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Mateus-Pinheiro, A.; Alves, N. D.; Patricio, P.; Machado-Santos, A. R.; Loureiro-Campos, E.; Silva, J. M.; Sardinha, V. M.; Reis, J.; Schorle, H.; Oliveira, J. F.; Ninkovic, J.; Sousa, N. and Pinto, L. (2017): AP2 gamma controls adult hippocampal neurogenesis and modulates cognitive, but not anxiety or depressive-like behavior. In: Molecular Psychiatry, Vol. 22, No. 12: pp. 1725-1734

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Hippocampal neurogenesis has been proposed to participate in a myriad of behavioral responses, both in basal states and in the context of neuropsychiatric disorders. Here, we identify activating protein 2 gamma (AP2 gamma, also known as Tcfap2c), originally described to regulate the generation of neurons in the developing cortex, as a modulator of adult hippocampal glutamatergic neurogenesis in mice. Specifically, AP2 gamma is present in a sub-population of hippocampal transient amplifying progenitors. There, it is found to act as a positive regulator of the cell fate determinants Tbr2 and NeuroD, promoting proliferation and differentiation of new glutamatergic granular neurons. Conditional ablation of AP2 gamma in the adult brain significantly reduced hippocampal neurogenesis and disrupted neural coherence between the ventral hippocampus and the medial prefrontal cortex. Furthermore, it resulted in the precipitation of multimodal cognitive deficits. This indicates that the sub-population of AP2 gamma-positive hippocampal progenitors may constitute an important cellular substrate for hippocampal-dependent cognitive functions. Concurrently, AP2 gamma deletion produced significant impairments in contextual memory and reversal learning. More so, in a water maze reference memory task a delay in the transition to cognitive strategies relying on hippocampal function integrity was observed. Interestingly, anxiety- and depressive-like behaviors were not significantly affected. Altogether, findings open new perspectives in understanding the role of specific sub-populations of newborn neurons in the (patho) physiology of neuropsychiatric disorders affecting hippocampal neuroplasticity and cognitive function in the adult brain.

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