RESUMO
NMDA receptor (NMDAR) activation is required for many forms of learning and memory as well as sensory system receptive field plasticity, yet the relative contribution of presynaptic and postsynaptic NMDARs over cortical development remains unknown. Here we demonstrate a rapid developmental loss of functional presynaptic NMDARs in the neocortex. Presynaptic NMDARs enhance neurotransmitter release at synapses onto visual cortex pyramidal cells in young mice [before postnatal day 20 (P20)], but they have no apparent effect after the onset of the critical period for receptive field plasticity (>P23). Immunoelectron microscopy revealed that the loss of presynaptic NMDAR function is likely attributable in part to a 50% reduction in the prevalence of presynaptic NMDARs. Coincident with the observed loss of presynaptic NMDAR function, there is an abrupt change in the mechanisms of timing-dependent long-term depression (tLTD). Induction of tLTD before the onset of the critical period requires activation of presynaptic but not postsynaptic NMDARs, whereas the induction of tLTD in older mice requires activation of postsynaptic NMDARs. By demonstrating that both presynaptic and postsynaptic NMDARs contribute to the induction of synaptic plasticity and that their relative roles shift over development, our findings define a novel, and perhaps general, property of synaptic plasticity in emerging cortical circuits.
Assuntos
Genes de Troca/fisiologia , Depressão Sináptica de Longo Prazo/fisiologia , Receptores de N-Metil-D-Aspartato/fisiologia , Receptores Pré-Sinápticos/fisiologia , Animais , Animais Recém-Nascidos , Potenciais Pós-Sinápticos Excitadores/fisiologia , Regulação da Expressão Gênica no Desenvolvimento , Camundongos , Camundongos Endogâmicos C57BL , Neocórtex/crescimento & desenvolvimentoRESUMO
Many aspects of synaptic development, plasticity, and neurotransmission are critically influenced by NMDA-type glutamate receptors (NMDARs). Moreover, dysfunction of NMDARs has been implicated in a broad array of neurological disorders, including schizophrenia, stroke, epilepsy, and neuropathic pain. Classically, NMDARs were thought to be exclusively postsynaptic. However, substantial evidence in the past 10 years demonstrates that NMDARs also exist presynaptically and that presynaptic NMDA receptors (preNMDARs) modulate synapse function and have critical roles in plasticity at many synapses. Here the authors review current knowledge of the role of preNMDARs in synaptic transmission and plasticity, focusing on the neocortex. They discuss the prevalence, function, and development of these receptors, and their potential modification by experience and in brain pathology.
Assuntos
Córtex Cerebral/citologia , Plasticidade Neuronal/fisiologia , Terminações Pré-Sinápticas/metabolismo , Receptores de N-Metil-D-Aspartato/fisiologia , Animais , Neurônios/citologia , Neurônios/fisiologiaRESUMO
Use-dependent modifications of synapses have been well described in the developing visual cortex, but the ability for experience to modify synapses in the adult visual cortex is poorly understood. We found that 10 d of late-onset visual deprivation modifies both presynaptic and postsynaptic elements at the layer 4-->2/3 connection in the visual cortex of adult mice, and these changes differ from those observed in juveniles. Although visual deprivation in juvenile mice modifies the subunit composition and increases the current duration of synaptic NMDA receptors (NMDARs), no such effect is observed at synapses between layer 4 and layer 2/3 pyramidal neurons in adult mice. Surprisingly, visual deprivation in adult mice enhances the temporal summation of NMDAR-mediated currents induced by bursts of high-frequency stimulation. The enhanced temporal summation of NMDAR-mediated currents in deprived cortex could not be explained by a reduction in the rate of synaptic depression, because our data indicate that late-onset visual deprivation actually increases the rate of synaptic depression. Biochemical and electrophysiological evidence instead suggest that the enhanced temporal summation in adult mice could be accounted for by a change in the molecular composition of NMDARs at perisynaptic/extrasynaptic sites. Our data demonstrate that the experience-dependent modifications observed in the adult visual cortex are different from those observed during development. These differences may help to explain the unique consequences of sensory deprivation on plasticity in the developing versus mature cortex.
Assuntos
Ácido Glutâmico/metabolismo , Terminações Pré-Sinápticas/metabolismo , Receptores de N-Metil-D-Aspartato/fisiologia , Privação Sensorial/fisiologia , Córtex Visual/metabolismo , Percepção Visual/fisiologia , Fatores Etários , Animais , Antagonistas de Aminoácidos Excitatórios/farmacologia , Potenciais Pós-Sinápticos Excitadores/efeitos dos fármacos , Potenciais Pós-Sinápticos Excitadores/fisiologia , Feminino , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Terminações Pré-Sinápticas/efeitos dos fármacos , Receptores de N-Metil-D-Aspartato/antagonistas & inibidores , Sinapses/efeitos dos fármacos , Sinapses/metabolismo , Córtex Visual/efeitos dos fármacos , Percepção Visual/efeitos dos fármacosRESUMO
Sensory experience orchestrates the development of cortical circuitry by adaptively modifying neurotransmission and synaptic connectivity. However, the mechanisms underlying these experience-dependent modifications remain elusive. Here we demonstrate that visual experience suppresses a presynaptic NMDA receptor (preNMDAR)-mediated form of timing-dependent long-term depression (tLTD) at visual cortex layer (L) 4-2/3 synapses. This tLTD can be maintained during development, or reinstated in adulthood, by sensory deprivation. The changes in tLTD are mirrored by changes in glutamate release; visual deprivation enhances both tLTD and glutamate release. These effects require the GluN3A NMDAR subunit, the levels of which are increased by visual deprivation. Further, by coupling the pathway-specific optogenetic induction of tLTD with cell-type-specific NMDAR deletion, we find that visual experience modifies preNMDAR-mediated plasticity specifically at L4-L2/3 synapses.
