Rescue of Cyclic AMP Mediated Long Term Potentiation Impairment in the Hippocampus of Mecp2 Knockout (Mecp2(-/y) ) Mice by Rolipram.

Saju Balakrishnan,Diethelm W. Richter,Marcus Niebert

doi:10.3389/fncel.2016.00015

Saju Balakrishnan, Diethelm W. Richter + Show 1 more

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https://doi.org/10.3389/fncel.2016.00015

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Abstract

Rett syndrome (RTT) patients experience learning difficulties and memory loss. Analogous deficits of hippocampal plasticity are reported in mouse models of RTT. To elucidate the underlying pathophysiology, we studied long term potentiation (LTP) at the CA3 to CA1 synapses in the hippocampus in acute brain slices from WT and Mecp2-/y mice, by either activating cAMP dependent pathway or using high frequency stimulation, by means of patch clamp. We have observed that, the NMDA channel current characteristics remain unchanged in the Mecp2-/y mice. The adenylyl cyclase (AC) agonist forskolin evoked a long lasting potentiation of evoked EPSCs in WT CA1 neurons, but only minimally enhanced the EPSCs in the Mecp2-/y mice. This weaker potentiation in Mecp2-/y mice was ameliorated by application of phosphodiesterase 4 inhibitor rolipram. The hyperpolarization activated cyclic nucleotide gated channel current (Ih) was potentiated to similar extent by forskolin in both phenotypes. Multiple tetanus induced cAMP-dependent plasticity was also impaired in the Mecp2-/y mice, and was also partially rescued by rolipram. Western blot analysis of CA region of Mecp2-/y mice hippocampus revealed more than twofold up-regulation of protein kinase A (PKA) regulatory subunits, while the expression of the catalytic subunit remained unchanged. We hypothesize that the overexpressed PKA regulatory subunits buffer cAMP and restrict the PKA mediated phosphorylation of target proteins necessary for LTP. Blocking the degradation of cAMP, thereby saturating the regulatory subunits alleviated this defect.

Highlights

Patients with Rett syndrome (RTT) have severe mental retardation. Amir et al (1999) discovered that the majority of RTT cases result from mutations in the X-linked MECP2 gene richly expressed in the neurons
Our results show that long term potentiation (LTP) mediated by adenylyl cyclase pathway is defective in the Mecp2−/y mouse due to the uncoupling of downstream signaling by protein kinase A (PKA)
NMDA channel mediated currents play a crucial role in the induction of neuronal plasticity evoked by both tetanic stimulation and cAMP pathway activation

Summary

Introduction

Patients with Rett syndrome (RTT) have severe mental retardation. Amir et al (1999) discovered that the majority of RTT cases result from mutations in the X-linked MECP2 (methyl-CpG-binding protein 2) gene richly expressed in the neurons. Amir et al (1999) discovered that the majority of RTT cases result from mutations in the X-linked MECP2 (methyl-CpG-binding protein 2) gene richly expressed in the neurons. Intact Mecp function is pivotal to the normal development of nervous system and Rolipram Recues LTP in Mecp2−/y Mice its absence or mutation can lead to defective dendritic structure, synapse formation and decreased size of the neurons (Gao et al, 2015; Rietveld et al, 2015). A mouse model for RTT, which shows typical symptoms of the disease, was developed by deletion of the MECP2 gene. Reduced cognitive ability of RTT patients is mirrored in the Mecp2−/y mice by the lack of neuronal network modulation such as LTP that underlie learning and memory (Moretti et al, 2006). Weng et al (2011) have described a saturation of LTP in a RTT mouse model, which could be reversed by the NMDA antagonist Memantine

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