A Biphasic and Brain-Region Selective Down-Regulation of Cyclic Adenosine Monophosphate Concentrations Supports Object Recognition in the Rat

Background: We aimed to further understand the relationship between cAMP concentration and mnesic performance. Methods and Findings: Rats were injected with milrinone (PDE3 inhibitor, 0.3 mg/kg, i.p.), rolipram (PDE4 inhibitor, 0.3 mg/ kg, i.p.) and/or the selective 5-HT4R agonist RS 67333 (1 mg/kg, i.p.) before testing in the object recognition paradigm. Cyclic AMP concentrations were measured in brain structures linked to episodic-like memory (i.e. hippocampus, prefrontal and perirhinal cortices) before or after either the sample or the testing phase. Except in the hippocampus of rolipram treated-rats, all treatment increased cAMP levels in each brain sub-region studied before the sample phase. After the sample phase, cAMP levels were significantly increased in hippocampus (1.8 fold), prefrontal (1.3 fold) and perirhinal (1.3 fold) cortices from controls rat while decreased in prefrontal cortex (,0.83 to 0.62 fold) from drug-treated rats (except for milrinone+RS 67333 treatment). After the testing phase, cAMP concentrations were still increased in both the hippocampus (2.76 fold) and the perirhinal cortex (2.1 fold) from controls animals. Minor increase were reported in hippocampus and perirhinal cortex from both rolipram (respectively, 1.44 fold and 1.70 fold) and milrinone (respectively 1.46 fold and 1.56 fold)-treated rat. Following the paradigm, cAMP levels were significantly lower in the hippocampus, prefrontal and perirhinal cortices from drug-treated rat when compared to controls animals, however, only drug-treated rats spent longer time exploring the novel object during the testing phase (inter-phase interval of 4 h)

The absence of 5-HT4 receptors modulates depression- and anxiety-like responses and influences the response of fluoxetine in olfactory bulbectomised mice: Adaptive changes in hippocampal neuroplasticity markers and 5-HT1A autoreceptor

reclinical studies support a critical role of 5-HT4 receptors (5-HT4Rs) in depression and anxiety, but their influence in depression- and anxiety-like behaviours and the effects of antidepressants remain partly unknown. We evaluated 5-HT4R knockout (KO) mice in different anxiety and depression paradigms and mRNA expression of some neuroplasticity markers (BDNF, trkB and Arc) and the functionality of 5-HT1AR. Moreover, the implication of 5-HT4Rs in the behavioural and molecular effects of chronically administered fluoxetine was assessed in naïve and olfactory bulbectomized mice (OBX) of both genotypes. 5-HT4R KO mice displayed few specific behavioural impairments including reduced central activity in the open-field (anxiety), and decreased sucrose consumption and nesting behaviour (anhedonia). In these mice, we measured increased levels of BDNF and Arc mRNA and reduced levels of trkB mRNA in the hippocampus, and a desensitization of 5-HT1A autoreceptors. Chronic administration of fluoxetine elicited similar behavioural effects in WT and 5-HT4R KO mice on anxiety-and depression-related tests. Following OBX, locomotor hyperactivity and anxiety were similar in both genotypes. Interestingly, chronic fluoxetine failed to reverse this OBX-induced syndrome in 5-HT4R KO mice, a response associated with differential effects in hippocampal neuroplasticity biomarkers. Fluoxetine reduced hippocampal Arc and BDNF mRNA expressions in WT but not 5-HT4R KO mice subjected to OBX. These results demonstrate that the absence of 5-HT4Rs triggers adaptive changes that could maintain emotional states, and that the behavioural and molecular effects of fluoxetine under pathological depression appear to be critically dependent on 5-HT4RsThis research was supported by Spanish Ministry of Economy and Competitiveness (SAF2011-25020), and Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM)

