RESUMO
Evidence accumulated over recent years has shown that genetic neurological channelopathies can cause many different neurological diseases. Presentations relating to the brain, spinal cord, peripheral nerve or muscle mean that channelopathies can impact on almost any area of neurological practice. Typically, neurological channelopathies are inherited in an autosomal dominant fashion and cause paroxysmal disturbances of neurological function, although the impairment of function can become fixed with time. These disorders are individually rare, but an accurate diagnosis is important as it has genetic counselling and often treatment implications. Furthermore, the study of less common ion channel mutation-related diseases has increased our understanding of pathomechanisms that is relevant to common neurological diseases such as migraine and epilepsy. Here, we review the molecular genetic and clinical features of inherited neurological channelopathies.
Assuntos
Doenças do Sistema Nervoso Central/genética , Doenças do Sistema Nervoso Central/patologia , Canalopatias/genética , Canalopatias/patologia , Humanos , Biologia Molecular , FenótipoRESUMO
BACKGROUND AND PURPOSE: Acute severe exacerbations of myasthenia gravis (MG) are common in both early and late onset MG. We wished to examine the current management in the intensive care unit (ICU) of severe exacerbations of MG and to study the long-term prognosis of MG following discharge from the ICU. METHODS: We retrospectively reviewed the medical records of all patients admitted to a specialist neuro-ICU with acute exacerbations of MG over a 12-year period. RESULTS: We identified 38 patients. Over 60% were over the age of 50 years, and MG was newly diagnosed in over 40%. Intubation was required in 63%, and over 90% of patients were treated with prednisolone and/or intravenous immunoglobulin. Four patients died in hospital. The remainder of patients were followed up for a mean of 4 years, and the majority were either asymptomatic or had mild symptoms of MG at clinical review. CONCLUSIONS: Despite the significant morbidity and mortality associated with severe exacerbations of MG, specialized neurointensive care can result in a good long-term prognosis in both early- and late-onset MG.
Assuntos
Unidades de Terapia Intensiva/estatística & dados numéricos , Miastenia Gravis/terapia , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Imunoglobulinas Intravenosas/uso terapêutico , Masculino , Pessoa de Meia-Idade , Prednisolona/uso terapêutico , Prognóstico , Estudos Retrospectivos , Adulto JovemRESUMO
Electrophysiology has proven invaluable to record neural activity, and the development of Neuropixels probes dramatically increased the number of recorded neurons. These probes are often implanted acutely, but acute recordings cannot be performed in freely moving animals and the recorded neurons cannot be tracked across days. To study key behaviors such as navigation, learning, and memory formation, the probes must be implanted chronically. An ideal chronic implant should (1) allow stable recordings of neurons for weeks; (2) be light enough for use in mice; (3) allow reuse of the probes after explantation. Here, we present the "Apollo Implant", an open-source and editable device that meets these criteria and accommodates up to two Neuropixels 1.0 or 2.0 probes. The implant comprises a "payload" module that is attached to the probe and is recoverable, and a "docking" module that is cemented to the skull. The design is adjustable, making it easy to change the distance between probes, the angle of insertion, and the depth of insertion. We tested the implant across seven labs in head-fixed mice, freely moving mice, and freely moving rats. The number of neurons recorded across days was stable, even after repeated implantations of the same probe. The Apollo implant provides an inexpensive, lightweight, and flexible solution for reusable chronic Neuropixels recordings.
RESUMO
BACKGROUND: Episodic ataxia type 2 (EA2) and familial hemiplegic migraine type 1 (FHM1) are autosomal dominant disorders characterised by paroxysmal ataxia and migraine, respectively. Point mutations in CACNA1A, which encodes the neuronal P/Q-type calcium channel, have been detected in many cases of EA2 and FHM1. The genetic basis of typical cases without CACNA1A point mutations is not fully known. Standard DNA sequencing methods may miss large scale genetic rearrangements such as deletions and duplications. The authors investigated whether large scale genetic rearrangements in CACNA1A can cause EA2 and FHM1. METHODS: The authors used multiplex ligation dependent probe amplification (MLPA) to screen for intragenic CACNA1A rearrangements. RESULTS: The authors identified five previously unreported large scale deletions in CACNA1A in seven families with episodic ataxia and in one case with hemiplegic migraine. One of the deletions (exon 6 of CACNA1A) segregated with episodic ataxia in a four generation family with eight affected individuals previously mapped to 19p13. In addition, the authors identified the first pathogenic duplication in CACNA1A in an index case with isolated episodic diplopia without ataxia and in a first degree relative with episodic ataxia. CONCLUSIONS: Large scale deletions and duplications can cause CACNA1A associated channelopathies. Direct DNA sequencing alone is not sufficient as a diagnostic screening test.
