Types Of Receptors And Potential Sites Of Plasticity

and phospholipase A2 (PLA2), which liberates free arachidonic acid that can be converted into a wide variety of active metabolites. We will explore these systems and others in excruciating detail in Chapters 6-8.

Finally, it is important to note that the targets of these various signaling pathways are as diverse as the genome itself. In terms of neuronal function, particularly important targets are the presynaptic proteins associated with neurotransmitter release, membrane K+ channels, Ca2+ channels and Na+ channels, nuclear transcription factors regulating gene expression, the protein synthesis machinery, and the cytoskeleton.

function in a broad sense, and mechanisms of learning specifically.

When Tim Bliss was a young man, he likewise had (he still has) confidence that understanding long-term alterations in synaptic function in the hippocampus would yield valuable insights into the mechanisms of mammalian memory. He acted on this confidence by displacing himself as a postdoctoral researcher from England to Per Anderson's lab in Oslo, a focal point of physiologic studies of the hippocampus then and now. Tim set out to find a long-lasting form of synaptic plasticity in the hippocampus, and by teaming up with Terje Lomo he did just that. The seminal report by Bliss and Lomo in 1973, describing a phenomenon they termed "long-term potentiation" of synap-tic transmission, set the stage for what is now three decades of progress in understanding the basics of long-term synaptic alteration in the CNS.

As a personal aside, I once asked Tim how LTP was discovered. His recollection was that, before he came to Anderson's lab, Terje Lomo had serendipitously discovered that brief periods of high-frequency synaptic stimulation could lead to an enhancement of synaptic transmission in hippocampal recordings from rabbits. The physiologists there used this trick to prolong their experiments; when they started to lose their preparation they would give a quick "buzz" to the hippocampus to increase synaptic strength so that they could get some more data. I find this a fascinating example of chance favoring the prepared mind—Tim's insight was to appreciate the importance of the phenomenon.

In their experiments, Bliss and Lomo recorded synaptic responses in the dentate gyrus, stimulating the perforant path inputs from the entorhinal cortex (4). They used extracellular stimulating and recording electrodes that they implanted into the animal. The basic experiment was begun by recording baseline synaptic transmission in this pathway. Then they delivered a brief period of high-frequency (100 Hz "tetanic") stimulation, and after this brief period of stimulation they saw an increase in the strength of synaptic connections between the perforant path inputs from the entorhi-nal cortex onto the dentate granule neurons in the dentate gyrus (Figure 2). They also observed an increased likelihood of the cells firing action potentials in response to a constant synaptic input, a phenomenon they termed E-S (EPSP-to-Spike) potentia-tion. These two phenomena together were termed LTP. LTP lasted many, many hours

Bliss And Lomo Ltp

FIGURE 2 Bliss and Lomo's first published LTP experiment. As described in more detail in the text, in this pioneering work Tim Bliss and Terje Lomo demonstrated long-term potentiation of synaptic transmission. This specific experiment investigated synaptic transmission at perforant path inputs into the dentate gyrus (see Figure 1). Arrows indicate the delivery of high-frequency synaptic stimulation, resulting in LTP. Filled circles are responses from the tetanized pathways, open circles are a control pathway that did not receive tetanic stimulation. The bar, where no data points are available, indicates a period of time where Tim Bliss fell asleep. Data acquisition in this era involved the investigator directly measuring by hand synaptic responses from an oscilloscope screen. Moreover, it was not unusual for experiments to extend overnight owing to the long amount of time involved in preparing the rabbit for the experiment, implanting the electrodes into the brain, and establishing a stable recording configuration. Reproduced with permission from Bliss and Lomo (4).

FIGURE 2 Bliss and Lomo's first published LTP experiment. As described in more detail in the text, in this pioneering work Tim Bliss and Terje Lomo demonstrated long-term potentiation of synaptic transmission. This specific experiment investigated synaptic transmission at perforant path inputs into the dentate gyrus (see Figure 1). Arrows indicate the delivery of high-frequency synaptic stimulation, resulting in LTP. Filled circles are responses from the tetanized pathways, open circles are a control pathway that did not receive tetanic stimulation. The bar, where no data points are available, indicates a period of time where Tim Bliss fell asleep. Data acquisition in this era involved the investigator directly measuring by hand synaptic responses from an oscilloscope screen. Moreover, it was not unusual for experiments to extend overnight owing to the long amount of time involved in preparing the rabbit for the experiment, implanting the electrodes into the brain, and establishing a stable recording configuration. Reproduced with permission from Bliss and Lomo (4).

in this intact rabbit preparation. The appeal of LTP as an analog of memory was immediately apparent - it is a long-lasting change in neuronal function that is produced by a brief period of unique stimulus, exactly the sort of mechanism that had long been postulated to be involved in memory formation. This pioneering work of Bliss and Lomo set in motion a several-decades-long pursuit by numerous investigators geared toward understanding the attributes and mechanisms of LTP.

A. The Hippocampal Slice Preparation

Bliss and Lomo did their experiment using the intact rabbit, stimulating and recording in the anesthetized animal using implanted electrodes. In recent times, this preparation has been largely supplanted by the use of recordings from hippocampal slices maintained in vitro. (See Figure 3.) Because most of the LTP experiments that I will be describing in the rest of the book come from this type of preparation, I will briefly describe one typical procedure for preparation of hippocampal slices from rodents and then give an overview of extracellular recording in a typical LTP experiment (see Box 2).

To prepare the raw material for a hippocampal-slice experiment, brains of rats or mice are rapidly removed and

Stimulating Recording

Electrode Electrode

Stimulating Recording

Electrode Electrode

Brain Slice Recording Chamber

FIGURE 3 Electrodes in a living hippocampal slice. This photograph illustrates the appearance of a mouse hippocampal slice, maintained in a recording chamber. Responses in area CA1 are recorded using a saline-filled glass micropipette electrode (right) and a bipolar platinum stimulating electrode (left). See text and Figure 4 for additional details.

FIGURE 3 Electrodes in a living hippocampal slice. This photograph illustrates the appearance of a mouse hippocampal slice, maintained in a recording chamber. Responses in area CA1 are recorded using a saline-filled glass micropipette electrode (right) and a bipolar platinum stimulating electrode (left). See text and Figure 4 for additional details.

Mind and Memory Mastery

Mind and Memory Mastery

Tap into the memory secrets of geniuses… Discover The Untold Mind And Memory Secrets Used By The World’s Smartest People To Help You Unleash Your Full Potential! Finally You Can Fully Equip Yourself With These “Must Have” Mind And Memory Tools For Creating Your Ideal Lifestyle! Let’s face it, We all know the fact that we aren't using more than 10% of our brains. If we could, we'd be achieving much more and giving our fullest gifts to the world.

Get My Free Ebook


Post a comment