RAPID COMMUNICATION Acute Intrahippocampal Infusion of BDNF Induces Lasting Potentiation of Synaptic Transmission in the Rat Dentate Gyrus

Messaoudi, Elhoucine, Kjetil Bårdsen, Bolek Srebro, and Clive knockout mice (Korte et al. 1995; Patterson et al. 1996) R. Bramham. Acute intrahippocampal infusion of BDNF induces as well as in slices pretreated with TrkB-IgG, a BDNFlasting potentiation of synaptic transmission in the rat dentate scavenging fusion protein (Figurov et al. 1996). gyrus. J. Neurophysiol. 79: 496–499, 1998. The effect of acute One important, and largely unexplored issue, is whether intrahippocampal infusion of brain-derived neurotrophic factor BDNF regulates long-term synaptic efficacy in the hippo(BDNF) on synaptic transmission in the dentate gyrus was investicampus in vivo. Using freely moving rats, we previously gated in urethan-anesthetized rats. Medial perforant path-evoked found that LTP induction at medial perforant path-granule field potentials were recorded in the dentate hilus and BDNFcell synapses triggers a delayed and sustained increase in containing buffer was infused (4 ml, 25 min) immediately above BDNF mRNA expression in granule cells (Bramham et al. the dentate molecular layer. BDNF led to a slowly developing increase of the field excitatory postsynaptic potential ( f EPSP) 1996). Enhanced BDNF production and release therefore slope and population spike amplitude. The potentiation either may contribute to LTP’s late maintenance phase, which is reached a plateau level at Ç2 h after BDNF infusion or continued both mRNA and protein synthesis-dependent (Nguyen and to increase for the duration of experiment; the longest time point Kandel 1996). Here, acute intrahippocampal infusion of recorded was 10 h. Mean increases at 4 h after BDNF infusion BDNF was used to assess directly the effect of this neurowere 62.2 and 224% for the f EPSP slope and population spike, trophin on synaptic efficacy in the medial perforant path. respectively. No changes in responses were observed in controls The results provide evidence for BDNF-induced long-lasting receiving buffer medium only or buffer containing cytochrome C. potentiation of synaptic transmission in intact, adult rats. BDNF-induced potentiation developed in the absence of epileptiform activity in the hippocampal electroencephalogram or changes in recurrent inhibition on granule cells as assessed by paired-pulse M E T H O D S inhibition of the population spike. We conclude that exogenous Twenty-three male Mol:SD rats (Møllegaards Avls-laboratoBDNF induces a lasting potentiation of synaptic efficacy in the rium, Denmark) weighing between 250 and 350 g were anesthedentate gyrus of anesthetized adult rats. tized with urethan (1.5 g/kg ip) and placed in a stereotaxic apparatus. Rectal temperature was maintained at 377C by a servo-heating pad. Electrophysiological methods for obtaining selective stimulaI N T R O D U C T I O N tion of the medial perforant path have been described in detail previously (Bramham et al. 1991). Stereotaxic coordinates relative The neurotrophin family of signaling proteins, including to Bregma were 7.9 mm posterior, 4.2 mm lateral for stimulation nerve growth factor (NGF), brain-derived neurotrophic facand 3.9 mm posterior, 2.2 mm lateral for recording. A pair of tor (BDNF), neurotrophin-3 (NT-3), and NT-4/5 are recogtwisted Teflon-coated stainless steel wire recording electrodes nized as playing critical roles in the survival, differentiation, (coated diam Å 112 mm) were glued to the outer wall of a metal and outgrowth of select peripheral and central neurons durguide cannula (24 gauge, Plastics One, Roanoke, VA), and the electrodes cut so that the longest tip extended 1 mm from the end ing development (Lewin and Barde 1996; Lindsay 1996). of the cannula. A bipolar stimulating electrode was lowered into The functions of neurotrophins in the adult brain are less the dorsomedial aspect of the angular bundle for stimulation of the well understood, although a number of studies suggest that medial perforant path. After making a small slit in the dura, the neurotrophins continue to exert growth-promoting or surguide cannula and attached recording electrodes were slowly lowvival-promoting effects into adulthood (Lewin and Barde ered into the dorsal hippocampus until a positive-going field excit1996; Prakash et al. 1996; Thoenen 1995). atory postsynaptic potential ( f EPSP) of maximum slope was obPerhaps more surprisingly, recent neurophysiological tained in the dentate hilus. The final depth of the recording elecstudies in the CA1 region of the in vitro hippocampal slice trode ranged between 200 and 300 mm below the level of the preparation have provided evidence directly linking neuromaximum negative-going f EPSP sink recorded in the middle third of the dentate molecular layer. An inner ‘‘infusion’’ cannula (31 trophins to long-term changes in synaptic strength, effects gauge) then was inserted so that it protruded 300 mm below the that may contribute to learning and memory. In a seminal end of the guide. The tip of the infusion cannula was located in report by Kang and Schuman (1995), exogenously applied deep stratum lacunosum moleculare of field CA1, 700 mm above BDNF and NT-3 induced a rapid and long-lasting enhancethe hilar recording site and 300–400 mm above the medial perforant ment of synaptic transmission at Schaffer collateral-CA1 synapses. Cannula placement was verified in two rats by dye injecpyramidal cell synapses. Furthermore, BDNF appears to be tion. necessary for long-term potentiation (LTP), an extremely Human recombinant met-BDNF (a generous gift of Amgenlong-lasting increase in synaptic efficacy induced by highRegeneron Partners) was obtained as a concentrated stock solution frequency afferent stimulation. Thus maintenance of LTP in in phosphate buffered saline [PBS: 150 mM NaCl, 10 mM sodium phosphate buffer (pH 7.0) , and 0.004% Tween-20], aliquoted in the CA1 region is impaired in slices obtained from BDNF