Assuntos
Ataxia/genética , Canais de Cálcio/genética , Rearranjo Gênico , Enxaqueca com Aura/genética , Adolescente , Adulto , Ataxia/diagnóstico , Ataxia/fisiopatologia , Criança , Pré-Escolar , Família , Feminino , Ligação Genética , Humanos , Masculino , Enxaqueca com Aura/diagnóstico , Enxaqueca com Aura/fisiopatologia , Linhagem , Reação em Cadeia da PolimeraseRESUMO
BACKGROUND: Dissociated primary neuronal cultures are widely used as a model system to investigate the cellular and molecular properties of diverse neuronal populations and mechanisms of action potential generation and synaptic transmission. Typically, rodent primary neuronal cultures are obtained from freshly-dissociated embryonic or postnatal brain tissue, which often requires intense animal husbandry. This can strain resources when working with genetically modified mice. NEW METHOD: Here we describe an experimental protocol for frozen storage of mouse hippocampi, which allows fully functional dissociated primary neuronal cultures to be prepared from cryopreserved tissue. RESULTS: We show that thawed hippocampal neurons have functional properties similar to those of freshly dissociated neurons, including neuronal morphology, excitability, action potential waveform and synaptic neurotransmitter release, even after cryopreservation for several years. COMPARISON TO THE EXISTING METHODS: In contrast to the existing methods, the protocol described here allows for efficient long-term storage of samples, allowing researchers to perform functional experiments on neuronal cultures from brain tissue collected in other laboratories. CONCLUSIONS: We anticipate that this method will facilitate collaborations among laboratories based at distant locations and will thus optimise the use of genetically modified mouse models, in line with the 3Rs (Replacement, Reduction and Refinement) recommended for scientific use of animals in research.
Assuntos
Potenciais de Ação/fisiologia , Hipocampo/fisiologia , Neurônios/fisiologia , Transmissão Sináptica/fisiologia , Animais , Técnicas de Cultura de Células , Células Cultivadas , Criopreservação , Hipocampo/citologia , Camundongos , Camundongos Endogâmicos C57BL , Neurônios/citologiaRESUMO
Kainate receptor agonists depress transmitter release at several synapses in the hippocampus. Distinct mechanisms appear to underlie this phenomenon at different synapses. Recently, it has emerged that presynaptic kainate receptors can also potentiate the release of both GABA and glutamate and that axonal kainate receptors can trigger ectopic action potentials in interneurons. Because synaptically released glutamate mimics many of the actions of exogenous agonists, presynaptic kainate receptors potentially play an extensive role in hippocampal signaling.
Assuntos
Hipocampo/fisiologia , Receptores de Ácido Caínico/fisiologia , Animais , Receptores Pré-Sinápticos/fisiologiaRESUMO
Quantal analysis has provided evidence for a presynaptic contribution to long-term potentiation in hippocampal CA1 cells. This however leaves unexplained the observation that long-term potentiation has little or no effect on the NMDA receptor-mediated component of the synaptic signal. Here, I report that, in baseline conditions, the coefficient of variation of the AMPA/kainate receptor-mediated signal (CVA/K) is consistently larger than that of the NMDA component (CVNMDA), a result which can be explained if AMPA/kainate receptors are absent or nonfunctional at a proportion of synapses. Long-term potentiation is associated with a reduction in CVA/K, but no change in either the average amplitude of the NMDA component or CVNMDA. This is consistent with the proposal that long-term potentiation induction uncovers clusters of latent AMPA/kainate receptors, with no change in transmitter release.