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

Abstract Serotonin, or 5-hydroxytryptamine (5-HT), is found to be involved in many physiological or pathophysiological processes including cognitive function. Seven distinct receptors (5-HT1–7), each with several subpopulations, have been identified for serotonin, which are different in terms of localization and downstream signaling. Because of the development of selective agonists and antagonists for these receptors as well as transgenic animal models of cognitive disorders, our understanding of the role of serotonergic transmission in learning and memory has improved in recent years. A large body of evidence indicates the interplay between serotonergic transmission and other neurotransmitters including acetylcholine, dopamine, γ-aminobutyric acid (GABA) and glutamate, in the neurobiological control of learning and memory. In addition,there has been an alteration in the density of serotonergic receptors in aging and Alzheimer’s disease, and serotonin modulators are found to alter the process of amyloidogenesis and exert cognitive-enhancing properties. Here, we discuss the serotonin-induced modulation of various systems involved in mnesic function including cholinergic, dopaminergic, GABAergic, glutamatergic transmissions as well as amyloidogenesis and intracellular pathways

A critical evaluation of the activity-regulated cytoskeleton-associated protein (Arc/Arg3.1)'s putative role in regulating dendritic plasticity, cognitive processes, and mood in animal models of depression

Major depressive disorder (MDD) is primarily conceptualized as a mood disorder but cognitive dysfunction is also prevalent, and may limit the daily function of MDD patients. Current theories on MDD highlight disturbances in dendritic plasticity in its pathophysiology, which could conceivably play a role in the production of both MDD-related mood and cognitive symptoms. This paper attempts to review the accumulated knowledge on the basic biology of the activity-regulated cytoskeleton-associated protein (Arc or Arg3.1), its effects on neural plasticity, and how these may be related to mood or cognitive dysfunction in animal models of MDD. On a cellular level, Arc is found to play an important role in modulating dendritic spine density and remodeling. Arc is also found to have a close, bidirectional relationship with postsynaptic glutamate neurotransmission, since it is stimulated by multiple glutamatergic receptor mechanisms but also modulates α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor internalization. The effects on AMPA receptor trafficking are likely related to Arc’s ability to modulate phenomena such as long-term potentiation, long-term depression, and synaptic scaling, each of which are important for maintaining proper cognitive function. Animal studies of chronic stress models of MDD show suppressed Arc expression in the frontal cortex but elevation in the amygdala. Interestingly, cognitive tasks depending on the frontal cortex are generally impaired by chronic stress, while those depending on the amygdala are enhanced, and antidepressant treatments stimulate cortical Arc expression with a timeline that is reminiscent of the treatment efficacy lag observed in the clinic or in preclinical models. However, pharmacological treatments that stimulate regional Arc expression do not universally improve relevant cognitive functions, and this highlights a need to further refine our understanding of Arc on a subcellular and network level

Monoaminergic Neuropathology in Alzheimer's disease

Acknowledgments This work was supported by The Croatian Science Foundation grant. no. IP-2014-09-9730 (“Tau protein hyperphosphorylation, aggregation, and trans-synaptic transfer in Alzheimer’s disease: cerebrospinal fluid analysis and assessment of potential neuroprotective compounds”) and European Cooperation in Science and Technology (COST) Action CM1103 (“Stucture-based drug design for diagnosis and treatment of neurological diseases: dissecting and modulating complex function in the monoaminergic systems of the brain”). PRH is supported in part by NIH grant P50 AG005138.Peer reviewedPostprin

Cell Type Specific Roles of Serotonin Receptor 4 in the Hippocampus and Neocortex in Emotion and Cognition

