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Intact long-term potentiation but reduced connectivity between neocortical layer 5 pyramidal neurons in a mouse model of Rett syndrome.

ABSTRACT: Mutations in MECP2 cause Rett syndrome and some related forms of mental retardation and autism. Mecp2-null mice exhibit symptoms reminiscent of Rett syndrome including deficits in learning. Previous reports demonstrated impaired long-term potentiation (LTP) in slices of symptomatic Mecp2-null mice, and decreased excitatory neurotransmission, but the causal relationship between these phenomena is unclear. Reduced plasticity could lead to altered transmission, or reduced excitatory transmission could alter the ability to induce LTP. To help distinguish these possibilities, we compared LTP induction and baseline synaptic transmission at synapses between layer 5 cortical pyramidal neurons in slices of wild-type and Mecp2-null mice. Paired recordings reveal that LTP induction mechanisms are intact in Mecp2-null connections, even after the onset of symptoms. However, fewer connections were found in Mecp2-null mice and individual connections were weaker. These data suggest that loss of MeCP2 function reduces excitatory synaptic connectivity and that this precedes deficits in plasticity.

SUBMITTER: Dani VS

PROVIDER: S-EPMC2765053 | biostudies-literature | 2009 Sep

REPOSITORIES: biostudies-literature

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Intact long-term potentiation but reduced connectivity between neocortical layer 5 pyramidal neurons in a mouse model of Rett syndrome.

Dani Vardhan S VS Nelson Sacha B SB

The Journal of neuroscience : the official journal of the Society for Neuroscience 20090901 36

Mutations in MECP2 cause Rett syndrome and some related forms of mental retardation and autism. Mecp2-null mice exhibit symptoms reminiscent of Rett syndrome including deficits in learning. Previous reports demonstrated impaired long-term potentiation (LTP) in slices of symptomatic Mecp2-null mice, and decreased excitatory neurotransmission, but the causal relationship between these phenomena is unclear. Reduced plasticity could lead to altered transmission, or reduced excitatory transmission co ...[more]

PMID: 19741133

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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

Intact long-term potentiation but reduced connectivity between neocortical layer 5 pyramidal neurons in a mouse model of Rett syndrome.

Publications

Intact long-term potentiation but reduced connectivity between neocortical layer 5 pyramidal neurons in a mouse model of Rett syndrome.

Similar Datasets

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