抗原变异可使得多种致病微生物易于逃避宿主免疫应答。表达在感染红细胞表面的恶性疟原虫红细胞表面蛋白1（PfPMP1）与感染红细胞、内皮细胞、树突状细胞以及胎盘的单个或多个受体作用，在黏附及免疫逃避中起关键的作用。每个单倍体基因组var基因家族编码约60种成员，通过启动转录不同的var基因变异体为抗原变异提供了分子基础。

疟原虫var基因转换速率变化导致抗原变异[英]／Paul H, Robert P, Christodoulou Z, et al//Proc Natl Acad Sci U S A

The adult brain is a plastic place. To ensure that the mature nervous system's control of behaviour is flexible in the face of a varying environment, morphological and physiological changes are possible at many levels, including that of the entire cell. In two areas of the adult brain - the olfactory bulb and the dentate gyrus - new neurons are generated throughout life and form an integral part of the normal functional circuitry. This process is not fixed, but highly modulated, revealing a plastic mechanism by which the brain's performance can be optimized for a given environment. The functional benefits of this whole-cell plasticity, however, remain a matter for debate.

Adult neurogenesis and functional plasticity in neuronal circuits

Ageing is the primary risk factor for most neurodegenerative diseases, including Alzheimer disease (AD) and Parkinson disease (PD). One in ten individuals aged ≥65 years has AD and its prevalence continues to increase with increasing age. Few or no effective treatments are available for ageing-related neurodegenerative diseases, which tend to progress in an irreversible manner and are associated with large socioeconomic and personal costs. This Review discusses the pathogenesis of AD, PD and other neurodegenerative diseases, and describes their associations with the nine biological hallmarks of ageing: genomic instability, telomere attrition, epigenetic alterations, loss of proteostasis, mitochondrial dysfunction, cellular senescence, deregulated nutrient sensing, stem cell exhaustion and altered intercellular communication. The central biological mechanisms of ageing and their potential as targets of novel therapies for neurodegenerative diseases are also discussed, with potential therapies including NAD+ precursors, mitophagy inducers and inhibitors of cellular senescence.

Ageing as a risk factor for neurodegenerative disease.

Developing networks follow common rules to shift from silent cells to coactive networks that operate via thousands of synapses. This review deals with some of these rules and in particular those concerning the crucial role of the neurotransmitter gamma-aminobuytric acid (GABA), which operates primarily via chloride-permeable GABA(A) receptor channels. In all developing animal species and brain structures investigated, neurons have a higher intracellular chloride concentration at an early stage leading to an efflux of chloride and excitatory actions of GABA in immature neurons. This triggers sodium spikes, activates voltage-gated calcium channels, and acts in synergy with NMDA channels by removing the voltage-dependent magnesium block. GABA signaling is also established before glutamatergic transmission, suggesting that GABA is the principal excitatory transmitter during early development. In fact, even before synapse formation, GABA signaling can modulate the cell cycle and migration. The consequence of these rules is that developing networks generate primitive patterns of network activity, notably the giant depolarizing potentials (GDPs), largely through the excitatory actions of GABA and its synergistic interactions with glutamate signaling. These early types of network activity are likely required for neurons to fire together and thus to "wire together" so that functional units within cortical networks are formed. In addition, depolarizing GABA has a strong impact on synaptic plasticity and pathological insults, notably seizures of the immature brain. In conclusion, it is suggested that an evolutionary preserved role for excitatory GABA in immature cells provides an important mechanism in the formation of synapses and activity in neuronal networks.

GABA: A Pioneer Transmitter That Excites Immature Neurons and Generates Primitive Oscillations

Depression is a common, devastating illness. Current pharmacotherapies help many patients, but high rates of a partial response or no response, and the delayed onset of the effects of antidepressant therapies, leave many patients inadequately treated. However, new insights into the neurobiology of stress and human mood disorders have shed light on mechanisms underlying the vulnerability of individuals to depression and have pointed to novel antidepressants. Environmental events and other risk factors contribute to depression through converging molecular and cellular mechanisms that disrupt neuronal function and morphology, resulting in dysfunction of the circuitry that is essential for mood regulation and cognitive function. Although current antidepressants, such as serotonin-reuptake inhibitors, produce subtle changes that take effect in weeks or months, it has recently been shown that treatment with new agents results in an improvement in mood ratings within hours of dosing patients who are resistant to typical antidepressants. Within a similar time scale, these new agents have also been shown to reverse the synaptic deficits caused by stress.

