Reduced GAP-43 mRNA in Dorsolateral Prefrontal Cortex of Patients with Schizophrenia

Abstract

Schizophrenia has been associated with anatomical and functional abnormalities of the dorsolateral prefrontal cortex (DLPFC), which may reflect abnormal connections of DLPFC neurons. We measured mRNA levels of growth-associated protein (GAP-43), a peptide linked to the modifiability of neuronal connections, in post-mortem brain tissue from two cohorts of patients with schizophrenia and controls. Using the RNase protection assay (RPA), we found a significant reduction in GAP-43 mRNA in the DLPFC, but not in the hippocampus, of patients with schizophrenia. With in situ hybridization histo- chemistry (ISHH), performed on a separate cohort, we confirmed the reduction of GAP-43 mRNA in the DLPFC of patients with schizophrenia. We detected reduced GAP-43 mRNA per neuron in layers III, V and VI of patients with schizophrenia compared with normal controls and patients with bipolar disorder. Thus, glutamate neurons in DLPFC of schizophrenic patients may synthesize less GAP-43, which could reflect fewer and/or less modifiable connections than those in normal human brain, and which may be consistent with the deficits of prefrontal cortical function that characterize schizophrenia.

Proteomic analysis of membrane microdomain-associated proteins in the dorsolateral prefrontal cortex in schizophrenia and bipolar disorder reveals alterations in LAMP, STXBP1 and BASP1 protein expression

“…Interestingly, reductions in GAP-43 gene and protein expression have been reported in the SCZ and BPD brain. [65][66][67] Limbic system-associated membrane protein is characterized in this paper for the first time as a MM-associated protein. LAMP is a glycoprotein expressed on the surface of somata and proximal dendrites of neurons in cortical and subcortical regions of the limbic system.…”

Molecular Mechanisms, Biological Actions, and Neuropharmacology of the Growth-Associated Protein GAP-43

“…This suggests that an abnormally high level of GAP-43 leads to synaptic dysfunction [75]. A reduced level of GAP-43 mRNA was found in the dorsolateral prefrontal cortex of post-mortem samples from patients with schizophrenia [97]. A disrupted cortical map and an absence of cortical barrels were seen in GAP-43 knockout mice [57].…”

Reduced brain-derived neurotrophic factor in prefrontal cortex of patients with schizophrenia

“…For each of the three separate studies, patients with schizophrenia and normal individuals were matched (all to0.34, P40.15) for age, tissue pH (determined for each case as previously described), 28 post-mortem interval (PMI, defined as time between death and brain freezing), and for gender, race, and brain hemisphere (Table 2). Unfortunately, we could not use all cases for all assays because some cases were not suitable for section-based analysis and because of limited tissue availability (see Table 1).…”

“…[22][23][24][25] Recent studies suggest that there may be a loss of mRNAs encoding presynaptic proteins, some of which are abundant in glutamate neurons, in the dorsolateral prefrontal cortex (DLPFC) of patients with schizophrenia. [26][27][28] Additionally, levels of synapse-associated proteins may be reduced in the frontal cortex of patients with schizophrenia, [29][30][31][32] and the density of dendritic spines in layer III pyramidal neurons of the DLPFC of patients with schizophrenia appears reduced. 33,34 Increased neuronal density with a decrease in somal size of pyramidal neurons and a putative diminution of cortical neuropil in the DLPFC [35][36][37][38] also support the notion of prefrontal subcellular or synaptic pathology in this disorder.…”