Modulation Of The Release Machinery

A third, less well-understood mechanism recruited by the PKA and PKC pathways is direct augmentation of the responsiveness of the neurotransmitter release machinery to the action-potential-associated calcium influx. Even though the effect recruited by serotonin to contribute to presynaptic facilitation is quite robust, at present the incompleteness of our understanding of the release process itself precludes a mechanistic description of this component. This is, however, a very active area of research, and hopefully elucidation of this important mechanism will be forthcoming.

the circuit. Sensitization lasting on the order of 24 hours or more is mediated by an actual increase in the number of synaptic contacts between siphon sensory neurons and follower motor neurons. Thereby stimulation of the siphon sensory neuron elicits a greater response in gill withdrawal because a greater number and density of excitatory connections are made between the two cells. Studies into long-term effects of serotonin on sensory neurons strongly suggests that these morphological changes are a result of a pathway involving cAMP-and MAPK-mediated changes in gene expression, resulting in increased synthesis of some proteins, down-regulation of others, and an overall remodeling of the zones of contact between sensory and motor neurons. The dissection of these molecular cascades is an active area of research at present. Future work hopefully will allow the definition of all the components of the complex molecular machinery involved.

With the discovery that morphological changes underlie long-lasting facilitation of neurotransmitter release and behavioral sensitization in the animal, the field has in a sense come full circle. I say this because pioneering work in Aplysia demonstrated that long-lasting habituation of the gill-and-siphon withdrawal response was associated with a decreased number of synaptic contacts between siphon sensory neurons and gill motor neurons. Both long-term inhibition and enhancement of behavior therefore have in common an underlying anatomical basis. Although our understanding of the molecular mechanisms underlying these types of anatomical changes is marginal at present, these observations about long-term sensitization and long-term habituation serve to illustrate that structural rearrangements of synaptic connections are likely to be a powerful and general mechanism underlying long-lasting behavioral changes.

However, remember the discussion that started this chapter. There is nothing inherently stable about morphological changes or increased synaptic contacts. All the component molecules that make up these structures are being continually broken down and resynthesized. How does the cell solve the problem of maintaining a change in the face of continual loss and replacement of its component molecules?

The answer to this question is based in a specific category of chemical reactions that Eric Roberson and I have referred to as mnemogenic chemical reactions (7).

The essential descriptor of a mnemogenic chemical reaction is given in Equation 1.

In this reaction, X is a molecule that can exist in either a basal state (X) or an activated or modified form (X-). The initiation of a learning event triggers activation of X by conversion into the X- , or activated form.

This activated X- leads to manifestation of the memory phenotype, affecting either directly or indirectly some biochemical process regulating neuronal function (e.g., synaptic strength or neuronal excitability).

The unique feature of the mnemogenic reaction is that the activated molecule, X- , can react with an inactive molecule of X and convert it to the X- form. This is how levels of X- are sustained despite molecular turnover. Although the nucleus synthesizes only the inactive form, the activated species at the synapse catalyzes its activation; thus, more active X- is created, perpetuating the reaction.

In the next section, we will return to several specific examples of mnemogenic chemical reactions that have been identified in mammalian systems. However, before proceeding, I will give a specific molecular example of the general category that has been identified as potentially maintaining long-lasting synaptic facilitation in Aplysia. This example is based on seminal work in this area by Arnold Eskin, Jack Byrne, and their colleagues (12, 13).

How is an increased number of synaptic contacts maintained in the face of continual breakdown and resynthesis of the synaptic molecular infrastructure? Eskin, Byrne, and co-workers have found that long-term facilitation is associated with increased expression of a tolloid/bone morpho-genetic protein referred to as Aplysia TBL-1 (Tolloid/Bone morphogenetic protein— Like protein—1). TBL-1 is, among other things, a protease that is involved in growth factor processing. The current hypothesis is that TBL-1 is induced with serotonin treatment and secreted into the extracellular space, where it converts pro-TGFp into active TGFp (Transforming Growth Factor

Beta). TGFp can then bind to its receptors on the cell surface, and activate signal transduction cascades that, like serotonin, lead to increased expression of TBL-1 (see Figure 7). In this way, a self-reinforcing loop is established and can persist beyond the breakdown and resynthesis of individual component molecules. The increased number of synaptic connections is maintained in this model by having the component molecules for synapse maintenance synthesized in parallel with the TBL-1—a conceptually straightforward mechanism for this is to simply have them read out from the same gene promoters that regulate TBL-1 expression.


Neuron j

FIGURE 7 This figure presents the Eskin/Byrne model of possible roles of aplysia TBL-1 (apTBL-1) in long-term presynaptic facilitation in Aplysia sensory neurons. A sensory neuron, motor neuron, and glial cell are represented schematically. The growth processes of sensory neurons and motor neurons are drawn with dotted lines. 5-HT increases the transcription of the apTBL-1 gene. apTBL-1 protein might remain in the cytoplasm by alternative translation and might play a role as a protease to modify the cytoskeleton structure in the growth process within the sensory neuron. apTBL-1 also might be secreted to modify the extracellular matrix (procollagen) or activate TGF-P-like growth factors. The activated growth factors could bind to Ser/Thr kinase receptors and trigger the signal transduction cascade, leading to the regulation of cell growth. The activated growth factors also might modify the motor neurons to complement the morphological changes in the sensory neurons, or they might activate glial cells to secrete extracellular matrix components that might then help stabilize the morphological changes. Some of the same events elicited by the activation of TGF-P also could be caused by modification of the extracellular matrix component collagen. Figure and legend reproduced from Liu et al. (13).

This process is an example of a mnemogenic chemical reaction, specifically a variant that Eric Roberson and I have termed a circular mnemogenic reaction. Mnemogenic reactions are not limited to a single molecule catalyzing production or activation of itself. Interacting sets of molecules can act in series to establish a regenerative molecular circuit. In this case, the reactions have the following forms, where X- catalyzes activation of Y, and Yin turn catalyzed activation of X:

By summing these partial reactions and rearranging to the form of equation 1, we see that this system creates a sort of double mnemogenic reaction:

Other examples of mnemogenic reaction systems such as this have recently been elaborated based on computer modeling of signal transduction mechanisms operating in synaptic plasticity (14). In the case of the Aplysia TBL-1/TGFP system, the interacting cascades produce a bistable molecular state of a synapse that is capable of perpetual memory storage.

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