Two functionally distinct forms of synaptic plasticity, Hebbian long-term potentiation (LTP) and homeostatic synaptic scaling, are thought to cooperate to promote information storage and circuit refinement. Both arise through changes in the synaptic accumulation of AMPA receptors (AMPARs), but whether they use similar or distinct receptor-trafficking pathways is unknown. Here, we show that TTX-induced synaptic scaling in cultured visual cortical neurons leads to the insertion of GluR2-containing AMPARs at synapses. Similarly, visual deprivation with monocular TTX injections results in synaptic accumulation of GluR2-containing AMPARs. Unlike chemical LTP, synaptic scaling is blocked by a GluR2 C-tail peptide but not by a GluR1 C-tail peptide. Knockdown of endogenous GluR2 with an short hairpin RNA (shRNA) also blocks synaptic scaling but not chemical LTP. Scaling can be rescued with expression of exogenous GluR2 resistant to the shRNA, but a chimeric GluR2 subunit with the C-terminal domain swapped with the GluR1 C-terminal domain (GluR2/CT1) does not rescue synaptic scaling, indicating that regulatory sequences on the GluR2 C-tail are required for the accumulation of synaptic AMPARs during scaling. Together, our results suggest that synaptic scaling and LTP use different trafficking pathways, making these two forms of plasticity both functionally and molecularly distinct.

Input to the central nervous system from olfactory sensory neurons (OSNs) is modulated presynaptically. We investigated the functional organization of this inhibition and its role in odor coding by imaging neurotransmitter release from OSNs in slices and in vivo in mice expressing synaptopHluorin, an optical indicator of vesicle exocytosis. Release from OSNs was strongly suppressed by heterosynaptic, intraglomerular inhibition. In contrast, inhibitory connections between glomeruli mediated only weak lateral inhibition of OSN inputs in slices and did not do so in response to odorant stimulation in vivo. Blocking presynaptic inhibition in vivo increased the amplitude of odorant-evoked input to glomeruli but had little effect on spatial patterns of glomerular input. Thus, intraglomerular inhibition limits the strength of olfactory input to the CNS, whereas interglomerular inhibition plays little or no role. This organization allows for control of input sensitivity while maintaining the spatial maps of glomerular activity thought to encode odorant identity.

We compare the circuit and cellular mechanisms for homeostatic plasticity that have been discovered in rodent somatosensory (S1) and visual (V1) cortex. Both areas use similar mechanisms to restore mean firing rate after sensory deprivation. Two time scales of homeostasis are evident, with distinct mechanisms. Slow homeostasis occurs over several days, and is mediated by homeostatic synaptic scaling in excitatory networks and, in some cases, homeostatic adjustment of pyramidal cell intrinsic excitability. Fast homeostasis occurs within less than 1 day, and is mediated by rapid disinhibition, implemented by activity-dependent plasticity in parvalbumin interneuron circuits. These processes interact with Hebbian synaptic plasticity to maintain cortical firing rates during learned adjustments in sensory representations. This article is part of the themed issue ‘Integrating Hebbian and homeostatic plasticity’.

Significance Neurons exhibit distinct homeostatic and Hebbian forms of plasticity that stabilize firing rate and adaptively alter synaptic input patterns, respectively. How these mechanisms are recruited in response to sensory experience in vivo is unclear. We studied plasticity in rodent somatosensory cortex, where the neural map of the whiskers adaptively changes to reflect sensory statistics but only after a prominent initial delay. By recording synaptic excitation and inhibition in vivo, we found that the delay reflects not a lack of plasticity but a rapid homeostasis, in which inhibition is powerfully reduced to offset the initial Hebbian reduction of whisker-evoked excitation. Thus, rapid homeostasis by disinhibition stabilizes the whisker map and precedes classical whisker map plasticity.