Cerebellar glomeruli : Does limited extracellular calcium implement a sparse encoding strategy ?
A class of synaptic learning models in which presynaptic terminals have access to a weighted sum of the postsynaptic activity has traditionally been dismissed as biologically unfeasible. This ;ejection is not surprising under traditional notions of synaptic connectivity, since postsynaptic cell bodies may be far apart, and there are no backwards signals known to sum activity in a terminal-specific manner. However, many synapses in the CNS become specialized by glial cell ensheathment. We suggest that such ensheathment may force neighboring cellular elements to share a limited resource: extracellular calcium. We propose the novel theory that certain glomeruli are configured so that the instantaneous external calcium concentration will encode the level of spike activity in postsynaptic cells. We concentrate on the specialized glomeruli that exist in the cerebellum at the interface of the mossy fiber and granule cell layers. Here, dendrites from scores of granule cells swirl around a mossy fiber terminal, and the whole structure is tightly ensheathed in an astrocyte. Simulations demonstrate that the calcium concentration is indeed proportional to a sum of postsynaptic activity in the granule cells. We demonstrate that these extracellular calcium changes are interpretable from an information-processing point of view, generating a novel learning rule for control of plasticity at the mossy fiberlgranule cell synapse. This learning rule implements a sparsely distributed and statistically independent representation in the parallel fibers. Both of these coding properties reduce the complexity of the credit assignment problem between active parallel fibers and climbing fiber at a Purkinje cell. Although traditional models of neural function only emphasize neurotransmitters and point-to-point connections, our results highlight the need to quantitatively address the extracellular context in which axon terminals and dendrites are found. Introduction One fifth of the mammalian brain is comprised of extracellular space (ECS). The extracellular space is not empty, but instead comprises a complex network of proteins and a variety of molecular species. One extracellular species, calcium, holds a prominent position as one of the most important messengers known in the brain. However, calcium exists in low concentrations in the ECS, and its diffusion is slowed by the restricted volumes of the extracellular space therefore, normal neural activity may cause calcium to move out of the ECS faster than diffusion can fill it in. As opposed to the traditional view that extracellular calcium exists at a stable concentration, theoretical analyses suggest that calcium concentrations may rapidly change as a reflection of local neural activity (1-6). The theory finds experimental support from microelectrode recordings (715), and more recently, from assays of neurotransmitter release in rat brainstem (1 6), measurement of tail current in chick ciliary ganglia (17), calcium-dependent binding of antibodies (1 8), effects on neighboring cells (1 9), and direct measurements with extracellular calcium dyes (20). Such changes in extracellular calcium are likely to carry significant functional impact, due to the many signaling roles calcium plays. Glial ensheathment: the Mossy fiber granule cell glomerulus The association of neurons and nerve fibers with glial cells is nearly ubiquitous throughout phylogeny, and seems to provide many mechanical functions. For example, myelinating sheaths around an axon enable salutatory conduction. In more specialized cases, many synapses in the CNS are ensheathed by glia (21); such synapses can be found in the retina, hippocampus, and cerebellum. As we will outline in this study, such ensheathment may serve a computational role. We concentrate on the intriguing example of the mossy fiber granule cell glomerulus in the cerebellum. This glomerulus is a strategic site for neuronal connectivity in the cerebellar cortex. Within this structure, mossy fiber axons originating from various regions of the CNS form synapses with the dendrites of granule cells. These claw-shaped dendrites, as well as axons of Golgi cells, swirl around the mossy fiber terminals, forming characteristic rosettes (22-24). A glial cell, known as the velate astrocyte, develops a tight sheath around each glomerulus (24, 25). The role of the glial ensheathment has been speculative and controversial, receiving essentially no attention from a computational point of view. Roles that have been postulated for the neuroglial sheaths are structural support, electrophysiological insulation of individual glomeruli, and the maintenance of chemical equilibrium in the interstitial fluid (26), (23), (27), (28), as well as chemical barriers to the further outgrowth of granule cell dendrites and Golgi cell axons (29). Our findings described in this paper suggest a different, novel role for the neuroglial sheath: this