Serotonin signaling is a primary target of antidepressant medication, and may be dysregulated in psychiatric diseases. Serotonergic afferents and serotonin 5-HT1B receptors to the hippocampus are concentrated in stratum lacunosum-moleculare (SLM), where glutamatergic synaptic input from the entorhinal cortex, the temporo-ammonic (TA) pathway, also terminates. The TA pathway provides the only direct input to CA1 pyramidal neurons from the cortex and is thus a main source of sensory information. OBJECTIVE: to determine how 5-HT1B receptors regulate TA-CA1 synaptic transmission and determine how these processes are dysregulated in depression and restored by chronic antidepressant treatment. PRELIMINARY RESULTS: activation of 5-HT1B receptors potentiates excitatory postsynaptic potentials (field EPSPs and EPSPs) elicited by TA stimulation in CA1 SLM, but not by Schaffer collateral stimulation. The potentiation is mediated by increased postsynaptic AMPA receptor mediated transmission and accompanied by phosphorylation of the AMPA receptor GluR1 at the PKC/CaMKII Ser831 site. The effects of 5-HT1B receptor activation on TA-CA1 synaptic transmission are enhanced in rats subjected to chronic unpredictable stress (CUS), an accepted animal model of depression, and blocked by chronic antidepressant treatment. SPECIFIC AIMS: 1. Test whether 5-HT1B receptor-induced potentiation and activity-dependent synaptic plasticity share common signaling mechanisms that lead to AMPA receptor insertion at TA-CA1 synapses. 2. Determine how potentiation of TA-CA1 synaptic transmission by 5-HT1B receptors is enhanced after chronic unpredictable stress. 3. Determine why potentiation of TA-CA1 synaptic transmission by 5-HT1B receptors is absent after chronic antidepressant treatment. 4. Test whether chronic antidepressant treatment can reverse a behavioral sign of depression, anhedonia, when 5-HT1B receptors are blocked pharmacologically or when serotonin-induced potentiation is absent in GluR1 S831A transgenic mice. RESEARCH DESIGN: we will combine electrophysiological techniques, including glutamate photolysis, with cell biological techniques such as transfection with constitutively active and dominant negative constructs, western blotting, and biotinylation assays, to investigate the actions of 5-HT1B receptors in hippocampal slices taken from control animals and animals subjected to CUS and chronic antidepressant treatment. OUTCOMES: The proposed project will expand our understanding of the physiological actions of serotonin and determine whether depression results, in part, from a dysregulation of the strength of excitatory synaptic transmission in multiple brain regions involved in cognitive and emotional function. A better understanding of serotonin actions and their alteration by stress will lead to improved antidepressant treatment strategies.