copy number deletion is unknown. Previous work has shown disturbances in white matter tracts in human carriers of the deletion. Here, in a novel rat model, we recapitulated low dosage of the candidate risk gene CYFIP1 present within the 15q11.2 interval. Using diffusion tensor imaging, we first showed extensive white matter changes in Cyfip1 mutant rats, which were most pronounced in the corpus callosum and external capsule. Transmission electron microscopy showed that these changes were associated with thinning of the myelin sheath in the corpus callosum. Myelin thinning was independent of changes in axon number or diameter but was associated with effects on mature oligodendrocytes, including aberrant intracellular distribution of myelin basic protein. Finally, we demonstrated effects on cognitive phenotypes sensitive to both disruptions in myelin and callosal circuitry.

BackgroundLarge-scale macrophage infiltration and reactive astrogliosis are hallmarks of early spinal cord injury (SCI) pathology. The exact nature of the macrophage response and relationship between these phenomena have not been explored in detail. Here, we have investigated these responses using a combination of in vivo SCI models, organotypic and primary cultures.MethodsIn vivo macrophage response was investigated using a contusive injury mouse model. Interactions between astrocytes and macrophages were studied in primary or organotypic cultures. Proliferation was assessed though MTT assay and nucleotide incorporation and gene expression changes through qPCR.ResultsSeven days following contusive SCI, a mixed M1/M2 macrophage response was seen in the injury site. Conditioned medium from primary M1, but not M2, macrophages are able to induce astrocyte proliferation in both organotypic spinal cord cultures and primary astrocytes. Soluble factors from M1 macrophages induce a reactive astrocyte gene expression pattern, whereas M2 factors inhibit expression of these genes. M2-stimulated astrocytes are also able to decrease both M1 and M2 macrophage proliferation and decrease TNFα production in M1 macrophages.ConclusionsThese results suggest a strong role of M1 macrophages in inducing reactive astrogliosis and the existence of an astrocyte-mediated negative feedback system in order to dampen the immune response. These results, combined with the poor outcomes of the current immunosuppressive steroid treatments in SCI, indicate the need for more targeted therapies, taking into account the significantly different effects of M1 and M2 macrophages, in order to optimise outcome.Electronic supplementary materialThe online version of this article (doi:10.1186/s12974-015-0327-3) contains supplementary material, which is available to authorized users.

Significance: Nervous system injuries, both in the peripheral nervous system (PNS) and central nervous system are a major cause for pain, loss-of-function, and impairment of daily life. As nervous system injuries commonly heal slowly or incompletely, new therapeutic approaches may be required. Recent Advances: The observation that cultured neurons are able to respond to exogenous electric fields (EFs) by sprouting more neurites and directing growth along the field, along with the presence of endogenous EFs in the developing vertebrate nervous system have led to the suggestion of the use of EFs in a regenerative therapeutic setting. This review discusses the effects of EFs on nervous cells, and their use in the treatment of nervous injuries in the eye, limb nerves, and the spinal cord. Exogenous EFs have been shown to be neuroprotective in various injury models of the eye, including traumatic injury, congenital degenerative retinopathy, and glaucoma. In the PNS, EFs are able to stimulate regrowth and functional recovery in damaged limb nerves. In the spinal cord, axonal regeneration and improved quality of life may be achieved using EF stimulation. Critical Issues: The optimal paradigm for electrical stimulation has not been determined, and the mechanisms behind the effect of EF are still largely unknown. Future Directions: Although the therapeutic use of EFs in the nervous system is still in its infancy, it is a promising therapeutic avenue for otherwise hard to treat injuries. The cellular/molecular mechanisms of such regulation need to be fully investigated, and the efficiency of applied EFs during wound healing needs to be optimized in a systematic approach in both animal models and future clinical trials. SCOPE AND SIGNIFICANCENervous system injuries can be divided into two categories: central nervous system (CNS) insult and peripheral nervous system (PNS) injury. CNS and PNS injuries commonly have poor clinical outcome, and cause heavy financial burdens to the society, as well as emotional and physical challenges to the patients and their families. In the United States alone *450,000 people have sustained traumatic spinal cord injuries (SCIs), with more than 10,000 new cases emerging every year. In China, the incidence of SCI is *60,000 per year. The average annual medical cost ranges from $15,000 to $30,000 per year per SCI patient, and the estimated lifetime cost ranges between $500,000 and more than $3 million, depending on injury severity.1 Despite various efforts in treatment of nervous system injuries; the clinical outcomes were not satisfactory largely due to the limited regeneration capacity of the nervous system. Many new

