LTP in hippocampal area CA1 is induced by burst stimulation over a broad frequency range centered around delta

Abstract

Long-term potentiation (LTP) is typically studied using either continuous high-frequency stimulation or theta burst stimulation. Previous studies emphasized the physiological relevance of theta frequency; however, synchronized hippocampal activity occurs over a broader frequency range. We therefore tested burst stimulation at intervals from 100 msec to 20 sec (10 Hz to 0.05 Hz). LTP at Schaffer collateral-CA1 synapses was obtained at intervals from 100 msec to 5 sec, with maximal LTP at 350-500 msec (2-3 Hz, delta frequency). In addition, a short-duration potentiation was present over the entire range of burst intervals. We found that N-methyl-D-aspartic acid (NMDA) receptors were more important for LTP induction by burst stimulation, but L-type calcium channels were more important for LTP induction by continuous high-frequency stimulation. NMDA receptors were even more critical for short-duration potentiation than they were for LTP. We also compared repeated burst stimulation with a single primed burst. In contrast to results from repeated burst stimulation, primed burst potentiation was greater when a 200-msec interval (theta frequency) was used, and a 500-msec interval was ineffective. Whole-cell recordings of postsynaptic membrane potential during burst stimulation revealed two factors that may determine the interval dependence of LTP. First, excitatory postsynaptic potentials facilitated across bursts at 500-msec intervals but not 200-msec or 1-sec intervals. Second, synaptic inhibition was suppressed by burst stimulation at intervals between 200 msec and 1 sec. Our data show that CA1 synapses are more broadly tuned for potentiation than previously appreciated.Long-term potentiation (LTP) is used as a model for studying synaptic events during learning and memory (Bliss and Collingridge 1993;Morris 2003;Lynch 2004). At most synapses, LTP is triggered by postsynaptic Ca 2+ influx through N-methyl-D-aspartic acid (NMDA) glutamate receptors (Collingridge et al. 1983;Harris et al. 1984;Herron et al. 1986) and, under some conditions, through L-type voltage-gated Ca 2+ channels Teyler 1990, 1994;Morgan and Teyler 1999). LTP was discovered in the dentate gyrus (Bliss and Lomo 1973) following several seconds of 10-100 Hz stimulation of the perforant path. Since then, many LTP studies have used similar long, high-frequency stimulation (HFS) protocols, most typically 100 Hz, 1 sec (Bliss and Collingridge 1993). Although effective, HFS does not resemble physiological patterns of activity (Albensi et al. 2007). Patterned stimulation resembling physiological activity, in particular theta burst stimulation, is also effective for LTP induction Staubli and Lynch 1987;Capocchi et al. 1992;Nguyen and Kandel 1997). Theta burst stimulation consists of short bursts (4-5 stimuli at 100 Hz) repeated at 5 Hz, which lies within the hippocampal theta frequency range (4-12 Hz) (Bland 1986;Buzsáki 2002). Primed burst stimulation, another form of patterned stimulation, involves delivery of a priming stimulus followed by a single shor...

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