Nerve cell function and synaptic mechanisms

Nerve cells (neurones) are ‘excitable’ cells that can transduce a variety of stimuli into electrical signals, continuously sending information about the external and internal environment (in the form of sequences of action potentials) to the central nervous system (CNS). Interneurones in the CNS integrate this information and send signals along output (efferent) neurones to various parts of the body for the appropriate actions to be taken in response to environmental changes. Networks of neurones have been arbitrarily classified into various nervous systems that gather and transmit sensory information and control skeletal muscle function and autonomic function, etc. The junctions between neurones (synapses) are either electrical or chemical. The former permit the direct transfer of electrical current between cells, whereas the latter utilize chemical signalling molecules (neurotransmitters) to transfer information between cells. Neurotransmitters are mainly amino acids, amines or peptides (although other molecules such as purines and nitric oxide are utilized by some cells), and can be excitatory or inhibitory. Individual neurones within the CNS may receive synaptic inputs from thousands of other neurones. Therefore, each neurone ‘integrates’ this vast complexity of inputs and responds accordingly (either by remaining silent or firing action potentials to other neurones). Adaptations in the function and structure of chemical synapses in particular (synaptic plasticity) are thought to underlie the mechanisms mediating cognitive functions (learning and memory).     

Nerve cell function and synaptic mechanisms

Nerve cells (neurones) are ‘excitable’ cells that can transduce a variety of stimuli into electrical signals, continuously sending information about the external and internal environment (in the form of sequences of action potentials) to the central nervous system (CNS). Interneurones in the CNS integrate this information and send signals along output (efferent) neurones to various parts of the body for the appropriate actions to be taken in response to environmental changes. Networks of neurones have been arbitrarily classified into various nervous systems that gather and transmit sensory information and control skeletal muscle function and autonomic function, etc. The junctions between neurones (synapses) are either electrical or chemical. The former permit the direct transfer of electrical current between cells, whereas the latter utilize chemical signalling molecules (neurotransmitters) to transfer information between cells. Neurotransmitters are mainly amino acids, amines or peptides (although other molecules such as purines and nitric oxide are utilized by some cells), and can be excitatory or inhibitory. Individual neurones within the CNS may receive synaptic inputs from thousands of other neurones. Therefore, each neurone ‘integrates’ this vast complexity of inputs and responds accordingly (either by remaining silent or firing action potentials to other neurones). Adaptations in the function and structure of chemical synapses in particular (synaptic plasticity) are thought to underlie the mechanisms mediating cognitive functions (learning and memory).     

Nerve cell function and synaptic mechanisms

Nerve cells (neurones) are ‘excitable’ cells which can transduce a variety of stimuli into electrical signals, continuously sending information about the external and internal environment (in the form of sequences of action potentials) to the central nervous system (CNS). Interneurones in the CNS integrate this information and send signals along output (efferent) neurones to various parts of the body for the appropriate actions to be taken in response to environmental changes. Networks of neurones have been arbitrarily classified into various nervous systems which gather and transmit sensory information and control skeletal muscle function and autonomic function, etc. The junctions between neurones (synapses) are either electrical or chemical. The former permit the direct transfer of electrical current between cells, whereas the latter utilize chemical signalling molecules (neurotransmitters) to transfer information between cells. Neurotransmitters are mainly amino acids, amines or peptides (although other molecules such as purines and nitric oxide are utilized by some cells), and can be excitatory or inhibitory. Individual neurones within the CNS may receive synaptic inputs from thousands of other neurones. Therefore, each neurone ‘integrates’ this vast complexity of inputs and responds accordingly (either by remaining silent or firing action potentials to other neurones). Adaptations in the function and structure of chemical synapses in particular (synaptic plasticity) are thought to underlie the mechanisms mediating cognitive functions (learning and memory).     

