Prior short-term synaptic disinhibition facilitates long-term potentiation and suppresses long-term depression at CA1 hippocampal synapses

Long-term potentiation (LTP) and long-term depression (LTD) are two main forms of activity-dependent synaptic plasticity that have been extensively studied as the putative mechanisms underlying learning and memory. Current studies have demonstrated that prior synaptic activity can influence the subsequent induction of LTP and LTD at Schaffer collateral-CA1 synapses. Here, we show that prior short-term synaptic disinhibition induced by type A gamma-aminobutyric acid (GABA) receptor antagonist picrotoxin exhibited a facilitation of LTP induction and an inhibition of LTD induction. This effect lasted between 10 and 30 min after washout of picrotoxin and was specifically inhibited by the L-type voltage-operated Ca2+ channel (VOCC) blocker nimodipine, but not by the N-methyl-D-aspartate (NMDA) receptor antagonist D-2-amino-5-phosphopentanoic acid (D-APV). Moreover, this picrotoxin-induced priming effect was mimicked by forskolin, an activator of cyclic adenosine monophosphate (cAMP)-dependent protein kinase (PKA), and was blocked by the adenylyl cyclase inhibitor 9-(tetrahydro-2-furanyl)-9H-purin-6-amine (SQ 22536) and the PKA inhibitor Rp-adenosine 3',5'-cyclic monophosphothioate (Rp-cAMPS). It was also found that following picrotoxin application, CA1 neurons have a higher probability of synchronous discharge in response to a population of excitatory postsynaptic potential (EPSP) of fixed slope (EPSP/spike potentiation). However, picrotoxin treatment did not significantly affect paired-pulse facilitation (PPF). These findings suggest that a brief of GABAergic disinhibition can act as a priming stimulus for the subsequent induction of LTP and LTD at Schaffer collateral-CA1 synapses. The increase in Ca2+ influx through L-type VOCCs in turn triggering a cAMP/PKA signalling pathway is a possible molecular mechanism underlying this priming effect.     

Cyclical changes in endogenous levels of oestrogen modulate the induction of LTD and LTP in the hippocampal CA1 region

The present study investigated the effects of naturally fluctuating endogenous levels of oestrogen on the induction and maintenance of long-term potentiation (LTP) and long-term depression (LTD) in the CA1 region of the hippocampus. Using an anaesthetized in vivo preparation, the results showed that the induction of LTP was augmented during the pro-oestrous stage of the oestrous cycle. In contrast to LTP, however, the induction of paired-pulse LTD was severely attenuated during pro-oestrous, but was clearly manifested by rats during met/dioestrous and oestrous stages of the cycle. These findings are discussed with reference to: (i) the modulatory effects of oestrogen on N-methyl-D-aspartate (NMDA) receptor function and gamma-aminobutyric acid (GABA) neurotransmission in the hippocampus; and (ii) the functional implications that such cyclical changes in synaptic plasticity have for learning and memory processes supported by the hippocampus.     

CCL2/CCR2 Contributes to the Altered Excitatory-inhibitory Synaptic Balance in the Nucleus Accumbens Shell Following Peripheral Nerve Injury-induced Neuropathic Pain

The medium spiny neurons (MSNs) in the nucleus accumbens (NAc) integrate excitatory and inhibitory synaptic inputs and gate motivational and emotional behavior output. Here we report that the relative intensity of excitatory and inhibitory synaptic inputs to MSNs of the NAc shell was decreased in mice with neuropathic pain induced by spinal nerve ligation (SNL). SNL increased the frequency, but not the amplitude of spontaneous inhibitory postsynaptic currents (sIPSCs), and decreased both the frequency and amplitude of spontaneous excitatory postsynaptic currents (sEPSCs) in the MSNs. SNL also decreased the paired-pulse ratio (PPR) of evoked IPSCs but increased the PPR of evoked EPSCs. Moreover, acute bath application of C–C motif chemokine ligand 2 (CCL2) increased the frequency and amplitude of sIPSCs and sEPSCs in the MSNs, and especially strengthened the amplitude of N-methyl-D-aspartate receptor (NMDAR)-mediated miniature EPSCs. Further Ccl2 overexpression in the NAc in vivo decreased the peak amplitude of the sEPSC/sIPSC ratio. Finally, Ccr2 knock-down improved the impaired induction of NMDAR-dependent long-term depression (LTD) in the NAc after SNL. These results suggest that CCL2/CCR2 signaling plays a role in the integration of excitatory/inhibitory synaptic transmission and leads to an increase of the LTD induction threshold at the synapses of MSNs during neuropathic pain.     

