Homer1a is a scaffold protein encoded by immediate early genes (IEG) in the central nervous system. Extensive clinical and basic studies have shown that Homer1a is not only involved in the pathogenesis of a variety of neuropsychiatric diseases, but also a key protein in a variety of antidepressant treatment regiments. The onset of depression is associated with the expression and availability of metabotropic glutamate receptor type 1 (mGluR1/5) and the dysfunction of N-methyl-D-aspartate receptor (NMDAR), which causes synaptic plasticity disorders. Homer1a is highly specific to mGluR1/5. The overexpression of Homer1a regulates the synaptic plasticity by increasing the expression and availability of mGluR1/5 in the postsynaptic membrane, and then regulating the ionic glutamate receptor NMDAR and α-amino-3-hydroxy 5-methyl-4-oxazolepropionic acid receptor (AMPAR) in the postsynaptic membrane, ultimately playing an antidepressant role. Because Homer1a plays a central role in the regulation of synaptic activity, understanding the mechanism about how Homer1a works provides new insights into researching antidepressant drugs that target homer1a proteins.