AMPA受体介导的突触可塑性与药物依赖

突触可塑性改变是形成药物依赖长期效应的病理基础,兴奋性氨基酸受体在其中起十分重要的作用。近年来的研究表明,多种药物依赖过程与AMPA受体有关。联系药物依赖所致的AMPA受体的变化与神经元的可塑性改变,探讨AMPA受体介导药物依赖的形成机制,可为进一步理解AMPA受体在药物依赖中的作用提供帮助。     

Neonatal administration with dexmedetomidine does not impair the rat hippocampal synaptic plasticity later in adulthood

Background and objective: The use of dexmedetomidine (DEX), a selective alpha‐2 agonist, in pediatric practice is expanding as a result of its desirable properties. To clarify the long‐term neurological consequences of neonatal administration of DEX, we investigated the long‐term effects of neonatal administration of DEX on hippocampal synaptic activity. Methods: The rat pups received a bolus intraperitoneal injection of either 5 or 10 μg·kg^?1 DEX, or an equivalent volume of vehicle on postnatal day 7 (P7). Nine weeks after administration, evoked potentials (population spike, PS) and long‐term potentiation (LTP) in the hippocampal CA1 region of rats were studied in vivo. Results: Dexmedetomidine had a considerable sedative effect at these doses with little respiratory depression on P7. Nine weeks after administration of DEX, the amplitude of PS in the two treated groups was similar to that in the control group. DEX‐treated rats showed no impairment in the induction of LTP. Furthermore, the response in PS to the paired stimuli was not impaired by neonatal administration of DEX. Conclusion: These findings demonstrate that a single administration of DEX to rats on P7 preserves hippocampal synaptic plasticity as well as synaptic transmission later in life. In view of the some evidence that have demonstrated the permanent detrimental impact of commonly used anesthetics on neurological outcomes after neonatal exposure, our findings may suggest the relative safety of DEX administered as a sedative agent to neonatal animals with regard to the development of hippocampal synaptic functions.     

Dynamic properties of excitatory synaptic connections involving layer 4 pyramidal cells in adult rat and cat neocortex

To investigate the properties of excitatory connections between layer 4 pyramidal cells and whether these differed between rat and cat, paired intracellular recordings were made with biocytin filling in slices of adult neocortex. These connections were also compared with those from layer 4 spiny cells to layer 3 pyramids and connections between layer 3 pyramids. Connectivity ratios for layer 4 pyramid-pyramid pairs (1:14 cat, 1:18 rat) appeared lower than for the other types of connections studied in parallel, but excitatory postsynaptic potential (EPSP) amplitudes and time course were not significantly different either between species or across types of connection. Layer 4 pyramids targeted postsynaptic basal dendrites in both species, whether the pyramidal target was in layer 4 or layer 3. Within layer 4, relationships between mean EPSP amplitude, numbers of putative contacts, and distance between connected pairs indicated a rapid decline in connectivity strength with distance, equivalent to 3.4 mV and 10 synapses per 100 microm separation, from a maximum of 4 mV and 10 synapses at 0 microm. However, a subset, of burst-firing layer 4 pyramids, appeared to make no connections with other layer 4 spiny cells. Second EPSPs were depressed by 36% in rat and 28% in cat relative to first EPSPs at interspike intervals <15 ms. Subsequent EPSPs in brief trains were further depressed. Depression was predominantly presynaptic in origin. Recovery from depression could not be described adequately by a simple exponential for individual connections; it included peaks and troughs with periodicities of 10-15 ms. Complex relationships between the first 2 interspike intervals and third EPSP amplitude were also apparent in all connections so studied. Large third EPSPs followed specific combinations of first and second interspike intervals so that increasing, or decreasing, one without changing the other resulted in a smaller third EPSP. Finally, the outputs of layer 4 spiny cells to layer 3 exhibited partial recovery from depression during longer high-frequency trains, a property not apparent in the other connections studied.     