Assuntos
Potenciais Evocados/fisiologia , Hipocampo/fisiologia , Potenciação de Longa Duração/fisiologia , Células Piramidais/fisiologia , 2-Amino-5-fosfonovalerato/farmacologia , Anestésicos Locais/farmacologia , Animais , Potenciais Evocados/efeitos dos fármacos , Cobaias , Técnicas In Vitro , Lidocaína/análogos & derivados , Lidocaína/farmacologia , Potenciação de Longa Duração/efeitos dos fármacos , Fibras Nervosas/efeitos dos fármacos , Fibras Nervosas/fisiologia , Células Piramidais/efeitos dos fármacos , Quinoxalinas/farmacologia , Receptores de AMPA/fisiologia , Receptores de Ácido Caínico/fisiologia , Receptores de N-Metil-D-Aspartato/efeitos dos fármacos , Receptores de N-Metil-D-Aspartato/fisiologia , Sinapses/efeitos dos fármacos , Sinapses/fisiologiaRESUMO
Synapses between hippocampal interneurons are an important potential target for modulatory influences that could affect overall network behavior. We report that the selective group III metabotropic receptor agonist L(+)-2-amino-4-phosphonobutyric acid (L-AP4) depresses GABAergic transmission to interneurons more than to pyramidal neurons. The L-AP4-induced depression is accompanied by changes in trial-to-trial variability and paired-pulse depression that imply a presynaptic site of action. Brief trains of stimuli in Schaffer collaterals also depress GABAergic transmission to interneurons. This depression persists when GABA(B) receptors are blocked, is enhanced by blocking glutamate uptake, and is abolished by the group III metabotropic receptor antagonist (alpha-methylserine-O-phosphate (MSOP). The results imply that GABAergic transmission among interneurons is modulated by glutamate spillover from excitatory afferent terminals.
Assuntos
Interneurônios/fisiologia , Receptores de Glutamato Metabotrópico/fisiologia , Transdução de Sinais/fisiologia , Ácido gama-Aminobutírico/fisiologia , 2-Amino-5-fosfonovalerato/farmacologia , Animais , Antagonistas de Aminoácidos Excitatórios/farmacologia , Potenciais Pós-Sinápticos Excitadores/efeitos dos fármacos , Potenciais Pós-Sinápticos Excitadores/fisiologia , Ácido Glutâmico/metabolismo , Cobaias , Hipocampo/fisiologia , Técnicas In Vitro , Interneurônios/química , Ácido Caínico/análogos & derivados , Ácido Caínico/farmacologia , Inibição Neural/fisiologia , Propionatos/farmacologia , Quinoxalinas/farmacologia , Transmissão Sináptica/efeitos dos fármacos , Transmissão Sináptica/fisiologiaRESUMO
We have addressed the expression of long-term potentiation (LTP) in hippocampal CA1 by comparing AMPA and NMDA receptor-(AMPAR- and NMDAR-) mediated postsynaptic signals. We find that potentiation of NMDAR-mediated signals accompanies LTP of AMPAR-mediated signals, and is associated with a change in variability implying an increase in quantal content. Further, tetanic LTP of NMDAR-mediated signals can be elicited when LTP of AMPAR-mediated signals is prevented. We propose that LTP is mainly expressed presynaptically, and that, while AMPARs respond only to glutamate from immediately apposed terminals, NMDARs also sense glutamate released from terminals presynaptic to neighboring cells. We also find that tetanic LTP increases the rate of depression of NMDAR-mediated signals by the use-dependent blocker MK-801, implying an increase in the glutamate release probability. These findings argue for a presynaptic contribution to LTP and for extrasynaptic spill-over of glutamate onto NMDARs.
Assuntos
Ácido Glutâmico/metabolismo , Potenciação de Longa Duração/fisiologia , Receptores de AMPA/fisiologia , Receptores de N-Metil-D-Aspartato/fisiologia , Transdução de Sinais/fisiologia , Análise de Variância , Animais , Transporte Biológico/fisiologia , Maleato de Dizocilpina/farmacologia , Eletrofisiologia , Antagonistas de Aminoácidos Excitatórios/farmacologia , Cobaias , Sinapses/química , Sinapses/fisiologia , Transmissão Sináptica/efeitos dos fármacos , Transmissão Sináptica/fisiologiaRESUMO
At excitatory synapses on CA1 pyramidal cells of the hippocampus, a larger quantal content is sensed by N-methyl-D-aspartic acid receptors (NMDARs) than by alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPARs). A novel explanation for this discrepancy is that glutamate released from terminals presynaptic to one cell can diffuse to and activate NMDARs, but not AMPARs, on a neighboring cell. If this occurs in the living brain, it could invalidate the view that glutamatergic synapses function as private communication channels between neurons. Here, we show that the discrepancy in quantal content mediated by the two receptors is greatly decreased at physiological temperature, compared with conventional recording conditions. This effect of temperature is not due to changes in release probability or uncovering of latent AMPARs. It is, however, partially reversed by the glutamate uptake inhibitor dihydrokainate. The results suggest that glutamate transporters play a critical role in limiting the extrasynaptic diffusion of glutamate, thereby minimizing cross-talk between neighboring excitatory synapses.
