Programmed cell death 1 (PD-1), encoded by the Pdcd1 gene, was identified as a target in cancer immunotherapy but may result in the overactivation of T cell function and emotional changes such as anxiety. The dynamic changes in neuronal activity related to the anxious status caused by Pdcd1−/− remain unclear. In this study, we addressed these physiological issues by simultaneously recording neuronal activity (spikes) and local field potentials (LFPs) in the medial prefrontal cortex (mPFC) and hippocampal CA3 region using in vivo multi-channel electrodes. Our results demonstrate that PD-1 deficiency induces anxiety-like behaviours and extensive neuronal firing disorders in the mPFC and CA3 regions of mice. The key finding was that in pyramidal neuron and interneurons in the CA3 region, the in vivo firing and spike-LFP encoding was disordered in the opposite direction by Pdcd1−/−. These changes leaded to abnormal oscillations in mPFC and CA3 and disturbed mPFC neuronal firing. Targeting the activation of excitatory neurons in CA3 regions could rescue anxiety-like behaviours in Pdcd1‐/‐ mice. This study provides physiological insights into the dynamic cooperation mechanisms between the mPFC and CA3 circuits in anxiety-like behaviours caused by Pdcd1−/− and other mental disorders associated with autoimmune problems.