Fibroblast growth factor-2 protects entorhinal layer II glutamatergic neurons from axotomy-induced death

Abstract

The entorhinal cortex is a major relay between the hippocampus and other cortical and subcortical regions. Glutamatergic axons from layer II neurons form the entorhinal cortical projection to the hippocampus via the perforant pathway. We have demonstrated previously that lesion of the perforant pathway causes the death of approximately 30% of entorhinal layer II (ECL2) neurons. To elucidate mechanisms contributing to neuronal death and to investigate strategies preventing it, we identified the phenotype of the vulnerable neuronal population. Sections were immunolabeled with antibodies to the neuronal markers NeuN, glutamate, and calbindin-D28k, and to receptors for fibroblast growth factor-2 (FGFR1) and NMDA (NMDAR1) and were examined using confocal microscopy. Calbindin immunoreactivity was strikingly lamina-specific to ECL2, where one-third of all ECL2 neurons were calbindin-positive. Localization of glutamate revealed that half of the glutamatergic ECL2 neurons coexpressed calbindin. Quantification using unbiased stereology at 9 weeks after lesion of the perforant pathway revealed that the only ECL2 neuronal population that experienced a significant (70%) loss (20% of the total) was the population of glutamatergic ECL2 neurons that did not coexpress calbindin. All ECL2 neurons expressed FGFR1; therefore, we tested the role of FGF-2 in the survival of glutamatergic ECL2 neurons. We grafted fibroblasts genetically engineered to express nerve growth factor or FGF-2 and found that only FGF-2 grafts prevented loss of the vulnerable glutamatergic/calbindin-negative neurons. We present a hypothesis for the selective vulnerability of these glutamatergic/calbindin-negative ECL2 neurons and address the role of FGF-2 in neuronal rescue.

Developmental and stress-related changes of neurotrophic factor gene expression in an animal model of schizophrenia

“…15,31 Its expression is regulated by neuronal activity, 32,33 neurotransmitters and hormones [34][35][36] as well as by learning and physical exercise. 37,38 It is well established that FGF-2 has neuroprotective activity over a wide range of neurons [39][40][41] and it may render the cells more resistant to potential lethal damage. 42,43 The animal model employed in our study is obtained by bilateral infusion of the excitotoxin ibotenic acid in the ventral hippocampus (VH) of rats on the 7th day of age 44 and reproduces some fundamental features of schizophrenia, including dopaminergic overactivity and emergence of behavioral abnormalities in early adulthood.…”

Fibroblast Growth Factor 1 Regulates Signaling via the Glycogen Synthase Kinase-3β Pathway

“…Of the four FGF receptors (FGFRs), three are found in the brain: FGFR1 is mainly expressed on neurons, while FGFR2 and FGFR3 are found on glial cells (1,2,6,7). Binding of FGF leads to dimerization of FGFR followed by tyrosine kinase activation (2).…”

“…Binding of FGF leads to dimerization of FGFR followed by tyrosine kinase activation (2). FGF2 promotes survival of cortical and hippocampal neurons (8,9) and is also capable of rescuing neurons from denervation and injury (1). Similarly, FGF1 protects selective neuronal populations against the neurotoxic effects of molecules involved in the pathogenesis of neurodegenerative disorders such as Alzheimer's disease (10,11) and HIV encephalitis (12).…”

Androgen Mitigates Axotomy-Induced Decreases in Calbindin Expression in Motor Neurons

“…Although protective effects of calbindin are controversial (Baimbridge et al, 1992), calbindin is thought to protect injured neurons and glial cells from excitotoxicity via reduction in intracellular calcium levels (Sloviter, 1989;Mattson et al, 1991;Bao-Kuan et al, 1996;Peterson et al, 1996). Calbindin-immunoreactive cells are spared in in vitro assays of neuronal survival, and calbindin expression is induced by brain-derived neurotrophic factor, tumor necrosis factor, and neurotrophin-3 (NT-3), all of which exert trophic effects on target neurons (Collazo et al, 1992;Mattson et al, 1995;Ventimiglia et al, 1995;Marty et al, 1996).…”

“…Some support for a protective role of this protein comes from the observation that calbindin-positive cells are selectively spared after lesions of the CNS. For instance, calbindin-immunopositive hippocampal cells are spared after excitotoxic-induced cell death (Sloviter, 1989;Mattson et al, 1991), after section of the perforant pathway (Peterson et al, 1996), and after degeneration induced by Ig-G cytotoxicity (BaoKuan et al, 1996).…”