Role for Reelin in Neurotransmitter Release

Abstract

The extracellular matrix molecule Reelin is known to control neuronal migration during development. Recent evidence suggests that it also plays a role in the maturation of postsynaptic dendrites and spines as well as in synaptic plasticity. Here, we aimed to address the question whether Reelin plays a role in presynaptic structural organization and function. Quantitative electron microscopic analysis of the number of presynaptic boutons in the stratum radiatum of hippocampal region CA1 did not reveal differences between wild-type animals and Reelin-deficient reeler mutant mice. However, additional detailed analysis showed that the number of presynaptic vesicles was significantly increased in CA1 synapses of reeler mutants. To test the hypothesis that vesicle fusion is altered in reeler, we studied proteins known to control transmitter release. SNAP25, a protein of the soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) complex, was found to be significantly reduced in reeler mutants, whereas other SNARE complex proteins remained unaltered. Addition of recombinant Reelin to organotypic slice cultures of reeler hippocampi substantially rescued not only SNAP25 protein expression levels but also the number of vesicles per bouton area indicating a role for Reelin in presynaptic functions. Next, we analyzed paired-pulse facilitation, a presynaptic mechanism associated with transmitter release, and observed a significant decrease at CA1 synapses of reeler mutants when compared with wild-type animals. Together, these novel findings suggest a role for Reelin in modulating presynaptic release mechanisms.

Reelin signaling in development, maintenance, and plasticity of neural networks

“…While acute reelin exposure at intervals less than twenty minutes predominantly affects NMDAR activity, increased reelin exposure at intervals above this temporal threshold modifies AMPAR-mediated synaptic responses through an increase in AMPARs at synaptic sites (Qiu et al, 2006c). Reelin has also been shown to influence synaptic function through modulation of presynaptic release mechanisms (Hellwig et al, 2011). Altered neurotransmitter release and vesicle fusion at Schaffer collateral synapses of adult reeler mice were attributable to a decrease in SNAP25, a protein necessary for vesicular fusion (Hellwig et al, 2011).…”

“…Reelin has also been shown to influence synaptic function through modulation of presynaptic release mechanisms (Hellwig et al, 2011). Altered neurotransmitter release and vesicle fusion at Schaffer collateral synapses of adult reeler mice were attributable to a decrease in SNAP25, a protein necessary for vesicular fusion (Hellwig et al, 2011). Vesicle release-dependent presynaptic plasticity was therefore impaired in the CA1 of the striatum radiatum in reeler mice, implicating reelin in pre- and post-synaptic forms of functional plasticity.…”

Interactions between ICAM-5 and β1 integrins regulate neuronal synapse formation

“…As synaptic adhesion molecules, b1 integrins are often considered to be located at the post-synaptic site, even though Hellwig and co-workers earlier showed a pre-synaptic localization of b1 integrins by electron microscopy (EM) (Hellwig et al, 2011). Our studies using fluorescent immunostaining and synaptosome fractionation show that, besides being present on dendrites, b1 integrins are also found in pre-synaptic structures.…”

The Amyloidogenic Pathway Meets the Reelin Signaling Cascade: A Cytoskeleton Bridge Between Neurodevelopment and Neurodegeneration

“…Therefore, Reelin modulates synaptic plasticity events involved in learning and memory processes in adults. Consistently with a role for Reelin in the control of neurotransmission, reeler mice show diminished expression of presynaptic (SNARE, SNAP-25) [44] and postsynaptic (PSD-95, PTEN) markers [43]. These defects cause failures in the release of neurotransmitters, impairing synaptic transmission.…”

“…Although Reelin function is mainly related to neurodevelopment, several recently studies assign roles in the adult brain, such as the development of dendrites and dendritic spines [36], modulation of synaptogenesis [39], modulation of synaptic plasticity [40][41][42][43] and neurotransmitter release [44]. The mechanism by which Reelin can modulate the synaptic transmission is not fully elucidated.…”