The Role Of 5-HT_1B Receptors In Hippocampal CA1 Area In Spatial Learning And Memory And Its Influence On Neuroplasticity

Learning and memory is not only a research topic highly concerned by neuroscience,psychology and pedagogy,but also important to psychiatric diseases like Alzheimer’s disease,Parkinson’s disease and depression.Therefore,more and more researchers focus on the research topics about learning and memory in many fields.Hippocampus is the key brain area which plays an irreplaceable role in the processing of spatial memory information.Serotonin(5-HT)is involved in many physiological functions including emotion,locomotor and cognitive activities.Dysfunction of serotonergic system induces memory deficit and a wide variety of neuropsychiatric disorders including depression,schizophrenia and anxiety.At least fourteen 5-HT receptor subtypes have been identified.Among these receptor subtypes,5-HT1B receptors(5-HT1BRs)are widely distributed throughout in the CNS with highest concentrations found in the brain regions that are highly associated with cognitive activities,such as the hippocampus,the dorsal subiculum,and the frontal cortex.Imaging studies illustrate the levels of 5-HT1BRs are reduced in the orbital frontal lobe and the hippocampus of early Parkinson’s patients followed by memory deficits.Subcutaneous and intraperitoneal injection of 5-HT1BR antagonists promotes memory acquisition and consolidation.In addition,study shows that 5-HT1BRs regulate emotion memory and hippocampal function bidirectionally.Moreover,global 5-HT1BRs deletion either facilitates or impairs spatial learning,depending on cognitive demand and task complexity.These findings suggest that 5-HT1BRs may play a crucial role in cognitive behaviors,particularly,hippocampal-dependent learning and memory.In hippocampal CA1,5-HT1BRs are present on glutamatergic pyramidal cells,GABAergic interneurons,and serotonergic terminals.It is widely accepted that 5-HT1BRs are expressed as autoreceptor or heteroreceptor in modulating serotonin and other neurotransmitter release.Electron microscopic study illustrates 5-HT1BRs are expressed on postsynaptic processes of the neurons in the suprachiasmatic nucleus and activation of 5-HT1BRs at hippocampal temporoammonic-CA1(TA-CA1)synapse produces a facilitation in AMPAR-induced excitatory synaptic transmission.Dendritic spines are the structure basis of excitatory synapses formation.The alternations in the size,structure and number of dendritic spines are essential to neural circuit reconstruction and excitatory synaptic transmission.Kalirin-7(Kal7),an essential component of the postsynaptic density(PSD)and plays an important role in the formation and maintenance of excitatory synapses.Studies showed that Kal7 regulates synaptic plasticity by affecting glutamate receptor function on the postsynaptic membrane,but whether Kal7 participates in hippocampal spatial learning and memory is unclear.In particular,the relationship between hippocampal Kal7 and glutamate synaptic plasticity remains unclear.However,the precise role of in hippocampal CA15-HT1BRs in cognitive behaviors,particularly,its underlying signaling,is far from clear.We therefore investigated the role of 5-HT1BRs in hippocampal CA1 in spatial working memory and 5-HT1BR stimulation-induced effects on glutamate receptors,synaptic proteins,Kal7 and dendritic spine density.Male SD rats were trained and tested in a Morris water maze after a bilateral CA1 injection of saline,the 5-HT1BR agonist CP93129(25μg/1μL),or the 5-HT1BR antagonist GR55562(25μg/1μL)or the Ca2+ permeability of AMPA receptors(CP-AMPARs)inhibitor PHTX-74(PHTX,10μg/1μL)into the dorsal hippocampal CA1.The levels of related proteins were detected by Western Blot,and dendritic spine density of hippocampal CA1 pyramidal neurons was detected by Golgi staining.Results:(1)Activation of 5-HT1BRs in hippocampal CA1 impaired spatial acquisition and consolidation,and decreased the dendritic spines of CA1 pyramidal cells and the expression of Kal7,while the levels of GluA2/3,GIuN2B and PSD-95 reduced.(2)Inactivation of 5-HT1BRs in hippocampal CA1 enhanced memory consolidation,and increased the dendritic spines of CA1 pyramidal cells and the expression of Kal7,while the levels of GluA2/3 and GluN2B increased.(3)The deficits which 5-HT1BRs in hippocampal CA1 caused in the acquisition process were reversed by blocking CP-AMPARs,and increased the dendritic spines of CA1 pyramidal cells and the expression of Kal7,while the levels of GluN2B,GluA2/3,PSD95 and the phosphorylation level of GluN2B and GluA2 recovered.Conclusions:(1)5-HT1BRs in hippocampal CA1 regulate the acquisition and the consolidation process of spatial working memory in rats.(2)5-HT1BRs in hippocampal CA1 alter spine density,which is accompanied by Kal7 and PSD95 in the hippocampus.5-HT1BRs in hippocampal CA1 alter the composition of AMPA receptors in the hippocampus.(3)In spatial memory acquisition process,hippocampal CA15-HT1BR activation-mediated deficits are reversed by CA1 infusion of CP-AMPAR antagonist.CP-APMAR may also down-regulated the expression of Kal7,PSD95,GluA2/3,GluN2B and the phosphorylation level of GluA2.(4)In spatial memory,Kal7 may be not only a mediator between 5-HT1BRs and dendritic spines in hippocampal CA1 pyramidal neurons,but also a mediator between 5-HT1BRs and the glutamatergic system.Therefore,Kal7 is a key factor in learning and memory.In summary,these results suggest that 5-HT1BRs:in hippocampal CA1 play an important role in spatial memory mainly through glutamatergic synaptic plasticity.5-HT1BR stimulation-induced inactivation of Kal7 may cause thus the malfunction of excitatory synaptic transmission and the impairment of hippocampal-dependent cognitive behaviors.A better understand of the role and underlying mechanism of serotonin in learning and memory process should lead to new therapeutic options for patients with cognitive disorders.