<p>A longed lack of control over harmful stimuli can lead to learned helplessness (LH), a significant factor in depression. However, the cellular and molecular mechanisms underlying LH, and eventually behavioral despair, remain largely unknown. The <i>deleted in colorectal cancer</i> (<i>dcc</i>) gene is associated with the risk of depression. However, the therapeutic potential and regulation mechanism of DCC in behavioral despair are still uncertain. In this study, we showed that depressive stimulators, including LH, lipopolysaccharide, and unpredictable chronic mild stress, triggered an elevation in DCC expression in the medial prefrontal cortex (mPFC). Additionally, elevated DCC expression in the mPFC was crucial in inducing behavioral despair, as evidenced by the induction of behavioral despair in normal mice and exacerbation of behavioral despair in LH mice upon DCC overexpression. By contrast, neutralizing DCC activity ameliorated LH-induced behavioral despair. Importantly, we elucidated that pathological DCC expression was attributable to the excessive excitation of CaMKII⁺ neurons in a manner dependent on the calpain-mediated degradation of SCOP and aberrant phosphorylation of the ERK signaling pathway. In addition, the increase in DCC expression led to a decreased excitability threshold in CaMKII⁺ neurons in the mPFC, which was supported by the observation that the ligand netrin 1 increased the frequency of action potential firing and of spontaneous excitatory postsynaptic currents in CaMKII⁺ neurons. In conclusion, our data indicate that LH triggers the excessive excitation of CaMKII⁺ neurons and activation of calpain-SCOP/ERK signaling to promote DCC expression, and DCC represents a crucial target for the treatment of LH-induced behavioral despair in male mice.</p><p></p>