Neurotrophin regulation of synaptic transmission
Introduction
The earliest demonstration of fast actions of neurotrophins on synaptic transmission was by Lohof and Poo [1]. They showed that the addition of brain-derived neurotrophic factor (BDNF) or neurotrophin-3 (NT-3) to developing frog neuromuscular synapses in culture causes a rapid, but reversible, increase in the frequency of miniature excitatory postsynaptic currents (mEPSCs). Many studies since have shown that BDNF and other neurotrophins can facilitate synaptic function, in nerve–muscle synapses 1, 2, 3, 4•, cultured hippocampal neurons 3, 4•, 5, 6, 7, 8•, hippocampal slices 9, 10, 11, 12, 13, 14, 15, the in vivo hippocampus [16•], and visual cortical slices 17, 18. A simple catalog of neurotrophin actions such as this can be misleading. There are important points in the details of these experiments and in the different results obtained, sometimes in the same experimental preparation. In this review, I will focus on the common emergent themes and highlight unresolved issues.
Section snippets
Similarities and differences between developing and adult synapses
It appears that neurotrophins can influence synaptic transmission at both developing and adult synapses. In one of the earliest tissue ages examined, McKay, Segal and colleagues [19•] have shown that neurotrophins can speed up the development of both excitatory and inhibitory synaptic transmission in cultured hippocampal neurons. Embryonic day 16 (E16) hippocampal cultures have little spontaneous or evoked synaptic activity; the addition of BDNF for 3 days induces the formation of both
Fast actions of neurotrophins
There are many examples of relatively fast modulation of inhibitory transmission by neurotrophins. These include an NT-3-induced decrease in inhibitory transmission seen in cultured hippocampal neurons [27] and a BDNF-induced decrease in inhibition in hippocampal slices 28, 29. Can neurotrophins such as BDNF also produce similarly rapid actions on excitatory synaptic transmission? In cultured nerve–muscle synapses 1, 2, 3, 4• and cultured hippocampal synapses 5, 6, 7, 8• the answer is a
Normal versus plastic synaptic transmission
Do neurotrophins participate in influencing normal synaptic transmission or are they linked exclusively to episodes of plasticity? The question itself may be inappropriate given that synapses in a living brain are never in a truly steady state: they have natural histories of plasticity that are as dynamic and varied as those we impose on them experimentally. Nonetheless, we can ask whether blocking neurotrophin actions, using either a genetic or immunochemical approach, influences normal
Presynaptic and postsynaptic actions of neurotrophins
Abundant evidence indicates that neurotrophins can modulate synaptic transmission by presynaptic as well as postsynaptic mechanisms. Evidence for a presynaptic change comes from a study in visual cortical slices where BDNF increased the frequency of spontaneous synaptic events and decreased the likelihood of synaptic failures [18]. In developing nerve–muscle synapses [2] and hippocampal slices 9, 38, several studies found that the application of BDNF influenced paired-pulse facilitation. More
Activity-dependent release and activity-dependent action — both or neither?
Are neurotrophins released in an activity-dependent manner or do they merely act in an activity-dependent manner? No experiment has conclusively distinguished between these possibilities. In vitro studies provide clear evidence that the neurotrophins can be secreted both constitutively and following depolarization of neurons 3, 41, 42; this secretion originates primarily from the somatic or dendritic compartments. Despite these data, in experiments using either genetic or pharmacological
In vivo actions?
Does the abundant evidence that neurotrophins can affect synaptic transmission in vitro imply that neurotrophins act similarly in the intact brain? Clive Bramham and colleagues [16•] have recently shown that local infusion of BDNF into the intact adult rat hippocampus causes a long-lasting enhancement of synaptic transmission, similar to that observed (by some) in slices of hippocampus 9, 13, 15 and visual cortex 17, 18. A recent study of water-maze learning in mice carrying a deletion in one
Conclusions
The plasticity of a chemical synapse — its ability to change over timescales ranging from seconds to days — is perhaps its most important feature. As more multifunctional and persistent signaling molecules are discovered, it will be important to distinguish the actions of neurotrophins from a (depressingly) long list of other molecules that modulate synaptic strength. Pushing our understanding of neurotrophin actions in the intact brain beyond a superficial level will require an understanding
Acknowledgments
I thank Gilles Laurent for discussion and comments. EM Schuman is a Pew Biomedical Scholar and an Assistant Investigator of the Howard Hughes Medical Institute.
References and recommended reading
Papers of particular interest, published within the annual period of review, have been highlighted as:
• of special interest
•• of outstanding interest
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