Dendritic spine pathologies in hippocampal pyramidal neurons from Rett syndrome brain and after expression of Rett-associated MECP2 mutations

Abstract

Rett syndrome (RTT) is an X chromosome-linked neurodevelopmental disorder associated with the characteristic neuropathology of dendritic spines common in diseases presenting with mental retardation (MR). Here, we present the first quantitative analyses of dendritic spine density in postmortem brain tissue from female RTT individuals, which revealed that hippocampal CA1 pyramidal neurons have lower spine density than age-matched non-MR female control individuals. The majority of RTT individuals carry mutations in MECP2, the gene coding for a methylated DNA-binding transcriptional regulator. While altered synaptic transmission and plasticity has been demonstrated in Mecp2-deficient mouse models of RTT, observations regarding dendritic spine density and morphology have produced varied results. We investigated the consequences of MeCP2 dysfunction on dendritic spine structure by overexpressing (∼twofold) MeCP2-GFP constructs encoding either the wildtype (WT) protein, or missense mutations commonly found in RTT individuals. Pyramidal neurons within hippocampal slice cultures transfected with either WT or mutant MECP2 (either R106W or T158M) showed a significant reduction in total spine density after 48hrs of expression. Interestingly, spine density in neurons expressing WT MECP2 for 96hrs was comparable to that in control neurons, while neurons expressing mutant MECP2 continued to have lower spines density than controls after 96hrs of expression. Knockdown of endogenous Mecp2 with a specific small hairpin interference RNA (shRNA) also reduced dendritic spine density, but only after 96hrs of expression. On the other hand, the consequences of manipulating MeCP2 levels for dendritic complexity in CA3 pyramidal neurons were only minor. Together, these results demonstrate reduced dendritic spine density in hippocampal pyramidal neurons from RTT patients, a distinct dendritic phenotype also found in neurons expressing RTT-associated MECP2 mutations or after shRNA-mediated endogenous Mecp2 knockdown, suggesting that this phenotype represent a cell-autonomous consequence of MeCP2 dysfunction.

Glutamate Delta-1 Receptor Regulates Metabotropic Glutamate Receptor 5 Signaling in the Hippocampus

“…The neuropathologies in the MeCP2 KO model of Rett syndrome include a reduction in dendritic spine density, lower glutamatergic synapses, and a shift in excitatoryinhibitory balance toward greater inhibition (Dani et al, 2005;Nelson et al, 2006;Chao et al, 2007;Blackman et al, 2012;Na et al, 2013). Reduction in spine density is also observed in brains from Rett syndrome patients (Chapleau et al, 2009). The majority of these features in animal models are reproduced in patients with MeCP2 mutation-derived neurons using the induced pluripotent stem cells (Marchetto et al, 2010).…”

The Impact of MeCP2 Loss- or Gain-of-Function on Synaptic Plasticity

“…Tao Short-term plasticity as measured by paired pulse stimulation is also bidirectionally regulated by MeCP2 expression with decreased expression and increased expression resulting in increased and decreased neurotransmitter release probability, respectively. Dendritic spine density is significantly altered by MeCP2 levels with decreased expression associated with lower spine density and increased expression associated with greater spine density (although lower spine density has also been reported following MeCP2 overexpression (Chapleau et al, 2009)). Longterm potentiation (LTP) does not appear bidirectionally influenced by MeCP2 expression as both knockout and overexpressing mice show similar deficits in LTP magnitude and maintenance (but see also Collins et al, 2004).…”

“…Nevertheless, in vitro experiments have shown that overexpression or elimination of MeCP2 levels in hippocampal and cortical cultures decreases dendritic arbor complexity and spine density (Chapleau et al, 2009;Kishi and Macklis, 2010;Zhou et al, 2006) although overexpression of MeCP2 has been shown to increase glutamateric synapse number (Chao et al, 2007). These abnormalities in dendritic branching and spine number may suggest a mechanism whereby MeCP2 dysfunction ultimately compromises CNS plasticity and as such may be a contributing factor to the learning and memory deficits that are a hallmark symptom of disorders related to Mecp2 mutations.…”

Reversing Synapse Loss in Alzheimer's Disease: Rho-Guanosine Triphosphatases and Insights from Other Brain Disorders

“…Indeed, in the last few decades, multiple lines of evidence have shown that disruptions in dendritic spine shape, size, or number invariably accompany various brains disorders, such as schizophrenia [6][7][8][9], Angelman syndrome [10], and Rett syndrome [11][12][13], and may be even be a characteristic feature of traumatic brain injuries [14,15]. What do these various neuropsychiatric and neurodevelopmental diseases share in common?…”