/pdf/synaptic-plasticity-and-depression-new-insights-from-stress-32jiyu1l5f.pdf

Synaptic plasticity and depression: new insights from stress and rapid-acting antidepressants

Bridging animal and human models of exercise-induced brain plasticity.

Accumulating evidence from animal and human research shows exercise benefits learning and memory, which may reduce the risk of neurodegenerative diseases, and could delay age-related cognitive decline. Exercise-induced improvements in learning and memory are correlated with enhanced adult hippocampal neurogenesis and increased activity-dependent synaptic plasticity. In this present chapter we will highlight the effects of physical activity on cognition in rodents, as well as on dentate gyrus (DG) neurogenesis, synaptic plasticity, spine density, neurotransmission and growth factors, in particular brain-derived nerve growth factor (BDNF).

All about running: synaptic plasticity, growth factors and adult hippocampal neurogenesis.

Adult hippocampal neurogenesis is considered important for cognition. The integration of newborn dentate gyrus granule cells into the existing network is regulated by afferent neuronal activity of unspecified origin. Here we combine rabies virus-mediated retrograde tracing with retroviral labelling of new granule cells (21, 30, 60, 90 days after injection) to selectively identify and quantify their monosynaptic inputs in vivo. Our results show that newborn granule cells receive afferents from intra-hippocampal cells (interneurons, mossy cells, area CA3 and transiently, mature granule cells) and septal cholinergic cells. Input from distal cortex (perirhinal (PRH) and lateral entorhinal cortex (LEC)) is sparse 21 days after injection and increases over time. Patch-clamp recordings support innervation by the LEC rather than from the medial entorhinal cortex. Mice with excitotoxic PRH/LEC lesions exhibit deficits in pattern separation but not in water maze learning. Thus, PRH/LEC input is an important functional component of new dentate gyrus neuron circuitry.

/pdf/monosynaptic-inputs-to-new-neurons-in-the-dentate-gyrus-244ka3s6ao.pdf

Monosynaptic inputs to new neurons in the dentate gyrus

Calcium (Ca2+) plays fundamental and diversified roles in neuronal plasticity. As second messenger of many signaling pathways, Ca2+ as been shown to regulate neuronal gene expression, energy production, membrane excitability, synaptogenesis, synaptic transmission, and other processes underlying learning and memory and cell survival. The flexibility of Ca2+ signaling is achieved by modifying cytosolic Ca2+ concentrations via regulated opening of plasmamembrane and subcellular Ca2+ sensitive channels. The spatiotemporal patterns of intracellular Ca2+ signals, and the ultimate cellular biological outcome, are also dependent upon termination mechanism, such as Ca2+ buffering, extracellular extrusion, and intra-organelle sequestration. Because of the central role played by Ca2+ in neuronal physiology, it is not surprising that even modest impairments of Ca2+ homeostasis result in profound functional alterations. Despite their heterogeneous etiology neurodegenerative disorders, as well as the healthy aging process, are all characterized by disruption of Ca2+ homeostasis and signaling. In this review we provide an overview of the main types of neuronal Ca2+ channels and their role in neuronal plasticity. We will also discuss the participation of Ca2+ signaling in neuronal aging and degeneration.

/pdf/physiology-and-pathology-of-calcium-signaling-in-the-brain-1dmgfe7log.pdf

Physiology and pathology of calcium signaling in the brain.

The hippocampus is crucial for memory formation. New neurons are added throughout life to the hippocampal dentate gyrus (DG), a brain area considered important for differential storage of similar experiences and contexts. To better understand the functional contribution of adult neurogenesis to pattern separation processes, we recently used a novel synapse specific trans-neuronal tracing approach to identify the (sub) cortical inputs to new dentate granule cells (GCs). It was observed that newly born neurons receive sequential innervation from structures important for memory function. Initially, septal-hippocampal cells provide input to new neurons, including transient innervation from mature GCs as well as direct feedback from area CA3 pyramidal neurons. After about 1 month perirhinal (PRH) and lateral entorhinal cortex (LEC), brain areas deemed relevant to integration of novel sensory and environmental information, become substantial input to new GCs. Here, we review the developmental time-course and proposed functional relevance of new neurons, within the context of their unique neural circuitry.

/pdf/functional-circuits-of-new-neurons-in-the-dentate-gyrus-53e3mvaaen.pdf

Carmen Vivar

Papers

Bridging animal and human models of exercise-induced brain plasticity.

All about running: synaptic plasticity, growth factors and adult hippocampal neurogenesis.

Monosynaptic inputs to new neurons in the dentate gyrus

Physiology and pathology of calcium signaling in the brain.

Functional circuits of new neurons in the dentate gyrus