Role of Hippocampal Neurogenesis in Alcohol Withdrawal Seizures.

Chronic alcohol consumption results in alcohol use disorder (AUD). Interestingly, however, sudden alcohol withdrawal (AW) after chronic alcohol exposure also leads to a devastating series of symptoms, referred to as alcohol withdrawal syndromes. One key feature of AW syndromes is to produce phenotypes that are opposite to AUD. For example, while the brain is characterized by a hypoactive state in the presence of alcohol, AW induces a hyperactive state, which is manifested as seizure expression. In this review, we discuss the idea that hippocampal neurogenesis and neural circuits play a key role in neuroadaptation and establishment of allostatic states in response to alcohol exposure and AW. The intrinsic properties of dentate granule cells (DGCs), and their contribution to the formation of a potent feedback inhibitory loop, endow the dentate gyrus with a "gate" function, which can limit the entry of excessive excitatory signals from the cortex into the hippocampus. We discuss the possibility that alcohol exposure and withdrawal disrupts structural development and circuitry integration of hippocampal newborn neurons, and that this altered neurogenesis impairs the gate function of the hippocampus. Failure of this gate function is expected to alter the ratio of excitatory to inhibitory (E/I) signals in the hippocampus and to induce seizure expression during AW. Recent functional studies have shown that specific activation and inhibition of hippocampal newborn DGCs are both necessary and sufficient for the expression of AW-associated seizures, further supporting the concept that neurogenesis-induced neuroadaptation is a critical target to understand and treat AUD and AW-associated seizures.