Memory Synaptic FormationWhat is the evidence relating synaptic plasticity to memory formation?
The term ‘memory’ refers to the encoding, storage and retrieval of learned information (Purves et al., 2004b). A human’s capacity for committing “relatively meaningless information” to memory is fairly limited but this capacity can be increased, indicating that changes in the brain can occur to accommodate this increase. Studies involving research into memory formation all share a “common core”: synaptic plasticity (Martin et al., 2000).
A Simple Hypothesis
Hebb’s postulate of 1949 stated: “When an axon of cell A is near enough to excite a cell B and repeatedly and persistently takes part in firing it, some growth process or metabolic change takes place in one or both cells such that A’s efficiency, as one of the cells firing B, is increased.” (Stent, 1973) This defines “correlated activity” (Tsien et al., 1996) and the phenomenon of synaptic plasticity which has been investigated at length for its link with memory formation.
A Note on Synaptic Strengthening
Synaptic strengthening or Long Term Potentiation (LTP) is the form of synaptic plasticity that has been strongly associated with memory. It was first demonstrated by Bliss and Lomo in 1973 (Martin et al., 2000) where they studied the dentate gyrus, an area of the hippocampus, in a rabbit. “Brief high-frequency stimulation” was applied at the perforant path resulting in dentate gyrus LTP.
Berger, in 1984, found this process increased the rate at which an animal learned a conditioning task (Berger, 1984). Since the 1970s extensive research has been carried out showing that LTP does not only occur in the hippocampus but in many different regions of the brain across many different species (Martin et al., 2000). LTP is now considered to be the “cellular correlate” (Whittington, 2008) of memory i.e. enable memory, not equal it (Martin et al., 2000).
LTP requires the NMDA receptor (NMDAR) which allows influx of calcium and “the drive of AMPA receptors into synapses” (Maren, 2005a).
Memories include those “emotionally-fuelled experiences” (BBC, 2007). In humans, the amygdala work closely with the brain’s memory centres to form emotional memories. Various studies have been undertaken using fear memories as an example of associative memory:
An experiment conducted by Eric Kandel and his team at Colombia University involved the use of a mollusc Aplysia californica, which has a small number of neurons in its nervous system, to examine the synaptic circuits involved in two forms of behavioural plasticity (Purves et al., 2004b) :
This is displayed by touching the siphon. Initially the gill “contracts vigorously” thereby withdrawing it but if the siphon is touched repeatedly, this contraction becomes weaker, shown by the green graphs below.
At a cellular level, the number of vesicles available for release between sensory and motor neurons, and therefore synaptic transmission, is decreased. This is known as synaptic depression and results in the decreased magnitude of contraction shown in the graphs above.
A strong electrical (noxious) stimulus is then applied to the tail and paired with touching the siphon (a non-noxious stimulus). The noxious stimulus “sensitises the gill withdrawal reflex” so we see an increase in the magnitude of gill contraction.
If the tail is then shocked without following it with a touch of the siphon the “gill withdrawal reflex remains enhanced for at least an hour”.
Over a course of days the stimulus coupling can be repeated and changes can be seen in the mollusc’s behaviour, for example a decline in intensity of the gill withdrawal response, providing evidence for a long term memory
Again, if the neuronal network is studied additional sensory neurons innervating the tail can be seen to become involved. This recruitment is a evidence of synaptic plasticity.
This is an example of associative memory and “Pavlovian fear conditioning”, referring to the way in which Pavlov conditioned his dogs to respond by ringing a bell before giving them food (Maren, 2005a). This principle can also be applied to mammals:
Malinow and colleagues discovered a way in which to “label plastic synapses and prevent synaptic plasticity during fear conditioning” (Maren, 2005a) in the lateral nucleus of the amygdala in a rat. Plastic synapses were easy to identify as the GluR1 subunit of the AMPA-R was labelled with green fluorescent protein (GFP). It is worth noting that the GluR1 and GluR5 subunits are vital in plasticity (Kim and Linden, 2007). The “plasticity block” was achieved by truncating GluR1 so only the GluR1 C-terminus was expressed, also labelled with GFP. Figure 2 shows the results of the experiment. All plastic synapses have their plasticity blocked when the GluR1 subunit is truncated.
Figure 2: Viral-Mediated Gene Transfer Procedures (Maren, 2005b)
Modifying the AMPA-R renders them inactive and prevents synaptic plasticity. If rats are subjected to this antagonistic effect on the AMPA-R prior to fear conditioning, their short term and long term fear memories are impaired, further demonstrating a link between synaptic plasticity and memory.
If the hippocampus is removed the brain loses its ability to create new memories. A very important case study is that of H.M. In an attempt to cure his epilepsy certain parts of his brain were removed in 1953, including the hippocampus. Post-operation H.M. suffered from anterograde amnesia and still suffers to this day. Memories of events prior to the operation remain intact but he “lacked the ability to commit anything new to memory” (BBC, 2007). The hippocampus is an observed site of synaptic plasticity so H.M. is living evidence of a connection between synaptic plasticity and memory formation.
Rodent Study – The Morris Water Maze
An experiment involving the study of spatial memory in rats was conducted (Purves et al., 2004b). A wild type rat was placed in a circular pool of “opaque water” containing a small platform, with the surrounding environment providing “visual cues”. The rat’s pattern of movement was recorded during several trials.
A rat with lesions in its hippocampus underwent the same number of trials in the same pool.
It can be seen that the route taken by wild type rats to locate the platform becomes more direct with more trials, and with this the time taken decreases. On the other hand, the mutated rats’ route remains very complicated and time taken remains approximately the same as it was on the first trial. The conclusion is that wild type rats are able to remember the location of the platform but those rats with hippocampal lesions are not. This is a further piece of evidence that the hippocampus, together with its synaptic plasticity, is essential in memory encoding storage and retrieval.
