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Synaptic Plasticity I: Long-Term Potentiation

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1 Synaptic Plasticity I: Long-Term Potentiation
1. The mystery of memory 2. The Hebbian synapse & memory 3. Long-term potentiation 4. Synapse specificity & associativity of LTP 5. Phases of LTP 6. Pre- versus post-synaptic changes in LTP 7. Changes in the shape dendritic spines in LTP 8. The connection between LTP & memory 9. Can memory be enhanced?

2 The Mystery of Memory - Long-term memory is an exotic
biological phenomenon…it is encoded immediately, yet can last for 100 years or more. - Presumably, there are physical changes to neurons that underlie memory formation…however, the proteins and lipids that comprise neurons are turned over every few hours or days. - How can stable memories be stored by such unstable components?

3 Synapses & Memory Capacity
- The legendary Spanish neuroanatomist Santiago Ramon y Cajal, who showed that the brain is not a syncytium but is in fact made up of discrete cells, postulated that synaptic connections between neurons were probably the sites of memory storage. - There are 10 billion neurons in the human brain, with an average of 10,000 synaptic connections each…thus, if whole neurons must change properties to encode memories, the information storage capacity of the human brain is roughly 10 billion bits, whereas if memories are encoded by changes to synapses, then the storage capacity increases 4 orders of magnitude to 100 trillion bits.

4 Hebbian Synapses - In 1949, Canadian psychologist Donald Hebb
published “The Organization of Behavior”, an influential book in which he described his vision for how synaptic plasticity might give rise to memory formation. - Hebb’s Postulate: “When an axon of cell A is near enough to excite cell B or repeatedly or consistently takes part in firing it, some growth or metabolic change takes place in one or both cells such that A’s efficiency, as one of the cells firing B, is increased.” A + B are active at the same time weak synapse strong synapse A B A B To put it another way: “Cells that fire together, wire together.”

5 Long-Term Potentiation
- There are many different forms of synaptic plasticity, which probably underlie different types of memory, but the most intensively-studied example of synaptic plasticity over the past 40 years has been long-term potentiation (LTP), which can be observed in certain regions of the hippocampus and cerebral cortex. - A lot is now known about LTP, so to help make sense of this massive amount of information, we will discuss work on LTP chronologically, using the history of classic experiments performed in this field as an organizing principle to understand what is presently known versus unknown.

6 The Discovery of LTP - Terje Lomo & Tim Bliss first described the LTP phenomenon in a 1973 paper that described experiments where they recorded from the dentate gyrus (a part of the hippocampus) in anethestized rabbits. - Lomo & Bliss found that when they delivered a strong tetanic stimulation (for 10 seconds) to the perforant path (the connection between the entorhinal cortex & dentate gyrus), the responses to test pulses of the perforant path were much stronger following the tetanic stimulation…this effect lasted for at least 3 hours. (from Bliss & Lomo, J. Physiol., 1973)

7 Hippocampal Slices - Following the report from
Bliss and Lomo, there were only a handful of papers about LTP over the next few years, mainly because it was very difficult to record from intact animals. - By the mid-1970’s, there were great improvements in understanding how to make brain slices and keep them alive for hours in vitro, which allowed work on LTP to proceed on hippocampal slice preparations.

8 Synapse Specificity of LTP
- Lynch & colleagues demonstrated that LTP in region CA1 of the hippocampus is specific to only the set of synapses receiving the tetanic stimulation. - This demonstrated that LTP does in fact represent “synaptic plasticity” rather than simply reflecting a change in the global excitability of the neurons under study. (based on Dunwiddie & Lynch, J. Physiol., 1978)

9 Associativity of LTP - The synapse-specificity of LTP
has now been studied in many labs, and it has been widely found that pairing a weak stimulation of one set of inputs (insufficient on its own to create LTP) with a concurrent strong stimulation of another set of inputs can result in LTP of both pathways. - This “associative” property of LTP has received much attention because it seems to many neuroscientists to fulfill the prediction of Hebb’s Postulate (“cells that fire together, wire together”).

10 Phases of LTP - LTP can be divided into three discrete phases, which have distinct mechanistic underpinnings: induction, expression & stabilization: Expression Stabilization Induction (“early LTP”) (“late LTP”) Stable for many hours, days, weeks

11 Induction of LTP Requires Postsynaptic Ca2+
- Lynch & colleagues showed that injection of calcium chelators such as EGTA into the postsynaptic neuron completely blocked the induction of LTP. - This finding was soon replicated in many labs and considered very surprising, since most concurrent work on other types of synaptic plasticity (i.e., Kandel’s work on Aplysia, to be discussed in the next lecture) was focused on presynaptic changes…indeed, some labs of this era had already claimed to have found increased glutamate release with LTP, although these findings could not be consistently replicated in other labs. EGTA (based on Lynch et al., Nature, 1983)

12 Induction of LTP Requires NMDA Receptors
- Collingridge & colleagues showed that treatment of hippocampal slices with NMDA receptor antagonists (such as AP5) blocked the induction of LTP. - It was soon discovered that NMDA receptors are permeable to calcium and are also voltage-dependent, and thus the mechanisms underlying LTP induction became quite clear: postsynaptic depolarization facilitated glutamate activation of NMDA receptors, leading to postsynaptic calcium influx and the generation of LTP. AP5 (based on Collingridge et al., J. Physiol., 1983)