Assuntos
Glutamatos/metabolismo , Hipocampo/fisiologia , Receptores de AMPA/fisiologia , Receptores de N-Metil-D-Aspartato/fisiologia , Sinapses/metabolismo , Animais , Transporte Biológico Ativo , Difusão , Estimulação Elétrica , Potenciais Evocados , Cobaias , Técnicas In Vitro , Ácido Caínico/análogos & derivados , Ácido Caínico/farmacologia , N-Metilaspartato/administração & dosagem , Neurotransmissores/metabolismo , Transmissão Sináptica/efeitos dos fármacos , Temperatura , Ácido alfa-Amino-3-hidroxi-5-metil-4-isoxazol Propiônico/administração & dosagemRESUMO
Glutamatergic transmission at mossy fiber (MF) synapses on CA3 pyramidal neurons in the hippocampus is mediated by AMPA, kainate, and NMDA receptors and undergoes presynaptic modulation by metabotropic glutamate receptors. The recruitment of different receptors has thus far been studied by altering presynaptic stimulation to modulate glutamate release and interfering pharmacologically with receptors and transporters. Here, we introduce two novel experimental manipulations that alter the fate of glutamate molecules following release. First, an enzymatic glutamate scavenger reduces the postsynaptic response as well as presynaptic modulation by metabotropic receptors. At physiological temperature, however, the scavenger is effective only when glutamate uptake is blocked, revealing a role of active transport in both synaptic and extrasynaptic communication. Second, AMPA and kainate receptor-mediated postsynaptic signals are enhanced when extracellular diffusion is retarded by adding dextran to the perfusion solution, as is feedback modulation by metabotropic receptors, suggesting that the receptors are not saturated under baseline conditions. These results show that manipulating the spatiotemporal profile of glutamate following exocytosis can alter the involvement of different receptors in synaptic transmission.
Assuntos
Ácido Glutâmico/fisiologia , Hipocampo/fisiologia , Fibras Nervosas/fisiologia , Células Piramidais/fisiologia , Receptores de AMPA/fisiologia , Receptores de Ácido Caínico/fisiologia , Receptores de Glutamato Metabotrópico/fisiologia , Sinapses/fisiologia , Animais , Estimulação Elétrica , Antagonistas de Aminoácidos Excitatórios/farmacologia , Potenciais Pós-Sinápticos Excitadores/efeitos dos fármacos , Exocitose , Cobaias , Técnicas In Vitro , Masculino , Fibras Nervosas/efeitos dos fármacos , Células Piramidais/efeitos dos fármacos , Quinoxalinas/farmacologia , Receptor Cross-Talk/fisiologia , Sinapses/efeitos dos fármacosRESUMO
Mossy fibers are the sole excitatory projection from dentate gyrus granule cells to the hippocampus, where they release glutamate, dynorphin, and zinc. In addition, mossy fiber terminals show intense immunoreactivity for the inhibitory neurotransmitter GABA. Fast inhibitory transmission at mossy fiber synapses, however, has not previously been reported. Here, we show that electrical or chemical stimuli that recruit dentate granule cells elicit monosynaptic GABA(A) receptor-mediated synaptic signals in CA3 pyramidal neurons. These inhibitory signals satisfy the criteria that distinguish mossy fiber-CA3 synapses: high sensitivity to metabotropic glutamate receptor agonists, facilitation during repetitive stimulation, and NMDA receptor-independent long-term potentiation. GABAergic transmission from the dentate gyrus to CA3 has major implications not only for information flow into the hippocampus but also for developmental and pathological processes involving the hippocampus.