Complement is a key component of the immune system with roles in inflammation and host-defence. Here we reveal novel functions of complement pathways impacting on emotional reactivity of potential relevance to the emerging links between complement and risk for psychiatric disorder. We used mouse models to assess the effects of manipulating components of the complement system on emotionality. Mice lacking the complement C3a Receptor (C3aR -/-) demonstrated a selective increase in unconditioned (innate) anxiety whilst mice deficient in the central complement component C3 (C3 -/-) showed a selective increase in conditioned (learned) fear. The dissociable behavioural phenotypes were linked to different signalling mechanisms.Effects on innate anxiety were independent of C3a, the canonical ligand for C3aR, consistent with the existence of an alternative ligand mediating innate anxiety, whereas effects on learned fear were due to loss of iC3b/CR3 signalling. Our findings show that specific elements of the complement system and associated signalling pathways contribute differentially to heightened states of anxiety and fear commonly seen in psychopathology.

Background The dentate gyrus exhibits life-long neurogenesis of granule-cell neurons, supporting hippocampal dependent learning and memory. Both temporal lobe epilepsy patients and animal models frequently have hippocampal-dependent learning and memory difficulties and show evidence of reduced neurogenesis. Animal and human temporal lobe epilepsy studies have also shown strong innate immune system activation, which in animal models reduces hippocampal neurogenesis. We sought to determine if and how neuroinflammation signals reduced neurogenesis in the epileptic human hippocampus and its potential reversibility. Methods We isolated endogenous neural stem cells from surgically resected hippocampal tissue in 15 patients with unilateral hippocampal sclerosis. We examined resultant neurogenesis after growing them either as neurospheres in an ideal environment, in 3D cultures which preserved the inflammatory microenvironment and/or in 2D cultures which mimicked it. Results 3D human hippocampal cultures largely replicated the cellular composition and inflammatory environment of the epileptic hippocampus. The microenvironment of sclerotic human epileptic hippocampal tissue is strongly anti-neurogenic, with sustained release of the proinflammatory proteins HMGB1 and IL-1β. IL-1β and HMGB1 significantly reduce human hippocampal neurogenesis and blockade of their IL-1R and TLR 2/4 receptors by IL1Ra and Box-A respectively, significantly restores neurogenesis in 2D and 3D culture. Conclusion Our results demonstrate a HMGB1 and IL-1β-mediated environmental anti-neurogenic effect in human TLE, identifying both the IL-1R and TLR 2/4 receptors as potential drug targets for restoring human hippocampal neurogenesis in temporal lobe epilepsy.

Genetic risk factors can significantly increase chances of developing psychiatric disorders, but the underlying biological processes through which this risk is effected remain largely unknown. Here we show that haploinsufficiency of Cyfip1, a candidate risk gene present in the pathogenic 15q11.2(BP1–BP2) deletion may impact on psychopathology via abnormalities in cell survival and migration of newborn neurons during postnatal hippocampal neurogenesis. We demonstrate that haploinsufficiency of Cyfip1 leads to increased numbers of adult-born hippocampal neurons due to reduced apoptosis, without altering proliferation. We show this is due to a cell autonomous failure of microglia to induce apoptosis through the secretion of the appropriate factors, a previously undescribed mechanism. Furthermore, we show an abnormal migration of adult-born neurons due to altered Arp2/3 mediated actin dynamics. Together, our findings throw new light on how the genetic risk candidate Cyfip1 may influence the hippocampus, a brain region with strong evidence for involvement in psychopathology.