Abstract
Reelin expression is reduced in various regions in the post-mortem brain of schizophrenia patients but the exact role of reelin function in the neurobiology of schizophrenia remains elusive. Absence of reelin in knockout mouse causes inverted lamination of the neocortex due to aberrant neuronal migration. The aim of this study was to utilize patient-derived olfactory neurosphere-derived (ONS) cells to investigate whether extracellular reelin alters cell motility in schizophrenia patient-derived cells. ONS cells from nine patients were compared with cells from nine matched healthy controls. Automated high-throughput imaging and analysis were used to track motility of individual living cells on reelin-coated surfaces produced from reelin secreted into the medium by HEK293FT cells transfected with the full-length reelin plasmid pCrl. Automated assays were used to quantify intracellular cytoskeleton composition, cell morphology, and focal adhesions. Expression of reelin and components of the reelin signaling pathway were measured by western blot and flow cytometry. Reelin inhibited the motility of control cells but not patient cells, and increased the number and size of focal adhesions in control cells but not patient cells. Patient and control cells expressed similar levels of the reelin receptors and the reelin signaling protein, Dab1, but patient cells expressed less reelin. Patient cells were smaller than control cells and had less actin and acetylated α-tubulin, components of the cytoskeleton. These findings are the first direct evidence that cellular responses to reelin are impaired in schizophrenia and are consistent with the role of reelin in cytoarchitectural deficits observed in schizophrenia patient brains.
Highlights
By denaturing total cell protein samples and running samples on a reducing polyacrylamide gel, we identified the key reelin fragments that are widely regarded as the full-length reelin reduced reelin expression reported for post-mortem patient brains, supports the use of our proposed olfactory neurosphere-derived (ONS) cell model to probe further into the cellular mechanisms of the effects of reelin in schizophrenia
This study demonstrates that schizophrenia patient-derived cells were deficient in reelin-dependent cell motility and focal adhesion formation
Control cells reduced their motility when exposed to extracellular reelin, whereas patient cells did not alter their motility
Summary
Reelin gene (RELN) encodes a large secreted glycoprotein whose signaling pathway is implicated in neurotransmission,[1] synaptic plasticity,[2,3] and memory formation.[2,4] Reelin protein and mRNA expression are reduced in various regions of the post-mortem brain in schizophrenia patients, e.g., prefrontal cortex, temporal cortex, cerebellum, hippocampus, and caudate nucleus.[5,6,7,8,9] The concurrent observation of reduced reelin expression and abnormal interstitial neuron distribution in the same superficial white matter region in schizophrenia patient brains led to speculation that reelin could have a key role in brain development and schizophrenia disease etiology.[5]. Extracellular reelin signals via a dedicated intracellular signaling pathway. Reelin may activate focal adhesion kinase (FAK) pathway via interaction with integrin receptors α3β1 14) and α5β1.15 Focal adhesions are cell membrane structures that link the extracellular matrix (ECM) with the intracellular actin cytoskeleton and are essential for cell adhesion and motility.[16] The FAK signaling pathway, which regulates cell adhesion to extracellular proteins via integrin receptors, is impaired in schizophrenia patient-derived olfactory cells.[17] The exact mechanism of reelindependent modulation of cell migration remains debatable. Reelin acts as a chemoattractant that stimulates newborn neurons to move towards the cortical surface in the neocortex,[21] more recently modeled in silico,[22] and supported by evidence that reelin activates growth cones and filopodia,[23] structures that depend on active modulation of the actin and microtubule cytoskeleton
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