Assuntos
Giro Denteado/fisiologia , Fibras Musgosas Hipocampais/fisiologia , Células Piramidais/fisiologia , Transdução de Sinais , Sinapses/fisiologia , Ácido gama-Aminobutírico/fisiologia , Animais , Estimulação Elétrica , Potenciais Pós-Sinápticos Excitadores , Ácido Glutâmico/fisiologia , Cobaias , Potenciação de Longa Duração , Quinoxalinas/farmacologia , Ratos , Receptores de Glutamato Metabotrópico/agonistas , Receptores de N-Metil-D-Aspartato/fisiologiaRESUMO
We have studied the role of Ca2+ entry via voltage-sensitive Ca2+ channels in long-term potentiation (LTP) in the CA1 region of the hippocampus. Repeated depolarizing pulses, in the presence of the NMDA receptor antagonist D-APV and without synaptic stimulation, resulted in a potentiation of excitatory postsynaptic potentials (EPSPs) or currents (EPSCs). This depolarization-induced potentiation was augmented in raised extracellular Ca2+ and was blocked by intracellular BAPTA, a Ca2+ chelator, or by nifedipine, a Ca2+ channel antagonist, indicating that the effect was mediated by Ca2+ entry via voltage-sensitive Ca2+ channels. Although the peak potentiation could be as large as 3-fold, the EPSP(C)s decayed back to baseline values within approximately 30 min. However, synaptic activation paired with depolarizing pulses in the presence of D-APV converted the transient potentiation into a sustained form. These results indicate that a rise in postsynaptic Ca2+ via voltage-sensitive Ca2+ channels can transiently potentiate synaptic transmission, but that another factor associated with synaptic transmission may be required for LTP.
Assuntos
Canais de Cálcio/fisiologia , Cálcio/metabolismo , Hipocampo/fisiologia , Sinapses/fisiologia , Transmissão Sináptica , 2-Amino-5-fosfonovalerato/farmacologia , 6-Ciano-7-nitroquinoxalina-2,3-diona , Animais , Canais de Cálcio/efeitos dos fármacos , Ácido Egtázico/análogos & derivados , Ácido Egtázico/farmacologia , Estimulação Elétrica , Potenciais Evocados/efeitos dos fármacos , Cobaias , Técnicas In Vitro , Cinética , Masculino , Nifedipino/farmacologia , Quinoxalinas/farmacologia , Receptores de N-Metil-D-Aspartato/antagonistas & inibidores , Receptores de N-Metil-D-Aspartato/fisiologia , Fatores de TempoRESUMO
Myotonia congenita (MC) is the commonest genetic skeletal muscle ion channelopathy. It is caused by mutations in CLCN1 on chromosome 7q35, which alter the function of the major skeletal muscle voltage-gated chloride channel. Dominant and recessive forms of the disease exist. We have undertaken a clinical, genetic and molecular expression study based upon a large cohort of over 300 UK patients. In an initial cohort of 22 families, we sequenced the DNA of the entire coding region of CLCN1 and identified 11 novel and 11 known mutations allowing us to undertake a detailed genotype-phenotype correlation study. Generalized muscle hypertrophy, transient weakness and depressed tendon reflexes occurred more frequently in recessive than dominant MC. Mild cold exacerbation and significant muscle pain were equally common features in dominant and recessive cases. Dominant MC occurred in eight families. We noted that four newly identified dominant mutations clustered in exon 8, which codes for a highly conserved region of predicted interaction between the CLC-1 monomers. Expressed in Xenopus oocytes these mutations showed clear evidence of a dominant-negative effect. Based upon the analysis of mutations in this initial cohort as well as a review of published CLCN1 mutations, we devised an exon hierarchy analysis strategy for genetic screening. We applied this strategy to a second cohort of 303 UK cases with a suspected diagnosis of MC. In 23 individuals, we found two mutations and in 86 individuals we identified a single mutation. Interestingly, 40 of the cases with a single mutation had dominant exon 8 mutations. In total 48 individuals (from 34 families) in cohort 1 and 2 were found to harbour dominant mutations (37% of mutation positive individuals, 30% of mutation positive families). In total, we have identified 23 new disease causing mutations in MC, confirming the high degree of genetic heterogeneity associated with this disease. The DNA-based strategy we have devised achieved a genetic diagnosis in 36% of individuals referred to our centre. Based on these results, we propose that exon 8 of CLCN1 is a hot-spot for dominant mutations. Our molecular expression studies of the new exon 8 mutations indicate that this region of the chloride channel has an important role in dominant negative interactions between the two chloride channel monomers. Accurate genetic counselling in MC should be based not only upon clinical features and the inheritance pattern but also on molecular genetic analysis and ideally functional expression data.
