Multiple combinations of GPCR activation gate the induction of NMDAR-independent LTD in mouse visual cortex

Activity-dependent synaptic weakening, including long-term depression (LTD), is a fundamental mechanism underlying experience-dependent circuit remodeling. At excitatory synapses, two mechanistically distinct forms of LTD have been identified: NMDAR-LTD, triggered by activation of NMDA receptors, and mGluR-LTD, mediated by group I metabotropic glutamate receptors. NMDAR-LTD is the best-characterized form and has been described in numerous brain regions. In contrast, in cortical synapses mGluR-LTD has been investigated primarily in the hippocampus, where it requires mGluR5 activation and its molecular mechanisms are well established. Although NMDAR-LTD is also well documented in the neocortex, mGluR-LTD remains comparatively poorly characterized, particularly in primary sensory cortices, despite growing evidence that mGluR signaling contributes to sensory deprivation-induced synaptic remodeling. We examined mGluR-LTD in slices of primary visual cortex of rats and mice of all sexes and found that layer II/III pyramidal neurons do express an NMDAR-independent LTD. Like in CA1, mGluR-LTD in V1 depends on mGluR5 activation and ongoing protein synthesis regulated by FMRP. Unlike CA1, however, where activation of mGluR5 alone is sufficient to induce mGluR-LTD, induction in V1 requires the co-activation of at least two neuromodulatory receptors, including mGluR5 together with muscarinic, noradrenergic, or serotonergic receptors. This more stringent gating mechanism may reflect the tighter constraints on synaptic plasticity in the neocortex, consistent with the view that the hippocampus and neocortex are specialized for rapid and gradual learning, respectively. Significance statement At excitatory synapses, two mechanistically distinct forms of long-term depression (LTD) have been identified: NMDAR-LTD and mGluR-LTD. While NMDAR-LTD is widespread, mGluR-LTD has been studied primarily in the hippocampus and remains poorly characterized in sensory cortices, despite evidence that mGluRs contribute to sensory deprivation-induced synaptic remodeling. This study shows that an NMDAR-independent form of LTD can be induced in visual cortical slices. Unlike hippocampus, where activation of mGluR5 alone is sufficient to induce mGluR-LTD, induction in visual cortex requires the co-activation of at least two neuromodulatory receptors, including mGluR5 together with muscarinic, noradrenergic, or serotonergic receptors. This stricter gating mechanism may reflect the tighter constraints on synaptic plasticity in the neocortex, consistent with its role in gradual, rather than rapid, learning.