What is the basis for neural plasticity?

The current view of LTP/LTD and specifically AMPA-dependent plasticity, which underlies all theoretical work on neural networks, seems exceedingly narrow. It leaves out levels of plasticity that are well known, like epigenetic modifications, or internal protein signaling, in order to come up with a simple model of use-dependent plasticity, the Hebbian principle, or ‘neurons that fire together, wire together’.

It is interesting and important to tackle the complex task of reducing the large number of individual findings on behavioral memory and neural plasticity into a small set of principles that can be used for models of biologically realistic memorization. Such models should offer capabilities beyond machine learning, namely conceptual abstraction, information filtering, building knowledge.

Here is one such observation: Both AMPA receptor placement and dendritic ion channel expression are regulated by similar, overlapping internal protein pathways. These protein pathways are activated by NM receptors and by NMDA and L-type-calcium channel-based calcium influx. We may conjecture that NM receptors and NMDA-based calcium activation together orchestrate neural plasticity via e.g. the calcium/CaMKII route, and the cAMP/PKA/ERK route, and that these pathways are acting in synergy at the synaptic AMPA sites as well as on the dendritic/synaptic ion channel expression sites.

So what this means is that various forms of intrinsic and synaptic plasticity are guided by the same protein pathways and therefore can be expected to be activated together. Here are specific instances of this synergy:

For instance, strengthening of AMPA could be accompanied by insertion of Sk-channels and reduction of L-type calcium channels, which blocks the synapse from further strengthening (‚overwrite protection‘). Such a mechanism has recently been identified as necessary for the stability and the lasting memorization capabilities of a network. Activation of the cAMP pathway activates Ih (HCN channels) which decreases the intrinsic excitability of the neuron, and allows less synaptic input to be processed. In a way, this kind of activation could be used as a temporal lock to prevent high dendritic excitability after the NM system has become engaged and plasticity in the neuron has started. Vice versa, in the absence of cAMP, dendritic excitability is high and many synaptic inputs are processed by an increase of membrane resistance through a reduction of HCN. Reduction of synaptic activity also reduces dendritic HCN channels. HCN channels may therefore indicate the level of synaptic activation, where more channels limit the parallel processing of synaptic input.

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