Cellular and Molecular Neurobiology, Vol. 22, Nos. 5/6, December 2002 ( C  2002) Signaling Mechanisms Mediating BDNF Modulation of Memory Formation In Vivo in the Hippocampus Mariana Alonso, 1 Monica R. M. Vianna, 2 Ivan Izquierdo, 2 and Jorge H. Medina 1,3 Received June 14, 2002; accepted September 20, 2002 SUMMARY Given that brain-derived neutrophic factor (BDNF) modulates both short-term synap- tic function and activity-dependent synaptic plasticity in the adult hippocampus, here we examined signaling mechanisms in vivo in the hippocampus mediating BDNF modulation of long-term memory (LTM) formation of a one-trial fear-motivated learning task in rats. Bi- lateral infusions of function-blocking anti-BDNF antibody into the CA1 region of the dorsal hippocampus decreased extracellular-signal regulated kinase 2 (ERK2) and CREB activa- tion and impaired LTM retention scores. Inhibition of ERK1/2 activation by PD098059 produced similar effects and also reduced CREB phosphorylation. In contrast, intrahip- pocampal administration of recombinant human BDNF increased ERK1/2 and CREB ac- tivation and facilitated LTM. Activated-p38, activated-PKC isoforms, and activated-AKT were unaltered after BDNF or anti-BDNF infusion. In addition, no changes were found on αPKA and βPKA catalytic subunits in nuclear samples. Thus, our results suggest that BDNF exerts its role in LTM formation in vivo in CA1 region of the hippocampus, at least in part, via CREB activation. Moreover, BDNF-induced CREB activation appears to be mediated mainly through the activation of ERK1/2 signaling pathway. KEY WORDS: endogenous BDNF; anti-BDNF antibody; memory consolidation; inhibitory avoidance learning; signaling pathways; ERK1/2; CREB. INTRODUCTION Brain-derived neutrophic factor (BDNF) plays diverse roles in regulating neuronal structure, function, and long-term survival of specific populations of neurons in the developing and adult brain, and it is involved in activity-dependent modulation of dendritic and axonal growth (Lu and Chow, 1999; McAllister et al., 1999; Poo, 2001; Schinder and Poo, 2000). A growing body of evidence indicates that BDNF regulates both short-term synaptic function and long-term activity-dependent synaptic plasticity (Kafitz et al., 1999; Korte et al., 1998; Li et al., 1998; Rutherford et al., 1998; Tyler and Pozzo-Miller, 1 Instituto de Biologia Celular y Neurociencias, Facultad de Medicina, UBA, Buenos Aires, Argentina. 2 Centro de Memoria, Departamento de Bioquimica, Instituto de Biociencias, UFRGS, Porto Alegre, Brazil. 3 To whom correspondence should be addressed at Instituto de Biologia Celular y Neurociencias, Facultad de Medicina, UBA, Paraguay 2155, piso 3, 1121 Buenos Aires, Argentina; e-mail: jmedina@fmed.uba.ar. 663 0272-4340/02/1200-0663/0 C  2002 Plenum Publishing Corporation