Assuntos
Plasticidade Neuronal/fisiologia , Receptores de N-Metil-D-Aspartato/fisiologia , Receptores Pré-Sinápticos/fisiologia , Sinapses/fisiologia , Animais , Ácido Glutâmico/metabolismo , Depressão Sináptica de Longo Prazo/fisiologia , Camundongos , Optogenética , Estimulação Luminosa , Receptores de N-Metil-D-Aspartato/genética , Privação Sensorial/fisiologia , Córtex Visual/metabolismo , Córtex Visual/fisiologia , Percepção Visual/fisiologiaRESUMO
Recent evidence suggests that presynaptic-acting NMDA receptors (preNMDARs) are important for neocortical synaptic transmission and plasticity. We found that unique properties of the NR3A subunit enable preNMDARs to enhance spontaneous and evoked glutamate release and that NR3A is required for spike timing-dependent long-term depression in the juvenile mouse visual cortex. In the mature cortex, NR2B-containing preNMDARs enhanced neurotransmission in the absence of magnesium, indicating that presynaptic NMDARs may function under depolarizing conditions throughout life. Our findings indicate that NR3A relieves preNMDARs from the dual-activation requirement of ligand-binding and depolarization; the developmental removal of NR3A limits preNMDAR functionality by restoring this associative property.
Assuntos
Potenciais de Ação/fisiologia , Plasticidade Neuronal/fisiologia , Neurotransmissores/metabolismo , Receptores de N-Metil-D-Aspartato/metabolismo , Animais , Potenciais Pós-Sinápticos Excitadores/fisiologia , Ácido Glutâmico/metabolismo , Depressão Sináptica de Longo Prazo/fisiologia , Magnésio/metabolismo , Camundongos , Camundongos Transgênicos , Subunidades Proteicas/genética , Subunidades Proteicas/metabolismo , Receptores de N-Metil-D-Aspartato/genética , Transmissão Sináptica/fisiologia , Fatores de TempoRESUMO
The second messenger cyclic guanosine monophosphate (cGMP) plays many roles during nervous system development. Consequently, cGMP production shows complex patterns of regulation throughout early development. Elevated glutamate levels are known to increase cGMP levels in the mature nervous system. A number of clinical conditions including ischemia and perinatal asphyxia can result in elevated glutamate levels in the developing brain. To investigate the effects of elevated glutamate levels on cGMP in the developing cortex we exposed mouse brain slices to glutamate or N-methyl D-aspartate (NMDA). We find that at early postnatal stages when the endogenous production of cGMP is high, glutamate or NMDA exposure results in a significant lowering of the overall production of cGMP in the cortex, unlike the situation in the mature brain. However, this response pattern is complex with regional and cell-type specific exceptions to the overall lowered cGMP production. These data emphasize that the response of the developing brain to physiological disturbances can be different from that of the mature brain, and must be considered in the context of the developmental events occurring at the time of disturbance.
Assuntos
Córtex Cerebral/efeitos dos fármacos , GMP Cíclico/metabolismo , Ácido Glutâmico/farmacologia , N-Metilaspartato/farmacologia , Animais , Animais Recém-Nascidos , Córtex Cerebral/metabolismo , Imuno-Histoquímica , Camundongos , Técnicas de Cultura de ÓrgãosRESUMO
Spontaneous [Ca2+]i transients were measured in the mouse neocortex from embryonic day 16 (E16) to postnatal day 6 (P6). On the day of birth (P0), cortical neurones generated widespread, highly synchronous [Ca2+]i transients over large areas. On average, 52% of neurones participated in these transients, and in 20% of slices, an average of 80% participated. These transients were blocked by TTX and nifedipine, indicating that they resulted from Ca2+ influx during electrical activity, and occurred at a mean frequency of 0.91 min(-1). The occurrence of this activity was highly centred at P0: at E16 and P2 an average of only 15% and 24% of neurones, respectively, participated in synchronous transients, and they occurred at much lower frequencies at both E16 and P2 than at P0. The overall frequency of [Ca2+]i transients in individual cells did not change between E16 and P2, just the degree of their synchronicity. The onset of this spontaneous, synchronous activity correlated with a large increase in Na+ current density that occurred just before P0, and its cessation with a large decrease in resting resistance that occurred just after P2. This widespread, synchronous activity may serve a variety of functions in the neonatal nervous system.