流行性乙型脑炎疫苗纯化工艺的建立

目前我国流行性乙型脑炎 (乙脑 )疫苗已形成规模化生产 ,并取得了较好的预防效果[1 ] ,但此种疫苗属粗制疫苗 ,其抗原含量较低 ,异源蛋白和亚细胞成分较多 ,临床应用存在一定副反应 ,因此有必要将疫苗进行浓缩纯化 ,以提高疫苗的免疫效果和降低副反应。经过几年的探索 ,我们建立了乙脑疫苗的纯化工艺 ,并在国内率先通过国家新药评审。现将纯化工艺报告如下。1 .材料与方法 :①乙脑SA1 4 1 4 2减毒株 ,由中国药品生物制品检定所提供。②地鼠肾细胞制备 :按现行地鼠肾细胞乙脑疫苗 (PHKJE)生产工艺进行。地鼠从卫生部北京生物制品研究所…     

Adolescent brain maturation,the endogenous cannabinoid system and the neurobiology of cannabis-induced schizophrenia

Cannabis use during adolescence increases the risk of developing psychotic disorders later in life. However, the neurobiological processes underlying this relationship are unknown. This review reports the results of a literature search comprising various neurobiological disciplines, ultimately converging into a model that might explain the neurobiology of cannabis-induced schizophrenia. The article briefly reviews current insights into brain development during adolescence. In particular, the role of the excitatory neurotransmitter glutamate in experience-dependent maturation of specific cortical circuitries is examined. The review also covers recent hypotheses regarding disturbances in strengthening and pruning of synaptic connections in the prefrontal cortex, and the link with latent psychotic disorders. In the present model, cannabis-induced schizophrenia is considered to be a distortion of normal late postnatal brain maturation. Distortion of glutamatergic transmission during critical periods may disturb prefrontal neurocircuitry in specific brain areas. Our model postulates that adolescent exposure to Δ9-tetrahydrocannabinol (THC), the primary psychoactive substance in cannabis, transiently disturbs physiological control of the endogenous cannabinoid system over glutamate and GABA release. As a result, THC may adversely affect adolescent experience-dependent maturation of neural circuitries within prefrontal cortical areas. Depending on dose, exact time window and duration of exposure, this may ultimately lead to the development of psychosis or schizophrenia. The proposed model provides testable hypotheses which can be addressed in future studies, including animal experiments, reanalysis of existing epidemiological data, and prospective epidemiological studies in which the role of the dose–time–effect relationship should be central.     

Foot disorders in the elderly: A mini-review

Ageing process is associated with changes to the aspect, biomechanics, structure and function of the foot, it may be related with a marked presence of foot conditions, pain, disability and other overall health problems that constitute a major public health concern.Also, the prevalence of epidemiologic research found an incidence of foot problems which is even higher as a consequence of increasing life expectation. Several studies have also suggested that such foot disorders currently affect between 71 and 87% of older patients and are a frequent cause of medical and foot care.Thus, these kind problems are extremely common conditions in the general population, especially in the elderly who are associated with poor quality of life, balance impairment, increase the risk of falls, dificulty on putting shoes, fractures, restrict mobility and performance of activities of daily living that turn can produce serious physical, mental and social consequences in the older people.The role of the physician in the assessment, evaluation, and examination of foot problems is very important, yet it is often an overlooked and undervalued component of geriatric health care.The purpose of this article is to review and to provide an overview of the most common foot deformities precipitating factors, clinical presentation, evidence-based diagnostic evaluation, and treatment recommendations with a view to preventing medical conditions or deformities affecting the feet that may alter foot condition and general health amongst the elderly.     

Adenosine A2A receptors and basal ganglia physiology

Adenosine A2A receptors are highly enriched in the basal ganglia system. They are predominantly expressed in enkephalin-expressing GABAergic striatopallidal neurons and therefore are highly relevant to the function of the indirect efferent pathway of the basal ganglia system. In these GABAergic enkephalinergic neurons, the A2A receptor tightly interacts structurally and functionally with the dopamine D2 receptor. Both by forming receptor heteromers and by targeting common intracellular signaling cascades, A2A and D2 receptors exhibit reciprocal antagonistic interactions that are central to the function of the indirect pathway and hence to basal ganglia control of movement, motor learning, motivation and reward. Consequently, this A2A/D2 receptors antagonistic interaction is also central to basal ganglia dysfunction in Parkinson's disease. However, recent evidence demonstrates that, in addition to this post-synaptic site of action, striatal A2A receptors are also expressed and have physiological relevance on pre-synaptic glutamatergic terminals of the cortico-limbic-striatal and thalamo-striatal pathways, where they form heteromeric receptor complexes with adenosine A1 receptors. Therefore, A2A receptors play an important fine-tuning role, boosting the efficiency of glutamatergic information flow in the indirect pathway by exerting control, either pre- and/or post-synaptically, over other key modulators of glutamatergic synapses, including D2 receptors, group I metabotropic mGlu5 glutamate receptors and cannabinoid CB1 receptors, and by triggering the cAMP-protein kinase A signaling cascade.