Growth of neurites toward neurite- neurite contact sites increases synaptic clustering and secretion and is regulated by synaptic activity

The integrative properties of dendrites are determined by several factors, including their morphology and the spatio-temporal patterning of their synaptic inputs. One of the great challenges is to discover the interdependency of these two factors and the mechanisms which sculpt dendrites' fine morphological details. We found a novel form of neurite growth behavior in neuronal cultures of the hippocampus and cortex, when axons and dendrites grew directly toward neurite-neurite contact sites and crossed them, forming multi-neurite intersections (MNIs). MNIs were found at a frequency higher than obtained by computer simulations of randomly distributed dendrites, involved many of the dendrites and were stable for days. They were formed specifically by neurites originating from different neurons and were extremely rare among neurites of individual neurons or among astrocytic processes. Axonal terminals were clustered at MNIs and exhibited higher synaptophysin content and release capability than in those located elsewhere. MNI formation, as well as enhancement of axonal terminal clustering and secretion at MNIs, was disrupted by inhibitors of synaptic activity. Thus, convergence of axons and dendrites to form MNIs is a non-random activity-regulated wiring behavior which shapes dendritic trees and affects the location, clustering level and strength of their presynaptic inputs.     

Sparseness constrains the prolongation of memory lifetime via synaptic metaplasticity

Synaptic changes impair previously acquired memory traces. The smaller this impairment the larger is the longevity of memories. Two strategies have been suggested to keep memories from being overwritten too rapidly while preserving receptiveness to new contents: either introducing synaptic meta levels that store the history of synaptic state changes or reducing the number of synchronously active neurons, which decreases interference. We find that synaptic metaplasticity indeed can prolong memory lifetimes but only under the restriction that the neuronal population code is not too sparse. For sparse codes, metaplasticity may actually hinder memory longevity. This is important because in memory-related brain regions as the hippocampus population codes are sparse. Comparing 2 different synaptic cascade models with binary weights, we find that a serial topology of synaptic state transitions gives rise to larger memory capacities than a model with cross transitions. For the serial model, memory capacity is virtually independent of network size and connectivity.     

异丙酚对大鼠海马CA1区突触传递可塑性的影响

目的研究异丙酚对海马CAl区突触传递和可塑性的影响。方法断头分离Wistar大鼠海马半脑,制备400μm厚度海马脑片。45张脑片分为六组。脂肪乳剂组和异丙酚组的脑片以印防己毒素预孵30min,然后加入450μl脂肪乳剂或异丙酚(相当于500μmol/L),观察对兴奋性突触后电流(EPSC)的影响。脂肪乳剂长时程增强(LTP)组、脂肪乳剂长时程抑制(LTD)组、异丙酚LTP组、异丙酚LTD组的脑片以90μl脂肪乳剂或异丙酚(相当于100 μmol/L)预孵60 min,给予高频刺激(HFS)或低频刺激(LFS),记录LTP或LTD的发生情况。结果 脂肪乳剂对EPSC无影响(P>0.05);500 μmol/L异丙酚使2/3细胞EPSC下降至基础值的67.5％(P<0.05),使1,3细胞EPSC上升至基础值的140.3％(P<0.05)。脂肪乳剂LTP组给予HFS后EPSC值为基础值的151.6％(P<0.05),脂肪乳剂LTD组给予LFS后EPSC值为基础值的57.9％(P<0.05);异丙酚LTP组给予HFS后,LTP可以产生但不能维持,HFS后EPSC值为基础值的98.8％(P>0.05),异丙酚LTD组给予LFS后EPSC值为基础值的40.8％(P<0.05),明显低于脂肪乳剂LTD组(P<0.05)。结论异丙酚对大鼠海马CAl区突触传递具有双重影响,出现抑制和兴奋两种效果;异丙酚损害大鼠海马CAl区锥体神经元LTP的维持而易化LTD。     

The effect of intravesical electrical stimulation on bladder function and synaptic neurotransmission in the rat spinal cord after spinal cord injury

OBJECTIVE

To investigate the effects of intravesical electrical stimulation (IVES) on bladder function and synaptic neurotransmission in the lumbosacral spinal cord in the spinalized rat, as the clinical benefits of IVES in patients with increased residual urine or reduced bladder capacity have been reported but studies on the mechanism of IVES have mainly focused on bladder Aδ afferents in central nervous system‐intact rats.

