Monocular deprivation during early life weakens visual-cortical responses to the deprived eye, and a 1999 PNAS study by Blais, Shouval and Cooper showed that this disconnection follows the homosynaptic, temporal-competition picture of the BCM (Bienenstock–Cooper–Munro) theory of synaptic plasticity rather than heterosynaptic competition for a conserved resource. That paper noted that the two rule classes require different underlying molecular and physiological mechanisms, and that the theory's parameters should become determinable as experimental techniques evolve. This problem asks for the two linked deliverables that remain outstanding: (1) identification of the specific molecular and physiological mechanisms that implement homosynaptic BCM-like plasticity at neocortical synapses, above all the machinery implementing the activity-dependent sliding modification threshold that defines the theory; and (2) quantitative determination of the BCM parameters for neocortical synapses, such as the form of the modification function, the dynamics of the threshold, and the effective time constants. Later work has resolved part of the depression phase (monocular deprivation engages the molecular machinery of homosynaptic long-term depression) and has nominated several partial regulators of the threshold (NMDA-receptor subunit composition, inhibition, dendritic currents, glia, extracellular matrix), but reviews through 2025 and active experimental work in 2026 show that no complete, causally established, quantitatively parameterized account exists. The problem remains open.

Background

Neurons in the primary visual cortex of mammals with binocular vision are driven by both eyes, with each neuron's relative preference for one eye called its ocular dominance. Depriving one eye of patterned vision during early postnatal life (monocular deprivation, MD) causes cortical neurons to lose responsiveness to the deprived eye — a classic form of experience-dependent synaptic plasticity. Because the loss is much stronger when the other eye remains open, the phenomenon has often been interpreted as competition between the two eyes' inputs.

Two broad mechanistic pictures can generate such competition. In heterosynaptic (spatial-competition) rules, descended from proposals by Stent and by von der Malsburg and from neurotrophin hypotheses (the idea that synapses compete for diffusible neurotrophins, a family of growth-factor signaling molecules), synapses compete for a limited resource, so strengthening some inputs weakens others even at synapses that are themselves inactive. In homosynaptic rules, only synapses carrying presynaptic activity can be modified, and inputs compete in the temporal domain: activity patterns correlated with strong postsynaptic firing are strengthened, weakly correlated ones are depressed. The BCM theory (Bienenstock, Cooper and Munro, 1982) is the prototype homosynaptic rule. It posits that each synapse changes according to a modification function of the postsynaptic activity cc,

m˙j=dj φ(c,θM),θM∝⟨c2⟩slow,\dot{m}_j = d_j\,\varphi(c,\theta_M),\qquad \theta_M \propto \langle c^2 \rangle_{\text{slow}},

where djd_j is the presynaptic activity at synapse jj, φ\varphi is negative (long-term depression, LTD — a lasting weakening of synaptic transmission) for postsynaptic activities below a modification threshold θM\theta_M and positive (long-term potentiation, LTP — a lasting strengthening) above it, and the threshold θM\theta_M itself slides as an increasing function of a slowly averaged measure of the cell's own activity, averaged over times much longer than the stimulus-correlation time. This sliding threshold stabilizes total synaptic weight and gives the rule its selectivity and its metaplasticity — the dependence of the plasticity rules themselves on the prior history of activity.

By 1999 the general form of the BCM modification function had experimental support: homosynaptic LTD and its dependence on the NMDA subtype of glutamate receptor (a calcium-permeable channel that opens only when presynaptic release coincides with strong postsynaptic depolarization) had been established in hippocampal area CA1 (Dudek and Bear, 1992), and experience-dependent shifts of the LTP/LTD crossover — a sliding-threshold signature — had been measured in visual cortex (Kirkwood, Rioult and Bear, 1996). Blais, Shouval and Cooper (1999) sharpened the comparison between rule classes by simulating both with natural-scene input and deriving a critical test: in the homosynaptic class, the rate at which the closed eye disconnects in MD increases with the level of residual presynaptic activity from the deprived eye (noise-driven LTD), whereas heterosynaptic rules predict the opposite. The experiment of Rittenhouse, Shouval, Paradiso and Bear (1999) — comparing eyelid suture (retina still spontaneously active) with intraocular tetrodotoxin (a sodium-channel blocker that silences all retinal activity) in kittens — supported the homosynaptic, BCM prediction.

The paper's Discussion then makes the forward-looking statement that generates this problem: the two classes of rules "require different underlying molecular and physiological mechanisms," and "evolving experimental techniques will make it possible to determine the parameters of the theory with increasing precision." Knowing that neocortical plasticity behaves BCM-like is thus not the same as knowing which molecules and physiological processes implement the homosynaptic modification function and its sliding threshold, nor what the theory's quantitative parameters are at real neocortical synapses.

Problem Statement

Convert the behaviorally supported homosynaptic (BCM-like) description of experience-dependent synaptic plasticity in neocortex into a mechanistic and quantitative account, with two linked deliverables under one scientific objective. (1) Identify the specific molecular and physiological mechanisms that implement homosynaptic BCM-like plasticity at neocortical synapses — including, as the defining and least-understood feature, the machinery that implements the activity-dependent sliding modification threshold θM\theta_M that separates synaptic depression from potentiation and stabilizes synaptic weights. (2) Determine the quantitative parameters of the BCM theory for neocortical synapses, e.g., the exact form of the modification function φ(c,θM)\varphi(c,\theta_M), the law and time constants governing the dynamics of the threshold, and the effective time constants over which pre- and postsynaptic activity are integrated. The two deliverables are both required and jointly constitute one objective: a molecularly specified, quantitatively parameterized account of the homosynaptic modification rule operating in neocortex in vivo, of the kind anticipated in Blais, Shouval and Cooper's (1999) discussion of monocular deprivation. The account sought must be causal (perturbing the proposed mechanisms must predictably shift the modification function and threshold), quantitatively consistent with the phenomenology of deprivation and induction protocols, and must explain the BCM-defining signatures — bidirectional modification, activity-dependent threshold sliding, and homosynaptic (presynaptic-activity-dependent) competition such as the dependence of deprived-eye depression on residual presynaptic activity — rather than those of an adjacent rule class. Within each deliverable, the enumerated mechanisms and parameters are illustrative of the content an account must cover rather than an exhaustive checklist.

References

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