Cellular mechanisms underlying the pro-cognitive effects of serotonin 5-HT7 receptors in a mouse model of schizophrenia

Serotonin 5-HT7 receptors (5-HT7Rs) have emerged as promising targets for treating cognitive and affective disturbances in schizophrenia and other neuropsychiatric disorders, yet their cellular substrates and circuit-level mechanisms remain poorly defined. Here, we combined immunohistochemistry, multisite electrophysiology, and behavioral assays to investigate how 5-HT7Rs modulate hippocampal-prefrontal pathways in healthy mice and in a subchronic phencyclidine (sPCP) model of cognitive and negative symptoms in schizophrenia. We found that 5-HT7Rs are abundantly expressed in both excitatory and inhibitory neurons of the dorsal hippocampus (dHPC) and medial prefrontal cortex (mPFC), with high co-expression in PV and SST interneurons ([~]80% in dHPC; 55% PV and 75% SST in mPFC). In healthy mice, systemic 5-HT7R activation with the agonist AS-19 suppressed neuronal activity and synchrony within dHPC (CA1) - mPFC (PL) pathways, reducing theta and high-gamma power, theta-gamma coupling in CA1, theta coherence, and CA1[->]PL directional connectivity, consistent with recruitment of inhibitory microcircuits. The similarity between 5-HT7R-mediated inhibition and the circuit effects we previously described for 5-HT1AR activation, together with evidence for 5-HT7R-5-HT1AR heterodimerization, suggests that these receptors act in concert to dynamically constrain hippocampal-prefrontal circuits. sPCP treatment induced persistent recognition-memory impairments, heightened anxiety-like behavior, and pathological high-frequency synchronization of hippocampal-prefrontal networks. Blockade of 5-HT7Rs with SB-269970 or the atypical antipsychotic lurasidone (but not lurasidone combined with AS-19) rescued memory performance, reduced anxiety-like behavior, and normalized aberrant high-frequency hypersynchrony, while enhancing CA1[->]PL theta signaling immediately before memory acquisition. Together, these findings indicate that 5-HT7R activation exerts potent inhibitory control over hippocampal-prefrontal pathways, likely via PV and SST interneurons, and suggest that 5-HT7R blockade constitutes a promising therapeutic strategy to restore excitation-inhibition balance and enhance neural communication within brain circuits crucial for cognition and mood regulation in neuropsychiatric disorders.