MATERIALS AND METHODS

In all, 30 female Sprague‐Dawley rats were divided equally into three groups: normal control rats, sham‐stimulated spinalized rats and IVES‐treated spinalized rats. IVES was started 5 weeks after spinal cord injury (SCI) and was performed 20 min a day for 5 consecutive days. At 7 days after IVES, conscious filling cystometry was performed. Sections from the L6 and S1 spinal cord segments were examined for n ‐methyl‐d ‐aspartic acid receptor 1 (NMDAR1) subunit and γ‐aminobutyric acid (GABA) immunoactivity.

RESULTS

In IVES‐treated spinalized rats, the number and maximal pressure of nonvoiding detrusor contractions were significantly less than in sham‐stimulated spinalized rats. The mean maximal voiding pressure was also lower in IVES‐treated than in sham‐stimulated spinalized rats. IVES significantly reduced the interval between voiding contractions compared with the untreated spinalized rats. There was an overall increase in NMDAR1 immunoactivity after SCI, which was significantly lower in IVES‐treated spinalized rats. Immunoactivity of GABA after SCI was significantly lower than in the control group and was significantly higher in IVES‐treated spinalized rats.

CONCLUSION

Our results suggest that IVES might affect voiding contractions in addition to inhibiting C‐fibre activity and that IVES seems to have a more complex effect on the bladder control pathway. For synaptic neurotransmission in the spinal cord, IVES could possibly shift the balance between excitation and inhibition towards inhibition.     

钙黏蛋白在突触发育和突触可塑性调节中的作用

背景 钙黏蛋白（cadherin）是一类存在于细胞表面的跨膜糖蛋白,最初被认为是一种钙离子依赖性的细胞黏附分子,主要参与调节细胞黏附、促进细胞增殖、维持细胞极性等过程.近几年对cadherin调节突触发育和突触可塑性的研究取得了较大进展. 目的 围绕cadherin在突触发育和突触可塑性过程中的作用及其相关分子机制简要作一综述,旨在为神经系统疾病的治疗提供理论依据. 内容 Cadherin的概述,cadherin在突触发育和突触可塑性调节中的作用以及相关分子机制,cadherin与神经疾病. 趋向 随着cadherin在调节突触发育和突触可塑性过程中的研究不断深入,cadherin将成为治疗神经疾病的一个新型的靶点.     

γ-氨基丁酸递质及其受体系统在痛觉中的作用

γ-氨基丁酸（GABA）作为哺乳动物中枢神经系统中广泛分布的最重要的抑制性神经递质，其在疼痛方面的调制作用不容忽视。现就GABA及其受体在脊髓水平、脊髓上水平对痛觉的调制作用及其参与调节突触可塑性方面简单作一综述。     

Anesthetic-induced burst suppression EEG activity requires glutamate-mediated excitatory synaptic transmission

Many anesthetics evoke electroencephalogram (EEG) burst suppression activity in humans and animals during anesthesia, and the mechanisms underlying this activity remain unclear. The present study used a rat neocortical brain slice EEG preparation to investigate excitatory synaptic mechanisms underlying anesthetic-induced burst suppression activity. Excitatory synaptic mechanisms associated with burst suppression activity were probed using glutamate receptor antagonists (CNQX and APV), GABA receptor antagonists, and simultaneous whole cell patch clamp and microelectrode EEG recordings. Clinically relevant concentrations of thiopental (50--70 microM), propofol (5--10 microM) or isoflurane (0.7--2.1 vol%, 0.5--1.5 rat minimum aveolar concentration (MAC), 200--700 microM) evoked delta slow wave activity and burst suppression EEG patterns similar to in vivo responses. These effects on EEG signals were blocked by glutamate receptor antagonists CNQX (8.6 microM) or APV (50 microM). Depolarizing intracellular bursts (amplitude=34.7+/-4.5 mV; half width=132+/-60 ms) always accompanied EEG bursts, and hyperpolarization increased intracellular burst amplitudes. Barrages of glutamate-mediated excitatory events initiated EEG bursting activity. Glutamate-mediated excitatory postsynaptic currents were significantly depressed by higher anesthetic concentrations that depressed burst suppression EEG activity. A GABA(A) agonist produced a similar EEG effect to the anesthetics. It appears that anesthetic effects at both glutamate and GABA synapses contribute to EEG patterns seen during anesthesia.     

