This is a repost from my old blog, about a famous scientist, Dr. George Augustine, who came to UM to give a talk about LTP and LTD. Tho occasion was “NeuroDay,” a seminar series where us Neurokids get to invite our favorite scientists to come talk to us about brain stuff.
The third and last speaker at NeuroDay was Dr. George Augustine, of Duke University Neurobiology in Durham, NC. His research is focused on how calcium ions regulate the release of neurotransmitters at synapses. The lab works in identifying vesicular proteins important for neurotransmitter release and the physiological functions of synapsins in presynaptic terminals of neurons. According to his lab’s site, they are concerned with two main issues: the molecular mechanisms involved in neurotransmitter release, and signal transduction pathways underlying long-lasting synaptic plasticity (long term depression (LTD)and long term potentiation (LTP)). More specifically, they have identified secondary messenger molecules, such as calcium and IP3, which mediate long term depression in the cerebellum. (More under the fold…..)
What is LTP and LTD?
LTP and LTD are opposite sides of the same coin. LTD refers to synaptic stimulation happening over a sustained period of time, which results in the weakening of a synaptic connection. LTP, conversely, refers to stimulation resulting in the strengthening of a synaptic connection. LTD results from either strong synaptic stimulation (cerebellum Purkinje cells) or persistent weak synaptic stimulation (hippocampus). The theories and development of the field are long and involved, and I have included links and good reviews at the end of this post for those that want to dig deeper. But I’m going to specifically discuss Dr. Augustine’s talk on LTD and calcium signaling in the cerebellum.
The Calcium Wave
One type of dendritic signal is the calcium wave, which arise from the propagation of intracellular calcium release in dendrites following synaptic activity or by synergistic activity of metabotropic glutamate receptors (mGluRs) and back-propagating action potentials.
(Figure: Ca2 waves propagate for several microns in CA1 pyramidal cells. Left, image of a pyramidal cell filled with a Ca2 indicator dye. Right, a line scan of Ca2 concentration over time, measured along the apical dendrite, showing that a Ca2 wave elicited by synaptic activity starts at a dendritic branching point (dashed line) and spreads some distance along the dendrite (from Nakamura et al., 2002).
This type of calcium signal has been characterized most extensively in hippocampal CA1 pyramidal neurons, and have a single site of origin and can propagate bidirectionally. Calcium waves require the repetitive activation of mGluRs, which produces the second messenger IP3, which in turn binds to IP3 receptors in the smooth ER and frees calcium.
Post-synaptic Changes Mediated By Calcium
Most forms of long term synaptic plasticity, like LTP and LTD, require postsynaptic calcium signaling. As changes in synaptic strength arise from changes in local glutamate receptor trafficking within the spine head, it is likely that local calcium signaling in the spine plays important role in the modification of the synapse’s efficacy. A very clear example of the role for local Ca signaling in synaptic plasticity occurs at the glutamatergic synapses between the parallel fibers and Purkinje cells of the cerebellum. At these synapses, LTD is induced when both parallel fiber synapses and climbing fiber synapses on the Purkinje cell are simultaneously activated. This form of LTD requires the activation of mGluRs on spines of the parallel fiber-Purkinje cell synapse. Activation of this synapse leads to IP3 production and release of intracellular calcium, which is necessary and sufficient to trigger LTD. Both the dendrites and spines of Purkinje cells are filled with smooth ER that is studded with IP3 receptors. In mutant mice and rats lacking myosinVa, smooth ER is lost from the spines of Purkinje cells and LTD is abolished (Miyata et al. 2000). Local release from IP3-sensitive calcium stores in spines is required for induction of cerebellar LTD.
In hippocampal CA1 pyramidal neurons, both LTP and LTD can be induced by repetitive synaptic activity. The calcium source for both forms of plasticity is mainly influx through NMDA receptors on postsynaptic spines (Sabatini et al, 2001.) LTP is induced by conditions that lead to strong activation of NMDA receptors, such as a brief bout of high-freq synaptic activity, while LTD is induced when NMDA receptors are weakly activated during prolonged low-freq activity, LTP is caused by brief but large increases in postsynaptic calcium ccn, while LTD arises from prolonged but smaller calcium signals.
Augustine GJ, Santamaria F, Tanaka K. “Local calcium signaling in neurons.” Neuron. 2003 Oct 9;40(2):331-46. Review.
Augustine GJ. “How does calcium trigger neurotransmitter release?” Curr Opin Neurobiol. 2001 Jun;11(3):320-6. Review.
Miyata M, Finch EA, Khiroug L, Hashimoto K, Hayasaka S, Oda SI, Inouye M, Takagishi Y, Augustine GJ, Kano M. “Local calcium release in dendritic spines required for long-term synaptic depression.” Neuron. 2000 Oct;28(1):233-44.
Scientific American article about “Doogie Mice” (enchanced LTP = smarter mice!)
Morris RG, Anderson E, Lynch GS, Baudry M (1986). “Selective impairment of learning and blockade of long-term potentiation by an N-methyl-D-aspartate receptor antagonist, AP5”. Nature 319 (6056): 774-6. PMID 2869411.
Sweatt JD (1999). “Toward a molecular explanation for long-term potentiation”. Learn Mem 6 (5): 399-416. PMID 10541462
Segal M, Murphy DD (1998). “CREB activation mediates plasticity in cultured hippocampal neurons.”. Neural Plast 6 (3): 1-7. PMID 9920677.
Kasahara J, Fukunaga K, Miyamoto E (2001). “Activation of calcium/calmodulin-dependent protein kinase IV in long term potentiation in the rat hippocampal CA1 region.”. J Biol Chem 276 (26): 24044-50. PMID 11306573