Loss of synaptopodin impairs mGluR5 and protein synthesis-dependent mGluR-LTD at CA3-CA1 synapses.

Metabotropic glutamate receptor-dependent long-term depression (mGluR-LTD) is an important form of synaptic plasticity that occurs in many regions of the central nervous system and is the underlying mechanism for several learning paradigms. In the hippocampus, mGluR-LTD is manifested by the weakening of synaptic transmission and elimination of dendritic spines. Interestingly, not all spines respond or undergo plasticity equally in response to mGluR-LTD. A subset of dendritic spines containing synaptopodin (SP), an actin-associated protein is critical for mGluR-LTD and protects spines from elimination through mGluR1 activity. The precise cellular function of SP is still enigmatic and it is still unclear how SP contributes to the functional aspect of mGluR-LTD despite its modulation of the structural plasticity. In this study, we show that the lack of SP impairs mGluR-LTD by negatively affecting the mGluR5-dependent activity. Such impairment of mGluR5 activity is accompanied by a significant decrease of surface mGluR5 level in SP knockout (SPKO) mice. Intriguingly, the remaining mGluR-LTD becomes a protein synthesis-independent process in the SPKO and is mediated instead by endocannabinoid signaling. These data indicate that the postsynaptic protein SP can regulate the locus of expression of mGluR-LTD and provide insight into our understanding of spine/synapse-specific plasticity.