The metabotropic glutamate receptor mGluR3 is critically required for hippocampal long-term depression and modulates long-term potentiation in the dentate gyrus of freely moving rats

Group II metabotropic glutamate receptors (mGluRs) play an important role in the regulation of hippocampal synaptic plasticity in vivo: long-term potentiation (LTP) is inhibited and long-term depression (LTD) is enhanced by activation of these receptors. The contribution, in vivo, of the individual group II mGluR subtypes has not been characterized. We analysed the involvement of the subtype mGluR3 in LTD and LTP. Rats were implanted with electrodes to enable chronic measurement of evoked potentials from medial perforant path-dentate gyrus synapses. Neither the selective mGluR3 agonist, N-acetylaspartylglutamate (NAAG), nor the antagonist beta-NAAG, given intracerebrally, affected basal synaptic transmission. beta-NAAG significantly inhibited LTD expression. NAAG exhibited transient inhibitory effects on the intermediate phase of LTD. Whereas NAAG altered paired-pulse responses, beta-NAAG had no effect, suggesting that antagonism of mGluR3 prevents LTD via a postsynaptic mechanism, whereas agonist activation of mGluR3 modulates LTD at a presynaptic locus. NAAG impaired the expression of LTP, whereas beta-NAAG had no effect. NAAG effects on LTP were blocked by EGLU, a selective group II mGluR antagonist. Our data suggest an essential role for mGluR3 in LTD, and a modulatory role for mGluR3 in LTP, with effects being mediated by distinct pre- and post-synaptic loci.     

Morphological, electrophysiological, and synaptic properties of corticocallosal pyramidal cells in the neonatal rat neocortex

Neocortical pyramidal cells (PCs) project to various cortical and subcortical targets. In layer V, the population of thick tufted PCs (TTCs) projects to subcortical targets such as the tectum, brainstem, and spinal cord. Another population of layer V PCs projects via the corpus callosum to the contralateral neocortical hemisphere mediating information transfer between the hemispheres. This subpopulation (corticocallosally projecting cells [CCPs]) has been previously described in terms of their morphological properties, but less is known about their electrophysiological properties, and their synaptic connectivity is unknown. We studied the morphological, electrophysiological, and synaptic properties of CCPs by retrograde labeling with fluorescent microbeads in P13-P16 Wistar rats. CCPs were characterized by shorter, untufted apical dendrites, which reached only up to layers II/III, confirming previous reports. Synaptic connections between CCPs were different from those observed between TTCs, both in probability of occurrence and dynamic properties. We found that the CCP network is about 4 times less interconnected than the TTC network and the probability of release is 24% smaller, resulting in a more linear synaptic transmission. The study shows that layer V pyramidal neurons projecting to different targets form subnetworks with specialized connectivity profiles, in addition to the specialized morphological and electrophysiological intrinsic properties.     

右美托咪定对睡眠剥夺小鼠记忆能力和突触可塑性的影响

目的 观察右美托咪定对睡眠剥夺小鼠记忆能力和突触可塑性的影响。
方法 选取SPF级雄性健康C57BL/6小鼠63只,6～8周龄,体重21～25 g。随机分为四组：对照组（C组,n=12）、右美托咪定注射组（D组,n=14）、睡眠剥夺组（S组,n=18）和睡眠剥夺+右美托咪定注射组（SD组,n=19）。S组和SD组小鼠给予持续3 d的睡眠剥夺,C组和D组小鼠相同时间内置入条件完全相同的剥夺仪中不进行睡眠剥夺。剥夺期间,D组和SD组小鼠24 h内尾静脉注射右美托咪定（每次100 μg/kg,每天13:00和15:00共两次）,连续3 d;C组和S组小鼠同一时间尾静脉注射等容量生理盐水。剥夺结束后,实验第4天进行Y迷宫实验,实验第5天进行新物体实验,新物体实验结束后立即取海马组织,采用Western blot检测海马组织突触后PSD95蛋白含量。
结果 与S组比较,C组和D组摄食量明显增加（P＜0.05）;S组和SD组摄食量差异无统计学意义。与S组比较,C组、D组和SD组探索新物体时间比例及Y迷宫实验中进入正确臂循环次数所占比例明显升高,海马组织突触后PSD95蛋白含量明显升高（P＜0.05）。与C组比较,S组小鼠突触结构明显受损;与S组比较,SD组突触结构明显改善。
结论 右美托咪定可以改善睡眠剥夺小鼠记忆能力,促进突触可塑性。     

