ADNP is a transcription factor and a member of the SWI/SNF chromatin remodeling complex that is implicated in autism spectrum disorders (ASDs) and ADNP syndrome. Although many previous studies investigated in vivo functions of ADNP, ADNP functions in the brain and synapse regulations remain unclear. Here, I investigated in vivo ADNP function using Adnp haploinsufficient mice (Adnp∆5 HT mice) and found that these mice show suppressed neuronal excitability and long-term depression and enhanced long-term potentiation in the hippocampus CA1 region. In addition, Adnp∆5 HT mice display decreased social interaction, social communication, anxiety-like behavior, hyperactivity (juvenile), hypoactivity (adult), and learning and memory impairments. Transcriptomic and proteomic analyses of the Adnp∆5 HT hippocampus revealed changes in the expression of various synaptic and signaling proteins. These results suggest that ADNP regulates synaptic plasticity and neuronal excitability in the hippocampus and that these mechanisms may explain how ADNP deficiency leads to ASD and ADNP syndrome.