Assuntos
Canais de Cloreto/genética , Mutação , Miotonia Congênita/genética , Estudos de Coortes , Análise Mutacional de DNA/métodos , Éxons/genética , Feminino , Genes Dominantes , Testes Genéticos/métodos , Humanos , Masculino , Mutagênese Sítio-Dirigida , Miotonia Congênita/diagnóstico , Polimorfismo de Fragmento de RestriçãoRESUMO
Kainate receptor agonists are powerful chemoconvulsants and excitotoxins. These properties are in part explained by depolarization of hippocampal principal neurons. However, kainate also depresses evoked inhibitory signals in pyramidal neurons, and promotes spontaneous GABA release from interneurons. The mechanisms underlying these phenomena are not fully understood, nor are the consequences for the inhibitory traffic among interneurons. We report that both the amplitude and the frequency of spontaneous IPSCs recorded in interneurons were enhanced by low concentrations of kainate, but action potential-independent IPSCs were unaffected. In the presence of GABA(A) receptor antagonists, kainate lowered the threshold for antidromic action potential generation, suggesting that interneuron axons are directly depolarized; this effect was mimicked by synaptically released glutamate. Kainate application also induced spontaneous antidromic action potentials. Axonal receptors are thus important in initiating the intense interneuronal activity triggered by kainate, which in turn influences inhibitory signaling to principal cells.
Assuntos
Axônios/fisiologia , Interneurônios/fisiologia , Receptores de Ácido Caínico/fisiologia , Potenciais de Ação , Animais , Agonistas de Aminoácidos Excitatórios/farmacologia , Cobaias , Hipocampo/fisiologia , Hipocampo/ultraestrutura , Interneurônios/metabolismo , Ácido Caínico/farmacologia , Técnicas de Patch-Clamp , Sinapses/metabolismo , Sinapses/fisiologia , Ácido gama-Aminobutírico/metabolismoRESUMO
We report a retrospective review of 110 patients with acute Guillain-Barré syndrome (GBS) admitted to a specialised intensive care unit (ICU) in a tertiary referral centre over a 25 year period, the start of which coincided with the widespread introduction of plasma exchange (PE) and intravenous immunoglobulin (IVIG). The results were analysed by comparing 52 patients admitted in the first decade (1991-2000; Group 1) with 58 patients admitted between 2001-2014 (Group 2). Patients in both groups were comparable with respect to age and sex, and had a similar incidence and range of ICU complications. They received a comparable range of immunomodulatory treatments including IVIG and PE. However, the delay from presentation to referral to the tertiary ICU was longer in patients in Group 2. They also required mechanical ventilation for a longer duration, and had longer ICU and hospital stays. In Group 2, there was a higher incidence of axonal neuropathy (51%, compared to 24% in Group 1). Despite the longer delay to referral, the prevalence of axonal neuropathy and the duration of ventilation, overall mortality showed a downward trend (Group 1: 13.5%; Group 2: 5.2%). There was no late mortality in either group after step-down to neuro-rehabilitation or following discharge home or to the referring hospital. The rehabilitation outcomes were similar. This data show a shift in the pattern of referral to a tertiary referral ICU between the first and second decades following the wider availability of IVIG and PE for the treatment of GBS. The possible causes and implications of these findings are discussed.
