Reelin is preferentially expressed in neurons synthesizing γ-aminobutyric acid in cortex and hippocampus of adult rats

Pesold, Christine; Impagnatiello, Francesco; Pisu, M. O.; Uzunov, Doncho P.; Costa, E.; Guidotti, Alessandro; Caruncho, Héctor J.

doi:10.1073/pnas.95.6.3221

Cited by 370 publications

(352 citation statements)

References 25 publications

(50 reference statements)

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“…Although reelin is abundantly expressed in the postnatal brain (Pesold et al, 1998;Roberts et al, 2005;RamosMoreno et al, 2006), its functional role remains enigmatic. We have shown previously that reelin enhances tetanusinduced LTP in CA1 by activating apoER2 and VLDLR and hypothesized a potential role of reelin signaling in modulating synaptic transmission and plasticity (Weeber et al, 2002).…”

Section: Discussionmentioning

confidence: 99%

“…Transduction of reelin signaling occurs through interaction of disabled-1 (Dab1) with the intracellular NPxY motif of these receptors, resulting in tyrosine phosphorylation of Dab1, activation of the SFKs (Src family nonreceptor tyrosine kinases), and an ensuing signaling cascade that leads to proper neuronal migration (Howell et al, 1997(Howell et al, , 1999aTrommsdorff et al, 1998;Arnaud et al, 2003;Bock and Herz, 2003). Considering the fact that reelin is also abundantly expressed by interneurons, and all of the downstream signaling components exist in the postnatal hippocampus (Alcantara et al, 1998;Pesold et al, 1998;Abraham and Meyer, 2003;Zhao et al, 2004), it is intriguing to know whether reelinmediated signaling plays a physiological role in adult brain function.…”

Section: Introductionmentioning

confidence: 99%

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Differential Reelin-Induced Enhancement of NMDA and AMPA Receptor Activity in the Adult Hippocampus

Qiu¹,

Zhao²,

Korwek³

et al. 2006

J. Neurosci.

164

161

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The developmental lamination of the hippocampus and other cortical structures requires a signaling cascade initiated by reelin and its receptors, apoER2 (apolipoprotein E receptor 2) and VLDLR (very-low-density lipoprotein receptor). However, the functional significance of continued reelin expression in the postnatal brain remains poorly understood. Here, we show that reelin application to adult mice hippocampal slices leads to enhanced glutamatergic transmission mediated by NMDA receptors (NMDARs) and AMPA receptors (AMPARs) through distinct mechanisms. Application of recombinant reelin enhanced NMDAR-mediated currents through postsynaptic mechanisms, as revealed by the variance-mean analysis of synaptic NMDAR currents, assessment of spontaneous miniature events, and the levels of NMDAR subunits at synaptic surface. In comparison, nonstationary fluctuation analysis of miniature AMPAR currents and quantification of synaptic surface proteins revealed that reelin-induced enhancement of AMPAR responses was mediated by increased AMPAR numbers. Reelin enhancement of synaptic NMDAR currents was abolished when receptor-associated protein (RAP) or the Src inhibitor 4-amino-5-(4-methylphenyl)-7-(t-butyl)pyrazolo[3,4-d]-pyrimidine (PP1) was bath applied and was abrogated by includingPP1 in the recording electrodes. In comparison, including RAP or an inactive PP1 analog PP3 in the recording electrode was without effect. Interestingly, the increased AMPAR response after reelin application was not blocked by PP1 but was blocked by the phosphoinositide-3Ј kinase (PI3K) inhibitors wortmannin and LY294002 [2-(4-morpholinyl)-8-phenyl-1(4H)-benzopyran-4-one hydrochloride]. Furthermore, reelin-induced, PI3K-dependent AMPAR surface insertion was also observed in cultured hippocampal neurons. Together, these results reveal a differential functional coupling of reelin signaling with NMDAR and AMPAR function and define a novel mechanism for controlling synaptic strength and plasticity in the adult hippocampus.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Differential Reelin-Induced Enhancement of NMDA and AMPA Receptor Activity in the Adult Hippocampus

