The developing mammalian cerebral cortex contains a distinct class of cells, subplate neurons (SPns), that play an important role during early development. SPns are the first neurons to be generated in the cerebral cortex, they reside in the cortical white matter, and they are the first to mature physiologically. SPns receive thalamic and neuromodulatory inputs and project into the developing cortical plate, mostly to layer 4. Thus SPns form one of the first functional cortical circuits and are required to relay early oscillatory activity into the developing cortical plate. Pathophysiological impairment or removal of SPns profoundly affects functional cortical development. SPn removal in visual cortex prevents the maturation of thalamocortical synapses, the maturation of inhibition in layer 4, the development of orientation selective responses and the formation of ocular dominance columns. SPn removal also alters ocular dominance plasticity during the critical period. Therefore, SPns are a key regulator of cortical development and plasticity. SPns are vulnerable to injury during prenatal stages and might provide a crucial link between brain injury in development and later cognitive malfunction.

Experience can alter synaptic connectivity throughout life, but the degree of plasticity present at each age is regulated by mechanisms that remain largely unknown. Here, we demonstrate that Paired-immunoglobulin-like receptor B (PirB), a major histocompatibility complex class I (MHCI) receptor, is expressed in subsets of neurons throughout the brain. Neuronal PirB protein is associated with synapses and forms complexes with the phosphatases Shp-1 and Shp-2. Soluble PirB fusion protein binds to cortical neurons in an MHCI-dependent manner. In mutant mice lacking functional PirB, cortical ocular-dominance plasticity is more robust at all ages. Thus, an MHCI receptor is expressed in central nervous system neurons and functions to limit the extent of experience-dependent plasticity in the visual cortex throughout life. PirB is also expressed in many other regions of the central nervous system, suggesting that it may function broadly to stabilize neural circuits.

The sensory areas of the cerebral cortex possess multiple topographic representations of sensory dimensions. Gradient of frequency selectivity (tonotopy) is the dominant organizational feature in the primary auditory cortex, while other feature-based organizations are less well established. We probed the topographic organization of the mouse auditory cortex at the single cell level using in vivo two-photon Ca2+ imaging. Tonotopy was present on a large scale but was fractured on a fine scale. Intensity tuning, important in level-invariant representation, was observed in individual cells but was not topographically organized. The presence or near-absence of putative sub-threshold responses revealed a dichotomy in topographic organization. Inclusion of sub-threshold responses revealed a topographic clustering of neurons with similar response properties, while such clustering was absent in supra-threshold responses. This dichotomy indicates that groups of nearby neurons with locally shared inputs can perform independent parallel computations in ACX.

The subplate forms a transient circuit required for development of connections between the thalamus and the cerebral cortex. When subplate neurons are ablated, ocular dominance columns do not form in the visual cortex despite the robust presence of thalamic axons in layer 4. We show that subplate ablation also prevents formation of orientation columns. Visual responses are weak and poorly tuned to orientation. Furthermore, thalamocortical synaptic transmission fails to strengthen, whereas intracortical synapses are unaffected. Thus, subplate circuits are essential not only for the anatomical segregation of thalamic inputs but also for key steps in synaptic remodeling and maturation needed to establish the functional architecture of visual cortex.

The precise period when experience shapes neural circuits in the mouse visual system is unknown. We used Arc induction to monitor the functional pattern of ipsilateral eye representation in cortex during normal development and after visual deprivation. After monocular deprivation during the critical period, Arc induction reflects ocular dominance (OD) shifts within the binocular zone. Arc induction also reports faithfully expected OD shifts in cat. Shifts towards the open eye and weakening of the deprived eye were seen in layer 4 after the critical period ends and also before it begins. These shifts include an unexpected spatial expansion of Arc induction into the monocular zone. However, this plasticity is not present in adult layer 6. Thus, functionally assessed OD can be altered in cortex by ocular imbalances substantially earlier and far later than expected.

Patterned spontaneous activity in the developing retina is necessary to drive synaptic refinement in the lateral geniculate nucleus (LGN). Using perforated patch recordings from neurons in LGN slices during the period of eye segregation, we examine how such burst-based activity can instruct this refinement. Retinogeniculate synapses have a novel learning rule that depends on the latencies between pre- and postsynaptic bursts on the order of one second: coincident bursts produce long-lasting synaptic enhancement, whereas non-overlapping bursts produce mild synaptic weakening. It is consistent with “Hebbian” development thought to exist at this synapse, and we demonstrate computationally that such a rule can robustly use retinal waves to drive eye segregation and retinotopic refinement. Thus, by measuring plasticity induced by natural activity patterns, synaptic learning rules can be linked directly to their larger role in instructing the patterning of neural connectivity.

Synaptic plasticity during critical periods of development requires intact inhibitory circuitry. We report that subplate neurons are needed both for maturation of inhibition and for the proper sign of ocular dominance (OD) plasticity. Removal of subplate neurons prevents the developmental upregulation of genes involved in mature, fast GABAergic transmission in cortical layer 4, including GABA receptor subunits and KCC2, and thus prevents the switch to a hyperpolarizing effect of GABA. To understand the implications of these changes, a realistic circuit model was formulated. Simulations predicted that without subplate neurons, monocular deprivation (MD) paradoxically favors LGN axons representing the deprived (less active) eye, exactly what was then observed experimentally. Simulations also account for published results showing that OD plasticity requires mature inhibition. Thus, subplate neurons regulate molecular machinery required to establish an adult balance of excitation and inhibition in layer 4, and thereby influence the outcome of OD plasticity.

Major histocompatibility complex Class I (MHCI) genes were discovered unexpectedly in healthy CNS neurons in a screen for genes regulated by neural activity. In mice lacking just 2 of the 50+ MHCI genes H2-Kb and H2-Db, ocular dominance (OD) plasticity is enhanced. Mice lacking PirB, an MHCI receptor, have a similar phenotype. H2-Kb and H2-Db are expressed not only in visual cortex, but also in lateral geniculate nucleus (LGN) where protein localization correlates strongly with synaptic markers and complement protein C1q. In KbDb-/- mice developmental refinement of retinogeniculate projections is impaired, similar to C1q-/- mice. These phenotypes in KbDb-/- mice are strikingly similar to those in β2m-/-TAP1-/- mice, which lack cell surface expression of all MHCIs, implying that H2-Kb and H2-Db can account for observed changes in synapse plasticity. H2-Kb and H2-Db ligands, signaling via neuronal MHCI receptors, may enable activity-dependent remodeling of brain circuits during developmental critical periods.