Selectively increasing GHS-R1a expression in dCA1 excitatory/inhibitory neurons have opposite effects on memory encoding

Aim: Growth hormone secretagogue receptor 1a (GHS-R1a) is widely distributed in brain including the hippocampus. Studies have demonstrated the critical role of hippocampal ghrelin/GHS-R1a signaling in synaptic physiology, memory and cognitive dysfunction associated with Alzheimer’s disease (AD). However, current reports are inconsistent, and the mechanism underlying memory modulation of GHS-R1a signaling is uncertain. In this study, we aim to investigate the direct impact of selective increase of GHS-R1a expression in dCA1 excitatory/inhibitory neurons on learning and memory. Methods: Endogenous GHS-R1a distribution in dCA1 excitatory/inhibitory neurons was assessed by fluorescence in situ hybridization. Cre-dependent GHS-R1a overexpression in excitatory or inhibitory neurons was done by stereotaxic injection of aav-hSyn-DIO-hGhsr1a-2A-eGFP virus in dCA1 region of vGlut1-Cre or Dlx5/6-Cre mice respectively. Virus-mediated GHS-R1a upregulation in dCA1 neurons was confirmed by quantitative RT-PCR. Different behavioral paradigms were used to evaluate long-term memory performance. Results: GHS-R1a is distributed both in dCA1 excitatory pyramidal neurons (αCaMKII⁺) and in inhibitory interneurons (GAD67⁺). Selective increase of GHS-R1a expression in dCA1 pyramidal neurons impaired spatial memory and object-place recognition memory. In contrast, selective increase of GHS-R1a expression in dCA1 interneurons enhanced long-term memory performance. Our findings reveal, for the first time, a neuronal type-specific role that hippocampal GHS-R1a signaling plays in regulating memory. Therefore, manipulating GHS-R1a expression/activity in different subpopulation of neurons may help to clarify current contradictory findings and to elucidate mechanism of memory control by ghrelin/GHS-R1a signaling, under both physiological and pathological conditions such as AD.