Qiu¹,

Zhao²,

Korwek³

et al. 2006

J. Neurosci.

164

161

View full text Add to dashboard Cite

show abstract

“…The signal is terminated with Reelin targeted to the lysosome and Dab1 degraded by the proteasome (Arnaud et al, 2003;Bock et al, 2004;Morimura et al, 2005). In the adult brain, Reelin expression is maintained by GABAergic interneurons and glutamatergic pyramidal neurons in layer II of the entorhinal cortex (Alcantara et al, 1998;Miettinen et al, 2005;Pesold et al, 1998;Ramos-Moreno et al, 2006) and the same signalling cascade is used in adult synapses to modulate neuronal function and synaptic plasticity by regulating glutamate receptor activity through the phosphorylation of intracellular tyrosine residues (Beffert et al, , 2006Chen et al, 2005;Weeber et al, 2002).…”

Section: Introductionmentioning

confidence: 99%

Age-related accumulation of Reelin in amyloid-like deposits

Knuesel

Nyffeler

Mormède

et al. 2009

Neurobiology of Aging

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Age-related accumulation of Reelin in amyloid-like deposits Abstract Accumulating evidence suggest that alterations in Reelin-mediated signaling may contribute to neuronal dysfunction associated with Alzheimer's disease (AD), the most common form of senile dementia. However, limited information is available on the effect of age, the major risk factor of AD, on Reelin expression. Here, we report that normal aging in rodents and primates is accompanied by accumulation of Reelin-enriched proteinous aggregates in the hippocampal formation that are related to the loss of Reelin-expressing neurons. Both phenomena are associated with age-related memory impairments in wild-type mice. We provide evidence that normal aging involves loss of Reelin neurons, reduced production and elimination of the extracellular deposits, whereas a prenatal immune challenge or the expression of AD-causing gene products, result in earlier, higher, and more persistent levels of Reelin-positive deposits. These aggregates co-localize with non-fibrillary amyloid-plaques, potentially representing oligomeric Abeta species. Our findings suggest that elevated Reelin plaque load creates a precursor condition for senile plaque deposition and may represent a critical risk factor for sporadic AD. ABSTRACTAccumulating evidence suggest that alterations in Reelin-mediated signalling may contribute to neuronal dysfunction associated with Alzheimer's disease (AD), the most common form of senile dementia. However, limited information is available on the effect of age, the major risk factor of AD, on Reelin expression. Here, we report that normal aging in rodents and primates is accompanied by accumulation of Reelin-enriched proteinous aggregates in the hippocampal formation that are related to the loss of Reelin-expressing neurons. Both phenomena are associated with age-related memory impairments in wild-type mice. We provide evidence that normal aging involves loss of Reelin neurons, reduced production and elimination of the extracellular deposits, whereas a prenatal immune challenge or the expression of AD-causing gene products, result in earlier, higher, and more persistent levels of Reelin-positive deposits.These aggregates co-localize with non-fibrillary amyloid-plaques, potentially representing oligomeric Aβ species. Our findings suggest that elevated Reelin plaque load creates a precursor condition for senile plaque deposition and may represent a critical risk factor for sporadic AD.3

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“…11 Reelin binds several proteins as likely receptors, including apolipoprotein E receptor 2 (ApoER2), very-low-density lipoprotein receptor (VLDL-R) and a3b1 integrin protein. [12][13][14] Reelin binding to ApoER2 and VLDLR receptors induces clustering of the latter receptors, causing dimerization/oligomerization of the adaptor protein, disabled-1 (Dab-1), on the cytosolic aspect of the plasma membrane 15 with eventual tyrosine phosphorylation of Dab-1 adapter protein, 16 facilitating the transduction of signaling pathway from the Reelin-producing cells (GABAergic neurons 17 or Cajal-Retzius cells of layer I) 18 to downstream receptor sites on cortical pyramidal cells. 19 In vivo, Reelin is processed by cleavage at two locations, that is, between repeats 2 and 3 and repeats 6 and 7, 20 resulting in three final fragments.…”

mentioning

confidence: 99%