<p>Astrocyte elevated gene-1 (AEG-1) has been characterized as an oncogene promoting the progression of various tumors. The role of AEG-1 in neurological diseases was highlighted by recent researches. However, the physiological function of AEG-1 remains elusive. Our study aimed to investigate the physiological role of AEG-1 in the central nervous system by generating a mouse model with specific deletion of <i>Aeg-1</i> in the hippocampus and neocortex (<i>Aeg-1</i>^fl/flCre⁺ mice). Behavioral assessments revealed that <i>Aeg-1</i> deficiency caused impaired learning and memory capabilities in juvenile and adult mice. Depressive-like behaviors were also observed in <i>Aeg-1</i>^fl/flCre⁺ mice. Gene Ontology (GO) enrichment analyses indicated that AEG-1 was involved in the neuronal morphogenesis. Interestingly, <i>Aeg-1</i> knockout was irrelevant to the neuron loss but reduced the dendritic length and the dendritic spines density in hippocampus. Electrophysiological analyses showed a decreased response of paired-pulse facilitation (PPF) and a compromised efficiency of excitatory synaptic transmission following <i>Aeg-1</i> deletion in hippocampus. In conclusion, our findings suggest that <i>Aeg-1</i> deficiency in the hippocampus and neocortex leads to learning and memory impairments and depression in mice, which is mediated by the abnormalities of neuronal morphology and the impaired synaptic functions.</p>