5‐HT_1A and NMDA receptors interact in the rat medial septum and modulate hippocampal‐dependent spatial learning

Abstract

Cholinergic and GABAergic neurons in the medial septum/vertical limb of the diagonal band of Broca (MS/vDB) projecting to the hippocampus, constitute the septohippocampal projection, which is important for hippocampal-dependent learning and memory. There is also evidence for an extrinsic as well as an intrinsic glutamatergic network within the MS/vDB. GABAergic and cholinergic septohippocampal neurons express the serotonergic 5-HT(1A) receptor and most likely also glutamatergic NMDA receptors. The aim of the present study was to examine whether septal 5-HT(1A) receptors are important for hippocampal-dependent long-term memory and whether these receptors interact with glutamatergic NMDA receptor transmission in a manner important for hippocampal-dependent spatial memory. Intraseptal infusion of the 5-HT(1A) receptor agonist (R)-8-OH-DPAT (1 or 4 microg/rat) did not affect spatial learning in the water maze task but impaired emotional memory in the passive avoidance task at the higher dose tested (4 microg/rat). While intraseptal administration of (R)-8-OH-DPAT (4 microg) combined with a subthreshold dose of the NMDA receptor antagonist D-AP5 (1 microg) only marginally affected spatial acquisition, it produced a profound impairment in spatial memory. In conclusion, septal 5-HT(1A) receptors appears to play a more prominent role in emotional than in spatial memory. Importantly, septal 5-HT(1A) and NMDA receptors appear to interact in a manner, which is particularly critical for the expression or retrieval of hippocampal-dependent long-term spatial memory. It is proposed that NMDA receptor hypofunction in the septal area may unmask a negative effect of 5-HT(1A) receptor activation on memory, which may be clinically relevant.

The role of serotonin in memory: interactions with neurotransmitters and downstream signaling

“…Intraseptal administration of 8-OH-DPAT does not influence spatial memory (in water maze), but impairs emotional memory (in PA test); moreover, combination of intraseptal 8-OH-DPAT and subthreshold dose of the NMDA antagonist causes a profound impairment of spatial memory retention as well as mild deficit in spatial acquisition (Elvander-Tottie et al 2009). Although the localization of 5-HT 1A receptors in relation to the glutamatergic neurons in medial septum and the adjacent vertical limb of the diagonal band of Broca area (MS/vDB) is still not characterized (Elvander-Tottie et al 2009), in the hippocampus, 5-HT 1A receptors are expressed on both glutamatergic pyramidal cells and inhibitory GABAergic interneurons (Aznar et al 2003). Postsynaptic 5-HT 1A receptors are suggested to be co-located along with NMDA receptors in the dendritic compartments (Takumi et al 1998).…”

“…In addition, systemic or intrahippocampal administration of the 5-HT 1A R antagonist, WAY 100635, mitigates spatial learning deficit caused by blockade of hippocampal NMDA receptors in a two-platform spatial discrimination task (Carli et al 1999;Schiapparelli et al 2005). Intraseptal administration of 8-OH-DPAT does not influence spatial memory (in water maze), but impairs emotional memory (in PA test); moreover, combination of intraseptal 8-OH-DPAT and subthreshold dose of the NMDA antagonist causes a profound impairment of spatial memory retention as well as mild deficit in spatial acquisition (Elvander-Tottie et al 2009). Although the localization of 5-HT 1A receptors in relation to the glutamatergic neurons in medial septum and the adjacent vertical limb of the diagonal band of Broca area (MS/vDB) is still not characterized (Elvander-Tottie et al 2009), in the hippocampus, 5-HT 1A receptors are expressed on both glutamatergic pyramidal cells and inhibitory GABAergic interneurons (Aznar et al 2003).…”

“…Moreover, oral postlesion administration of the 5-HT 1A R agonists (repinotan and 8-OH-DPAT) ameliorates NMDA excitotoxicity and improves survival of cholinergic neurons and memory performance in rats (Harkany et al 2001).These results indicate a dual role for 5-HT 1A receptors in the modulation of Glu-induced excitatory input to hippocampus. On the one hand, activation of these receptors may hamper the NMDA-induced memory retention, thereby enhancing memory deficit caused by NMDA blockade (Elvander-Tottie et al 2009); on the other hand, they may ameliorate NMDA-induced excitotoxicity and consequent memory deficit (Harkany et al 2001). Taken together, the final outcome of 5-HT 1A receptor activation depends on (1) their localization in different brain areas, (2) interaction with inhibitory or excitatory neurons, (3) G-protein selectivity [5-HT 1A receptors are coupled to G i3 in the anterior raphe nucleus (ARN), while they mainly interact with G o proteins in the hippocampus (Mannoury la Cour et al 2006)], and (4) agonist-directed receptor trafficking, and consequent adaptive modifications (Kenakin 1995;Li et al 1997;Raap et al 1999;Hensler 2002).…”

Spatial memory alterations by activation of septal 5HT1A receptors: no implication of cholinergic septohippocampal neurons

“…Finally, intraseptal glutamatergic interneurons might also play a role in the 8-OH-DPAT action. Indeed, a recent study by Elvander-Tottie et al (2009) suggests that these interneurons are likely to participate in the modulation of the septohippocampal interface through NMDA receptors. More precisely, at the level of GABAergic septohippocampal neurons, 5-HT 1A receptor interacts with glutamatergic NMDA receptors to modulate spatial learning.…”

Implicación de PTTG1 en procesos celulares y fisiológicos controlados por RASGRF1

“…Los receptores NMDA del septo son dianas de los receptores de 5-HT1A y al acivarse estos úlimos las funciones de los primeros parecen suprimirse. La interacción 5-HT1A-NMDA podría consituir un nuevo mecanismo relacionado con el control de los procesos emocionales y cogniivos favorecidos por la proyección del septohipocampo [269].…”