Assuntos
Cuidados Críticos , Síndrome de Guillain-Barré/epidemiologia , Síndrome de Guillain-Barré/terapia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Cuidados Críticos/métodos , Cuidados Críticos/estatística & dados numéricos , Feminino , Seguimentos , Humanos , Imunomodulação , Unidades de Terapia Intensiva/estatística & dados numéricos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Índice de Gravidade de Doença , Resultado do Tratamento , Adulto JovemRESUMO
In the mammalian brain most excitatory transmission is mediated by glutamate binding to AMPA and NMDA receptors. These receptors have markedly different biophysical properties, and at synapses in the CAI region of the hippocampus they play complementary roles in long-term potentiation (LTP): while postsynaptic NMDA receptor activation is necessary for the induction of this form of plasticity, AMPA receptors play a larger role in its expression. Recent studies in hippocampal slices have revealed a further striking difference in the behaviour of the two receptor types: NMDA receptors consistently sense a larger number of quanta of glutamate released from presynaptic terminals than do AMPA receptors. Two alternative explanations for this are either that AMPA receptors are functionally silent at a proportion of synapses (although they can be uncovered by LTP), or that glutamate can spill over from neighbouring synapses and selectively activate NMDA (but not AMPA) receptors. Both of these competing hypotheses have extensive implications for the mechanisms of expression of LTP. Extrasynaptic glutamate diffusion appears to depend critically on the recording temperature, but if excitatory synapses are sufficiently close for cross-talk to occur under physiological conditions, it could have profound implications for the specificity of synaptic communication in the brain.
Assuntos
Ácido Glutâmico/metabolismo , Hipocampo/metabolismo , Sinapses/metabolismo , Animais , Humanos , Transmissão Sináptica/fisiologiaRESUMO
Recent experimental findings show that fast synaptic transmission can extend its actions beyond the immediate synaptic cleft. Whether this phenomenon results in significant crosstalk between typical neighbouring synapses remains unclear. This article considers two areas of the hippocampus, the CA1 and dentate gyrus, where important neural processing occurs. The results discussed do not provide a simple answer to the question of whether synapses can 'talk' to their neighbours, but they do reveal crucial physiological constraints that determine the significance of synaptic crosstalk, thus adding considerably to our understanding of chemical synaptic transmission.
Assuntos
Sinalização do Cálcio/fisiologia , Hipocampo/fisiologia , Receptor Cross-Talk/fisiologia , Transmissão Sináptica/fisiologia , Animais , Giro Denteado/fisiologia , Humanos , Modelos Neurológicos , Método de Monte CarloAssuntos
Epilepsia/etiologia , Febre/fisiopatologia , Convulsões Febris/fisiopatologia , Animais , Pré-Escolar , AMP Cíclico/fisiologia , Proteínas Quinases Dependentes de AMP Cíclico/fisiologia , Modelos Animais de Doenças , Febre/complicações , Hipocampo/fisiologia , Humanos , Lactente , Ratos , Receptores de GABA-A/fisiologia , Transmissão Sináptica/fisiologia , Ácido gama-Aminobutírico/fisiologiaRESUMO
It has been suggested that a functional deficit in NMDA-receptors (NMDARs) on parvalbumin (PV)-positive interneurons (PV-NMDARs) is central to the pathophysiology of schizophrenia. Supportive evidence come from examination of genetically modified mice where the obligatory NMDAR-subunit GluN1 (also known as NR1) has been deleted from PV interneurons by Cre-mediated knockout of the corresponding gene Grin1 (Grin1(ΔPV) mice). Notably, such PV-specific GluN1 ablation has been reported to blunt the induction of hyperlocomotion (a surrogate for psychosis) by pharmacological NMDAR blockade with the non-competitive antagonist MK-801. This suggests PV-NMDARs as the site of the psychosis-inducing action of MK-801. In contrast to this hypothesis, we show here that Grin1(ΔPV) mice are not protected against the effects of MK-801, but are in fact sensitized to many of them. Compared with control animals, Grin1(ΔPV)mice injected with MK-801 show increased stereotypy and pronounced catalepsy, which confound the locomotor readout. Furthermore, in Grin1(ΔPV)mice, MK-801 induced medial-prefrontal delta (4 Hz) oscillations, and impaired performance on tests of motor coordination, working memory and sucrose preference, even at lower doses than in wild-type controls. We also found that untreated Grin1(ΔPV)mice are largely normal across a wide range of cognitive functions, including attention, cognitive flexibility and various forms of short-term memory. Taken together these results argue against PV-specific NMDAR hypofunction as a key starting point of schizophrenia pathophysiology, but support a model where NMDAR hypofunction in multiple cell types contribute to the disease.