Modulation of Temporoammonic-CA1 Synapses by Neuropeptide Y is Through Y1 Receptors

The reduction of neuropeptide Y (NPY), an abundant neuromodulator in the brain, has been implicated in multiple neuropsychiatric disorders, such as depression and post-traumatic stress disorder (PTSD). The CA1 region of hippocampus is an important area for anxiety and highly expresses NPY. Injection of NPY into the CA1 is anxiolytic and has been shown to alleviate behavioral symptoms in a model of traumatic stress. It is known that activation of NPY Y1 receptors has anxiolytic effects and that NPY’s anxiolytic effects in CA1 are blocked by an NPY Y1 receptor antagonist. However, the location of Y1 receptors mediating NPY’s anxiolytic effects in CA1 is not yet known. CA1 receives inputs from entorhinal cortex through the temporammonic pathway (TA), which has been shown to be important for fear learning and sensitive to stress. Our lab previously showed that NPY reduces TA-evoked synaptic responses, however, the subtype of NPY receptor mediating this effect is not yet known. In this study, we show that Y1 receptors mediate the effects of both exogenous (bath-applied) and endogenously-released NPY in the TA pathway. This is the first demonstration of a Y1 receptor-mediated effect on synaptic function in CA1. Interestingly, chronic cell-type specific overexpression of NPY impairs the sensitivity of the TA pathway to NPY and the Y1 receptor agonist. However, the effect of NPY in the Schaffer collateral (SC) pathway, which is mediate by NPY Y2 receptors, is unaffected by NPY overexpression. There are pathway-specific differences in NPY receptors that modulate NPY’s effects in CA1 and respond differently to NPY overexpression. Our results demonstrating that NPY acts at Y1 receptors in the TA pathway are consistent with the idea that the TA pathway underlies the anxiolytic effects of NPY in CA1.