Hippocampal long-term potentiation is impaired in mice lacking brain-derived neurotrophic factor.

Abstract

Brain-derived neurotrophic factor (BDNF), a member of the nerve growth factor (NGF) gene family, has been shown to influence the survival and differentiation of specific classes of neurons in vitro and in vivo. The possibility that neurotrophins are also involved in processes of neuronal plasticity has only recently begun to receive attention. To determine whether BDNF has a function in processes such as long-term potentiation (LTP), we produced a strain of mice with a deletion in the coding sequence of the BDNF gene. We then used hippocampal slices from these mice to investigate whether LTP was affected by this mutation. Homo-and heterozygous mutant mice showed significantly reduced LTP in the CAl region of the hippocampus. The magnitude of the potentiation, as well as the percentage of cases in which LTP could be induced successfully, was clearly affected. According to the criteria tested, important pharmacological, anatomical, and morphological parameters in the hippocampus of these animals appear to be normal. These results suggest that BDNF might have a functional role in the expression of LTP in the hippocampus.Neurotrophic factors, in particular the members of the nerve growth factor (NGF) gene family, have so far been considered predominantly with regard to their function in regulating survival and differentiation of specific neuronal populations during embryonic development and the maintenance of characteristic neuronal function in adulthood (1-3). There is, however, evidence that neurotrophins might also be involved in neuronal plasticity (4-10). Long-term potentiation (LTP) is the most widely used paradigm to study cellular and molecular events underlying neuronal plasticity (11). We therefore used this paradigm in slices of the hippocampus from mice with targeted deletion of the brain-derived neurotrophic factor (BDNF) gene to test whether BDNF has a role in this important phenomenon of synaptic plasticity. MATERIALS AND METHODSIn the gene-targeting construct, a 560-bp fragment from the BDNF protein-coding exon was replaced by the selection marker-a neomycin-resistance gene flanked by a glycerate kinase gene promoter and a polyadenylylation signal-thus deleting most of the mature BDNF coding sequence (Fig. 1). Embryonic stem cells (D3, 129Sv) containing the disrupted BDNF gene were injected into BALB/c mouse blastocysts for subsequent generation of chimeric mice. Chimeric males were crossed with NMRI females to produce heterozygotes. In keeping with previously published reports (12, 13), homozygous BDNF (-/-) mutant mice were retarded in growth and had reduced weight (down to only 25% of the wild type) from postnatal day 3 (P3) on. They displayed aberrant limb coordination and balance, showed a loss of neurons in the dorsal root ganglia, and usually died between 2 and 4 weeks after birth. Such abnormalities were never observed in heterozygous BDNF (+/ -) mice.Transverse hippocampal slices (400 ,um thick) were prepared and maintained by standard procedures (medium, 124 mM NaCl/3 mM KCl/1.25 mM...

Neurotrophin signaling among neurons and glia during formation of tripartite synapses

“…Consistent with these findings, BDNF enhances glutamatergic transmission at mature hippocampal synapses, in part by increases in presynaptic glutamate release (Kang and Schuman, 1996;Carmignoto et al, 1997;Li et al, 1998). At hippocampal and cortical synapses in vivo and in vitro, BDNF facilitates long-term potentiation, attenuates long-term depression and promotes homeostatic and competitive interactions that refine neural circuitry (Korte et al, 1995;Akaneya et al, 1996;Cabelli et al, 1996;Huang et al, 1999;Turrigiano and Nelson, 2000;Turrigiano and Nelson, 2004). At hippocampal and cerebellar synapses in BDNF-deficient mice, high-frequency stimulation and paired-pulse facilitation are impaired, which is consistent with compromised presynaptic release (Pozzo-Miller et al, 1999;Carter and Regehr, 2002).…”

Human Bone Marrow Stem Cells Exhibit Neural Phenotypes and Ameliorate Neurological Deficits after Grafting into the Ischemic Brain of Rats

“…Numerous studies suggest that neurotrophic factors play important roles in brain plasticity. Neurotrophic factors can enhance neuronal sprouting (11), synaptogenesis (18), long-term potentiation (2,30,41), and neurotransmission (25) and increase neurotransmitter release (26,27,34). Humpel et al reported that human fetal cortical grafts expressed nerve growth factor, brain-derived neurotrophic factor, and neurotrophin-3 mRNA after transplantation to cortical cavities in rats (23).…”

The Corticosteroid Receptor Hypothesis of Depression

“…Because long-term administration of moclobemide suppresses HPA activity and activates cAMP-mediated CREB phosphorylation via PKA, the expression of BDNF may be enhanced and followed by a profound alteration in synaptic efficiency (Korte et al 1995(Korte et al , 1996Chen et al 1999;Kafitz et al 1999). Furthermore, in these transgenic mice, morphine-induced mesolimbic release of serotonin and dopamine as well as the psychomotor-stimulant effects of morphine were enhanced.…”