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Altered development of glutamatergic synapses in layer V pyramidal neurons in NR3A knockout mice.

ABSTRACT: Expression of the NMDA receptor (NMDAR) subunit NR3A reaches its highest level in layer V of the developing rodent cortex during the second postnatal week, a peak period of synaptogenesis. Incorporation of NR3A leads to the formation of non-canonical, Mg2+-insensitive NMDARs, but it is not known whether they participate in synaptic transmission and maturation. Here we show that in the second postnatal week, layer V pyramidal neurons in the somatosensory cortex of wild type (WT) mice exhibited evoked excitatory postsynaptic currents (eEPSCs) with 3- to 6-fold lower Mg2+ sensitivity than NR3A knockout (KO) mice and their reversal potential was approximately 2 mV more negative compared to KO mice consistent with decreased P(Ca) of NMDARs. Surprisingly, ablation of NR3A also led to a 20-fold reduction of the ratio of AMPAR- to NMDAR-mediated eEPSC amplitudes in KO mice. Insertion of AMPARs at the synapses of layer V pyramidal neurons appears to be facilitated by the expression of Mg2+-insensitive NMDARs. The data indicate that NR3A plays a significant role in the development of excitatory synapses in layer V of the developing neocortex.

SUBMITTER: Zhou C

PROVIDER: S-EPMC2818217 | biostudies-literature | 2009 Dec

REPOSITORIES: biostudies-literature

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Altered development of glutamatergic synapses in layer V pyramidal neurons in NR3A knockout mice.

Zhou Chengwen C Jensen Frances E FE Sucher Nikolaus J NJ

Molecular and cellular neurosciences 20090924 4

Expression of the NMDA receptor (NMDAR) subunit NR3A reaches its highest level in layer V of the developing rodent cortex during the second postnatal week, a peak period of synaptogenesis. Incorporation of NR3A leads to the formation of non-canonical, Mg2+-insensitive NMDARs, but it is not known whether they participate in synaptic transmission and maturation. Here we show that in the second postnatal week, layer V pyramidal neurons in the somatosensory cortex of wild type (WT) mice exhibited ev ...[more]

PMID: 19782137

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Project description:In this study, we present a theoretical framework combining experimental characterizations and analytical calculus to capture the firing rate input-output properties of single neurons in the fluctuation-driven regime. Our framework consists of a two-step procedure to treat independently how the dendritic input translates into somatic fluctuation variables, and how the latter determine action potential firing. We use this framework to investigate the functional impact of the heterogeneity in firing responses found experimentally in young mice layer V pyramidal cells. We first design and calibrate in vitro a simplified morphological model of layer V pyramidal neurons with a dendritic tree following Rall's branching rule. Then, we propose an analytical derivation for the membrane potential fluctuations at the soma as a function of the properties of the synaptic input in dendrites. This mathematical description allows us to easily emulate various forms of synaptic input: either balanced, unbalanced, synchronized, purely proximal or purely distal synaptic activity. We find that those different forms of dendritic input activity lead to various impact on the somatic membrane potential fluctuations properties, thus raising the possibility that individual neurons will differentially couple to specific forms of activity as a result of their different firing response. We indeed found such a heterogeneous coupling between synaptic input and firing response for all types of presynaptic activity. This heterogeneity can be explained by different levels of cellular excitability in the case of the balanced, unbalanced, synchronized and purely distal activity. A notable exception appears for proximal dendritic inputs: increasing the input level can either promote firing response in some cells, or suppress it in some other cells whatever their individual excitability. This behavior can be explained by different sensitivities to the speed of the fluctuations, which was previously associated to different levels of sodium channel inactivation and density. Because local network connectivity rather targets proximal dendrites, our results suggest that this aspect of biophysical heterogeneity might be relevant to neocortical processing by controlling how individual neurons couple to local network activity.

Project description:BACKGROUND:Interferon-? (IFN-?, a type II IFN) is present in the central nervous system (CNS) under various conditions. Evidence is emerging that, in addition to its immunological role, IFN-? modulates neuronal morphology, function, and development in several brain regions. Previously, we have shown that raising levels of IFN-? (a type I IFN) lead to increased neuronal excitability of neocortical layer 5 pyramidal neurons. Because of shared non-canonical signaling pathways of both cytokines, we hypothesized a similar neocortical role of acutely applied IFN-?. METHODS:We used semi-quantitative RT-PCR, immunoblotting, and immunohistochemistry to analyze neuronal expression of IFN-? receptors and performed whole-cell patch-clamp recordings in layer 5 pyramidal neurons to investigate sub- and suprathreshold excitability, properties of hyperpolarization-activated cyclic nucleotide-gated current (Ih), and inhibitory neurotransmission under the influence of acutely applied IFN-?. RESULTS:We show that IFN-? receptors are present in the membrane of rat's neocortical layer 5 pyramidal neurons. As expected from this and the putative overlap in IFN type I and II alternative signaling pathways, IFN-? diminished Ih, mirroring the effect of type I IFNs, suggesting a likewise activation of protein kinase C (PKC). In contrast, IFN-? did neither alter subthreshold nor suprathreshold neuronal excitability, pointing to augmented inhibitory transmission by IFN-?. Indeed, IFN-? increased electrically evoked inhibitory postsynaptic currents (IPSCs) on neocortical layer 5 pyramidal neurons. Furthermore, amplitudes of spontaneous IPSCs and miniature IPSCs were elevated by IFN-?, whereas their frequency remained unchanged. CONCLUSIONS:The expression of IFN-? receptors on layer 5 neocortical pyramidal neurons together with the acute augmentation of inhibition in the neocortex by direct application of IFN-? highlights an additional interaction between the CNS and immune system. Our results strengthen our understanding of the role of IFN-? in neocortical neurotransmission and emphasize its impact beyond its immunological properties, particularly in the pathogenesis of neuropsychiatric disorders.

Dataset Information

Altered development of glutamatergic synapses in layer V pyramidal neurons in NR3A knockout mice.

Publications

Altered development of glutamatergic synapses in layer V pyramidal neurons in NR3A knockout mice.

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