anatomical substrate limits the supply of extracellular calcium, such that the extracellular calcium concentration comes to represent a sum of total postsynaptic activity. This sum can then be used by the neural elements within the glomerulus to navigate plasticity. But is there a principled reason to think that it might be desirable for the cerebellum to need the knowledge of such a sum? From a theoretical point of view, there is a class of learning rules that describe the evolution of connection strengths within the glomerulus in terms of the coding strategy of the granule cells, and these rules require just such a sum over postsynaptic activity. Let us look at the motivation behind those rules now. How does the granule cell layer encode its input? A knowledge of the firing pattern of GCs is essential to any theory of the function of the cerebellar cortex. The only output neurons of the cerebellum, the Purkinje cells, receive synapses from up to 200,000 GCs (30). It is theorized that the activity of too many GCs would carry no information and abolish response selectivity (3 1). It is therefore reasonable to assume that the granule cells may be most effective by &coding their input sparsely. This would mean that for any given context (as carried by the mossy fibers), only a small subset of the granule cells would become active, while the rest would remain silent. Sparse encoding has two advantages: (1) lowering of the total amount of action potential generation greatly lowers metabolic cost, and (2) it simplifies the credit assignment problem at the Purkinje cell. That is, if only a very small number of granule cells drives a Purkinje cell, their responsibility is more easily assessed (they are given 'credit'), and plasticity can be appropriately distributed. If we assume sparseness, and desire to maximize the mutual information between the mossy fiber inputs and the granule cell outputs, then a learning rule for synaptic weights can be derived. The details of the rules and their derivation are relegated to the Appendix, but the point that will become important is quite simple: under the sparseness constraint, mutual information is maximized when the weight change is a function of a sum ofpostsynaptic activity. Given the neural arrangements in most parts of the brain, such a weight rule can usually be dismissed as biologically unfeasible. However, in the special case of the cerebellar glomerulus (and perhaps glomeruli in other brain regions), the configuration of parts suggests that such a learning rule might be feasible after all. By examining and simulating the relevant structures, we will now construct the logic that leads us to the suggestion that the glomerulus may be built to implement such a 'backward-sum' learning rule. Totality of ensheathment Ensheathment means that diffusion of extracellular calcium from neighboring regions of the ECS is cut off, or at best greatly restricted. In this situation, the competition for calcium is more fierce, since calcium taken from the shared pool in the glomerular extracellular space (GECS) immediately becomes absent from the point of view of the other dendrites. We have been speaking as though the ensheathrnent of a glomerulus is total, i.e., the extracellular calcium is a limited pool of fixed size, in which case the amount of calcium that fluxes into a dendrite equals the amount that is missing from the extracellular space. Of course, the glomerulus cannot be without communication to outside extracellular space, or else action potentials would not be able to propagate into the glomerulus along the mossy fiber axon and the granule cell dendrites, since such propagation requires an open circuit of ion flow. On this subject, it should be noted that lamellar processes of the velate astrocytes separate one glomerulus from another in the islet and interweave with the dendrites and Golgi cell axons at the periphery of the glomerulus (23). This means that although the GECS may have limited communication with surrounding ECS, the space outside the glomerulus is also quite restricted. In general, the extent to which the glomerular ECS communicates with outside ECS will not qualitatively change the results presented here. Even with a communicating GECS, the extracellular calcium concentration will still reflect a sum of the postsynaptic activity. The extent of outside communication will modulate the size of the calcium fluctuations and the speed of recovery to ambient levels. Action potentials in granule cell dendrites Granule cells are electrotonically compact, and both experiments and modeling indicate that the soma and dendrites of the granule cell will behave as a single electrical compartment (32-35); in other words, action potentials in the soma will appear almost immediately throughout the short dendrites. Granule cell dendrites contain voltage-gated calcium channels (VGCCs) (36,37), NMDA receptors (35, 38), ATP-ase calcium pumps (39) and Na+/Ca++ transporters (40), all of which exist not only on the granule c