Bidirectional regulation of emotional memory by 5-HT1B receptors involves hippocampal p11

Abstract

Cognitive impairments are common in depression and involve dysfunctional serotonin neurotransmission. The 5-HT1B receptor (5-HT1BR) regulates serotonin transmission, via presynaptic receptors, but can also affect transmitter release at heterosynaptic sites. This study aimed at investigating the roles of the 5-HT1BR, and its adapter protein p11, in emotional memory and object recognition memory processes by the use of p11 knockout (p11KO) mice, a genetic model for aspects of depression-related states. 5-HT1BR agonist treatment induced an impairing effect on emotional memory in wild type (WT) mice. In comparison, p11KO mice displayed reduced long-term emotional memory performance. Unexpectedly, 5-HT1BR agonist stimulation enhanced memory in p11KO mice, and this atypical switch was reversed after hippocampal adeno-associated virus mediated gene transfer of p11. Notably, 5-HT1BR stimulation increased glutamatergic neurotransmission in the hippocampus in p11KO mice, but not in WT mice, as measured by both pre- and postsynaptic criteria. Magnetic resonance spectroscopy demonstrated global hippocampal reductions of inhibitory GABA, which may contribute to the memory enhancement and potentiation of pre- and post-synaptic measures of glutamate transmission by a 5-HT1BR agonist in p11KO mice. It is concluded that the level of hippocampal p11 determines the directionality of 5-HT1BR action on emotional memory processing and modulates hippocampal functionality. These results emphasize the importance of using relevant disease models when evaluating the role of serotonin neurotransmission in cognitive deficits related to psychiatric disorders.

NMDA receptor antagonists ketamine and Ro25-6981 inhibit evoked release of glutamate in vivo in the subiculum

“…16,17,25 The evoked peaks were reproducible at the 1-min intervals between depolarizations. Results were analyzed offline with the Quanteon FAST Analysis 4.1 software (Quanteon) in conjunction with the calibration reports.…”

p11 and its role in depression and therapeutic responses to antidepressants

“…Constitutive p11 KO mice, which lack p11 in the whole brain and body, show a depression-like behavioral phenotype in several well-established models that measure behavioral despair (e.g., forced swim and tail suspension tests) or anhedonia (e.g., sucrose preference test) 2,14 . P11 KO mice also show a deficit in emotional learning, as indicated by impaired performance in the passive avoidance task 26 . In addition to the observed depressive-like phenotype in these tests, constitutive p11 KO mice show reduced responses to antidepressant administration in the forced swim, tail suspension and novelty suppressed feeding tests 2,14,27 .…”

Associations of the 5‐hydroxytryptamine (serotonin) Receptor 1B gene (HTR1B) with alcohol, cocaine, and heroin abuse

“…Decreased HTR1B activity enhanced locomotor response to cocaine self-administration (Rocha and others 1998) and alcohol consumption (Crabbe and others 1996) in the HTR1B receptor knockout mice while increased HTR1B function reduced cocaine self-administration in rats with HTR1B agonists (Parsons and others 1998). Recent studies indicated HTR1B in migraine medication (Pytliak and others 2011), emotional memory processing via the hippocampus (Eriksson and others 2012), regulation of serotonin transporter activity (Hagan and others 2012), and an altered relationship between childhood aggression and adulthood hostility (Hakulinen and others 2012). HTR1B appeared to differentially modulate cocaine abuse-related behaviors, with a facilitative influence during periods of active drug use in contrast to an inhibitory influence during protracted withdrawal, suggesting value in stage-based cocaine dependence treatment (Pentkowski and others 2012).…”