Modulation of temporoammonic-CA1 synapses by neuropeptide Y is through Y1 receptors in mice.

Reduced levels of neuropeptide Y (NPY), an abundant neuromodulator in the brain, are linked to multiple neuropsychiatric disorders, including post-traumatic stress disorder (PTSD). The CA1 region of hippocampus is important for anxiety regulation and highly expresses NPY. Injecting NPY into CA1 is anxiolytic and alleviates behavioral symptoms in a model of traumatic stress; these anxiolytic effects are blocked by a Y1 receptor antagonist. However the location of Y1Rs that mediate NPY's anxiolytic effects in CA1 remains unclear. CA1 receives inputs from entorhinal cortex through the temporammonic pathway (TA), which is 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 reduction is unknown. Here we demonstrate that in mice both exogenous (bath-applied) and endogenously-released NPY act through Y1 receptors in the TA pathway. This is the first demonstration of Y1 receptor-mediated effect on synaptic function in CA1. Interestingly, chronic overexpression of NPY (in NPY-expressing interneurons) impairs the sensitivity of the TA-evoked synaptic response to a Y1 receptor agonist. However, the long-known NPY Y2 receptor-mediated effect on the Schaffer collateral (SC) pathway is unaffected by NPY overexpression. Therefore, NPY can have a pathway-specific impact on synaptic transmission in CA1 based on the differential expression of NPY receptors and their response to overexpression of NPY. 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.