Asymmetric synaptic depression in cortical networks

Synaptic depression is essential for controlling the balance between excitation and inhibition in cortical networks. Several studies have shown that the depression of intracortical synapses is asymmetric, that is, inhibitory synapses depress less than excitatory ones. Whether this asymmetry has any impact on cortical function is unknown. Here we show that the differential depression of intracortical synapses provides a mechanism through which the gain and sensitivity of cortical circuits shifts over time to improve stimulus coding. We examined the functional consequences of asymmetric synaptic depression by modeling recurrent interactions between orientation-selective neurons in primary visual cortex (V1) that adapt to feedforward inputs. We demonstrate analytically that despite the fact that excitatory synapses depress more than inhibitory synapses, excitatory responses are reduced less than inhibitory ones to increase the overall response gain. These changes play an active role in generating selective gain control in visual cortical circuits. Specifically, asymmetric synaptic depression regulates network selectivity by amplifying responses and sensitivity of V1 neurons to infrequent stimuli and attenuating responses and sensitivity to frequent stimuli, as is indeed observed experimentally.     

Synaptic and vascular associations of neurons containing cyclooxygenase-2 and nitric oxide synthase in rat somatosensory cortex

Cyclooxygenase-2 (COX-2) is a rate-limiting enzyme for prostanoid synthesis that is present in cortical pyramidal neurons and highly implicated in control of cerebral blood flow during neural activity. We examined the electron microscopic localization of COX-2 and neuronal nitric oxide synthase (nNOS), a functionally related enzyme, in the somatosensory cortex of rat brain to determine the relevant functional sites. COX-2 immunoreactivity was detected in significantly more somatodendritic than axonal profiles, while nNOS was more often seen in axon terminals. The dendritic COX-2 was localized to endomembranes near synaptic inputs from axon terminals, some of which contained nNOS. Conversely, COX-2 terminals formed asymmetric, excitatory-type synapses with dendrites containing nNOS. The dendritic and axonal profiles containing COX-2 as well as those containing nNOS were minimally separated from penetrating arterioles and capillaries by filamentous glial processes. The perivascular COX-2 labeled terminals were among those that also formed axo-dendritic synapses, suggesting that the release of prostanoids and/or excitatory transmitters from a single terminal may simultaneously affect neuronal activity and cerebral blood flow. Thus, COX-2 has a compartmental distribution in somatosensory cortical neurons consistent with the local neuronal synthesis of prostanoids that are involved in neurovascular coupling and whose actions are modulated by nitric oxide.     

BDNF locally potentiates GABAergic presynaptic machineries: target-selective circuit inhibition

Inhibitory neurotransmission is critical for neuronal circuit formation. To examine whether inhibitory neurotransmission receives target-selective modulation in the long term, we expressed the cDNA of brain-derived neurotrophic factor (BDNF), which has been shown to induce the augmentation of GABAergic synapses in vivo and in vitro, in a small population of cultured hippocampal neurons. At 48 h after transfection, the expression level of glutamic acid decarboxylase 65 (GAD65), a GABA synthetic enzyme that resides mainly in GABAergic terminals, was selectively enhanced around the BDNF-expressing neurons, in comparison with the neighboring control neurons interposed between the BDNF-expressing neurons and inhibitory neurons. Exogenous BDNF application for 48 h also increased the GAD level and enhanced the GABA release probability. These potentiating effects were attenuated in inhibitory synapses on neurons expressing a dominant negative form of the BDNF receptor (tTrkB). This suggests that postsynaptic BDNF-TrkB signaling contributes to the target-selective potentiation of inhibitory presynaptic machineries. Since BDNF is expressed in an activity-dependent manner in vivo, this selectivity may be one of the key mechanisms by which the independence of functional neuronal circuits is maintained.