During critical periods of development, the brain easily changes in response to environmental stimuli, but this neural plasticity declines by adulthood. By acutely disrupting paired immunoglobulin-like receptor B(PirB) function at specific ages, we show that PirB actively represses neural plasticity throughout life. We disrupted PirB function either by genetically introducing a conditional PirB allele into mice or by minipump infusion of a soluble PirB ectodomain (sPirB) into mouse visual cortex. We found that neural plasticity, as measured by depriving mice of vision in one eye and testing ocular dominance, was enhanced by this treatment both during the critical period and when PirB function was disrupted in adulthood. Acute blockade of PirB triggered the formation of new functional synapses, as indicated by increases in miniature excitatory postsynaptic current (mEPSC) frequency and spine density on dendrites of layer 5 pyramidal neurons. In addition, recovery from amblyopia— the decline in visual acuity and spine density resulting from long-term monocular deprivation— was possible after a 1-week infusion of sPirB after the deprivation period. Thus, neural plasticity in adult visual cortex is actively repressed and can be enhanced by blocking PirB function.
C1q, the initiator of the classical complement cascade, mediates synapse elimination in the postnatal mouse dorsolateral geniculate nucleus of the thalamus and sensorimotor cortex. Here, we asked whether C1q plays a role in experience-dependent synaptic refinement in the visual system at later stages of development. The binocular zone of primary visual cortex (V1b) undergoes spine loss and changes in neuronal responsiveness following the closure of one eye during a defined critical period [a process referred to as ocular dominance plasticity (ODP)]. We therefore hypothesized that ODP would be impaired in the absence of C1q, and that V1b development would also be abnormal without C1q-mediated synapse elimination. However, when we examined several features of V1b development in mice lacking C1q, we found that the densities of most spine populations on basal and proximal apical dendrites, as well as firing rates and ocular dominance, were normal. C1q was only transiently required for the development of spines on apical, but not basal, secondary dendrites. Dendritic morphologies were also unaffected. Although we did not observe the previously described spine loss during ODP in either genotype, our results reveal that the animals lacking C1q had normal shifts in neuronal responsiveness following eye closure. Experiments were performed in both male and female mice. These results suggest that the development and plasticity of the mouse V1b is grossly normal in the absence of C1q.
Synapse pruning is an activity-regulated process needed for proper circuit sculpting in the developing brain. Major histocompatibility class I (MHCI) molecules are regulated by activity, but little is known about their role in the development of connectivity in cortex. Here we show that protein for 2 MHCI molecules H2-Kb and H2-Db is associated with synapses in the visual cortex. Pyramidal neurons in mice lacking H2-Kb and H2-Db (KbDb KO) have more extensive cortical connectivity than normal. Modified rabies virus tracing was used to monitor the extent of pyramidal cell connectivity: Horizontal connectivity is greater in the visual cortex of KbDb KO mice. Basal dendrites of L2/3 pyramids, where many horizontal connections terminate, are more highly branched and have elevated spine density in the KO. Furthermore, the density of axonal boutons is elevated within L2/3 of mutant mice. These increases are accompanied by elevated miniature excitatory postsynaptic current frequency, consistent with an increase in functional synapses. This functional and anatomical increase in intracortical connectivity is also associated with enhanced ocular dominance plasticity that persists into adulthood. Thus, these MHCI proteins regulate sculpting of local cortical circuits and in their absence, the excess connectivity can function as a substrate for cortical plasticity throughout life.
FCN architectures used in this work allow for automated dendritic spine detection. Superior outcomes are possible even with small training data-sets. The proposed method may generalize to other datasets on larger scales.
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