13 Expression of LTP Requires AMPA Receptors
- Lynch & colleagues showed that treatment of hippocampal slices with AMPA receptor antagonists (such as CNQX) masked the expression of LTP. - Since NMDA-R responses are the same before & after LTP, this is a further problem for the idea that LTP results from increased release of glutamate… recent work has shown an increased number of AMPA receptors at potentiated synapses. CNQX (based on Muller, Joly & Lynch, Science, 1988) Control NMDA receptors AMPA receptors Potentiated

14 LTP Requires Calcium-Activated Enzymes
- Calcium influx through NMDA receptors activates a variety of different enzymes that are found in the post-synaptic density… the three most intensively-studied enzymes with regard to LTP are the kinases CaMKII & PKC and the protease calpain. - CaMKII and PKC directly phosphorylate AMPA-R’s to alter their activity and trafficking, and also phosphorylate NMDA-R’s and other PSD targets… calpains cleave away at the cytoskeleton & other PSD components, resulting in changes to spine shape. NMDA Ca2+ AMPA CaMKII PKC Calpain Glutamate Dendritic spine

15 The Mystery of Memory - Long-term memory is a very exotic
biological phenomenon…it is encoded immediately, yet can last for 100 years or more. - Presumably, there are physical changes to neurons that underlie memory formation…however, the proteins and lipids that comprise neurons are turned over every few hours or days. - How can stable memories be stored by such unstable components?

16 Changes in Spine Shape Accompany LTP
- Stabilization of LTP is accompanied by changes in the shape and size of dendritic spines…this was first shown by Lynch and colleagues in 1980, and subsequently studied in exquisite detail by Kristen Harris and colleagues in analyses of 3-dimensional serial reconstructions of spines. - Changes to the shape of dendritic spines can radically alter the calcium dynamics within the spine, and can also help to make room for more AMPA receptors…this can strengthen the synapse in a stable manner, since the change in shape can be preserved even as the individual components are turned over.

17 Changes in Gene Expression with LTP?
- Kandel: “Behavior is the result of the interaction between genes and the environment.” (Ch. 62 of Principles) - Changes in gene expression have been found following high-frequency stimulation …however, it is uncertain if these changes play a role in the stabilization of LTP, as it is unclear how changes in transcription in the nucleus could give rise to synapse- specific functional changes. CREB “synaptic tagging?”

18 LTP & Memory - Does the formation of long-term memories depend on LTP in vivo? …there are several lines of evidence that indicate a connection: 1. LTP fits Hebb’s Postulate and is synapse-specific, which seems a pre-requisite for a biological process that would have a high capacity for information storage. 2. LTP is observed in regions of the brain known to be involved in the formation of long-term memories (hippocampus, cortex) and is either not observed at all, or has very different properties, in other regions of the brain (such as brainstem). 3. LTP is induced by brief stimulation and can be very stable, which are properties shared with the formation of long-term memories.

19 LTP & Memory (con’t) 4. LTP is optimally induced by brain rhythms associated with learning. - several-second bursts of 100 Hz activity do not occur naturally, except during seizures…Larson & Lynch (Science, 1986) studied the ability of more physiological rhythms to induce LTP, and found that separation of brief bursts by 200 msec (a 5 Hz rhythm) is optimal for LTP induction… interestingly, 5 Hz corresponds to the EEG “theta rhythm” observed in the hippocampus and cortex during learning (and REM sleep). Beta (15-30 Hz) (arousal, alertness, anxiety) Alpha (8-14 Hz) (relaxation, meditation, pre-sleep) Theta (5-6 Hz) (learning, novelty, REM sleep) Delta (1-4 Hz) (deep sleep, unconsciousness)

20 LTP & Memory (con’t) 5. Drugs or genetic manipulations that block LTP also impair memory. Morris water maze (Morris et al., Nature, 1986) Control rat Control rats rapidly learn how find the hidden platform. Treatment of rats with the NMDAR antagonist AP5 blocks hippocampal LTP and also blocks learning of the platform location. AP5- treated rat (and later, various KO mice)

21 LTP & Memory (con’t) 6. Drugs or genetic manipulations that enhance LTP also enhance certain types of memory. - Joe Tsien & colleagues (Nature, 1999) created a line of transgenic mice that over-express the NMDA receptor subunit NR2B in their forebrains… these mice exhibit enhanced LTP in various hippocampal and cortical regions, and also exhibit significantly enhanced performance on a number of different memory tasks, including the Morris water maze…thus, the official name for this line of smart mice is “Doogie”, derived from the brilliant lead character in the TV show “Doogie Howser, M.D.”

22 Can Memory Be Enhanced By Drugs?
- Cognition-enhancing drugs are common in our culture…caffeine, for example, blocks inhibitory adenosine signaling in the brain, and hundreds of papers have shown that caffeine enhances LTP and improves learning on certain tasks… furthermore, drugs like methylphenidate (Ritalin) and amphetamine (Adderall) enhance the release of dopamine, norepinephrine & serotonin, leading to increased NMDA & AMPA receptor function, enhanced LTP, and improved performance of certain memory tasks… problems: cardiovascular side effects, potential for addiction.

23 The Future of Memory-Enhancing Drugs
- Many companies, including some founded by top LTP researchers, are pursuing the development of memory-enhancing therapeutics: Cortex Pharmaceuticals Memory Pharmaceuticals Irvine, CA Founder: Gary Lynch New York Founder: Eric Kandel Concept: Use AMPA receptor positive allosteric modulators (“AMPAkines”) to specifically enhance LTP & memory. Currently in Phase II clinical trials. Concept: Use phosphodiesterase inhibitors to slow the breakdown of cAMP, enhance CREB activation, and improve memory. Currently in Phase II clinical trials. PDE inhibitors PDE PKA cAMP AMPAkines

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