Eva Pastalkova and colleagues suppressed LTP by inhibiting an integral molecule in maintaining LTP, called PKM?. If the inhibitor was injected into the hippocampus as many as several days after spatial learning the stored memory was lost, outlining the importance of LTP in memory maintenance (Bruel-Jungerman et al., 2007).
Injecting NMDAR antagonists, such as MK801 (Manahan-Vaughan et al., 2008), into the hippocampus during learning “disrupts acquisition” but has no effect on memory maintenance leading to the conclusion that the role of NMDAR dependent synaptic plasticity is memory formation, but not retrieval (Martin et al., 2000). The case is the same for rats with a deleted NMDAR1 gene restricted to a particular region of the hippocampus called CA1 (Tsien et al., 1996).
Metabotopic glutamate receptors (mGluR) are involved in LTP. Administration of mGluR antagonists such as MCPG or 4-CPG to rats 30 minutes before learning a new task (e.g. Morris water maze or Y-maze) has no effect on spatial mapping during the task. However 24 hours later the rats treated with an antagonist have impaired spatial memory compared to those treated with a saline placebo. “Contextual fear conditioning” is also impaired by action of these antagonists (Martin et al., 2000).
Research has led to the finding of new receptors involved in the process of LTP. One of these is the Tr?B receptor. If the gene encoding this receptor is ‘knocked-out’ hippocampal LTP is impaired and consequently spatial learning is “compromised” (Gruart et al., 2007).
A group of drugs called ampakines have been proven to “facilitate the induction of LTP” (Martin et al., 2000) by binding AMPA receptors (Motluk, 2005) increasing the size and duration of AMPA currents leading to increased magnitude of “NMDAR-mediated calcium influxes” (Lynch, 1998).
An ampakine named CX717 was used in a trial, run by Julia Boyle of the University of Surrey, in which 16 males were randomly administered with 100mg, 300mg or 1000mg of CX717, or a placebo and undertook tasks over 27 hours without rest (Lynch, 1998). The ampakine was found to improve memory in the various tasks, providing further indication that synaptic plasticity is related to memory formation.
A process called Transcranial Magnetic Stimulation (TMS) involves stimulating the production of electric fields in the brain by means of a magnetic coil. Scientists at the City University of New York treated mice with TMS for five days. They discovered that it modified GluR so activation was increased and thereby enhanced LTP in all areas of the brain (Geddes, 2007). As with the other experiments, the mice will have been subjected to memory tasks and outperformed control or untreated mice.
Other Forms of Synaptic Plasticity
Long Term Depression (LTD)
So far LTP has been covered with respect to memory formation, but as mentioned earlier, despite being a very important form, it is not the only form of synaptic plasticity. LTD, the weakening of synaptic transmission, is the “dominant form” of synaptic plasticity in the cerebellum, where motor learning and the associative learning takes place (Bruel-Jungerman et al., 2007).
It is possible to induce LTD using low frequency (1Hz) stimulation (Bruel-Jungerman et al., 2007) in Wistar rats but not in Hooded Lister rats. However if Hooded Lister rats are placed in a “novel (non-stressful)” environment then LTD can be induced. It is the same case for the Wistar strain but when placed into their former environment after two weeks LTD “facilitation” is lost (Bear, 1999). It can therefore be concluded that LTD has role in spatial mapping (Bruel-Jungerman et al., 2007).
In addition, LTD impairment by deletion of serum response factor (SRF) leads to memory deficiencies implicating a role of this form of synaptic plasticity in memory.
Synapse remodelling is simply existing synapses undergoing “morphological changes”. Changes in curvature occur following LTP induction, but these are not permanent implying that repeated stimulation may be required for them to be so (Bruel-Jungerman et al., 2007).
Synapses can appear “perforated” under a microscope (Bruel-Jungerman et al., 2007). This is said to be due to insertion of AMPAR into “silent” (NMDAR only) synapses during LTP maintenance (Martin et al., 2000).
Unlike LTP and LTD, synaptogenesis is not modification of synaptic transmission but rather the “growth of new synapses” (Bruel-Jungerman et al., 2007). Donald Hebb discovered that his pet rats outperformed his laboratory rats in memory tasks (Wurbel and Garner, 2007). This is thought to be due to environmental enrichment (e.g. inclusion of toys and nesting material) (Morgan, 2007) otherwise known as “enriched condition (EC)”. It leads to more synapses per neuron in rats as opposed to those rats raised without toys (Markham and Greenough, 2004).
Work done by a group of Mexican scientists supports the claim of a link between synaptogenesis and memory. They found that there was a positive correlation between an increase in mossy fibre (neurons extending from the dendate gyrus to the CA3 region of the hippocampus) branching and performance in memory task (Ramirez-Amaya et al., 2001).
Furthermore, evidence was also found for syaptogenesis being stimulated by “overtraining” animals in the Morris water maze. The birth of new synapses could be observed by means of Timm’s staining, which detects the zinc present in the mossy fibre boutons, and using a light microscope (Ramirez-Amaya et al., 2001).
I have outlined four synaptic plasticity processes: LTP, LTD, synaptic remodelling and synaptogensesis which contribute towards the “continuous, dynamic modification” (Bruel-Jungerman et al., 2007) of brain circuits. Furthermore these processes have not only been observed in the hippocampus but in various brain regions.
LTP in particular has been extensively researched and found to be heavily associated with memory formation, but all four processes work in conjunction to achieve the encoding and storage of memory.
It is worth noting that an additional process called neurogenesis can occur, which does not involve synaptic changes but is the birth of new neurons, displaying the sheer “plasticity” of the brain and the complexity of memory formation.
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