Anxiety and mood disorders are the most prevalent classes of mental disorders. However, current treatments for these debilitating diseases are limited due to their delayed onset of action and numerous side effects, emphasizing the need for faster acting and more efficacious therapies. Preclinical studies indicate a critical role for Serotonin Receptor 4 (5-HT4R, product of the Htr4 gene) in this direction as drugs that activate this receptor show fast-acting antidepressant-like properties. Unfortunately, 5-HT4R is widely expressed in the periphery, limiting its use as a direct therapeutic target due to various side effects. Understanding the cell type specific mechanisms of 5-HT4R function in the brain will facilitate the development of novel therapies. To dissect the function of 5-HT4R in genetically defined cell types of the hippocampus and neocortex, two regions highly implicated in emotive and cognitive function, I generated a novel Cre-dependent Htr4 knockout mouse line. Intriguingly, the loss of functional 5-HT4R specifically in the mature excitatory neurons of the hippocampus led to robust antidepressant-like behavioral, cellular and molecular responses. These phenotypes were accompanied by elevated innate anxiety levels and deficits in hippocampus-dependent memories. By slice electrophysiology, we showed that 5-HT4R was necessary for the proper excitability of dentate gyrus granule cells. To identify molecular adaptations underlying the observed changes in behavior and neuronal activity, I used the translating ribosome affinity purification (TRAP) approach combined with nextgeneration RNA sequencing to measure hippocampal region- and cell typespecific differential gene expression in the presence and absence of 5-HT4R. Analysis of these datasets revealed that the ventral and dorsal hippocampus underwent distinct molecular adaptations, and identified functionally relevant genes that may underlie these phenotypes and be potential therapeutic targets. My graduate work identified unique roles for hippocampal 5-HT4R in modulating mood, anxiety and memory. By regulating the excitability of individual neurons and relevant intracellular pathways, 5-HT4R mediates functionally distinct hippocampal circuits. Our findings suggest divergent molecular and functional roles for 5-HT4R along the dorsoventral axis of the hippocampus, and that specific cell type- or circuit-based strategies that target the 5-HT4R pathway may yield more effective antidepressant therapies

Dopamine neurotransmission and atypical antipsychotics in prefrontal cortex: a critical review

Schizophrenia has been historically characterized by the presence of positive symptomatology, however, decades of research highlight the importance of cognitive deficits in this disorder. At present, cognitive impairments remain one of the most important unmet therapeutic needs in schizophrenia. The prefrontal cortex (PFC) controls a large number of higher brain functions altered in a variety of psychiatric disorders, including schizophrenia. Histological studies indicate the presence of a large proportion of PFC neurons expressing monoaminergic receptors sensitive to the action of current atypical antipsychotics. Functional studies also show that these medications act at PFC level to increase dopamine neurotransmission in the mesocortical pathway. Here we focus on monoaminergic molecular targets that are actively being explored as potential therapeutic agents in the basic and clinical cognitive neuroscience research, to support the development of co-treatments used in conjunction with antipsychotic medications. These targets include dopamine and serotonin receptors in the prefrontal cortex, as well as elements of the noradrenergic system

Neural plasticity and proliferation in the generation of antidepressant effects: hippocampal implication

It is widely accepted that changes underlying depression and antidepressant-like effects involve not only alterations in the levels of neurotransmitters as monoamines and their receptors in the brain, but also structural and functional changes far beyond. During the last two decades, emerging theories are providing new explanations about the neurobiology of depression and the mechanism of action of antidepressant strategies based on cellular changes at the CNS level. The neurotrophic/plasticity hypothesis of depression, proposed more than a decade ago, is now supported by multiple basic and clinical studies focused on the role of intracellular-signalling cascades that govern neural proliferation and plasticity. Herein, we review the state-of-the-art of the changes in these signalling pathways which appear to underlie both depressive disorders and antidepressant actions. We will especially focus on the hippocampal cellularity and plasticity modulation by serotonin, trophic factors as brain-derived neurotrophic factor (BDNF), and vascular endothelial growth factor (VEGF) through intracellular signalling pathways-cAMP, Wnt/ β -catenin, and mTOR. Connecting the classic monoaminergic hypothesis with proliferation/neuroplasticity-related evidence is an appealing and comprehensive attempt for improving our knowledge about the neurobiological events leading to depression and associated to antidepressant therapies

The Dynamics of Serotonin Receptor Expression in the Developing Forebrain

Serotonin (5-hydroxytryptamine, 5-HT) serves an important modulatory role in the entire central nervous system (CNS), and serotonergic abnormalities have been implicated in many mental disorders. All of the CNS supply of 5-HT originates in the brainstem raphe nuclei. The midbrain dorsal raphe nucleus (DRN) sends widespread projections to the forebrain but receives direct input from only a small number of forebrain regions, including the medial prefrontal cortex (mPFC). We hypothesized that prenatal perturbations of 5-HT levels may alter the forebrain expression of 5-HT receptors (5-HTRs) in a time-sensitive manner and that these changes may result in persistent changes of the forebrain control of the DRN. Specifically, this thesis investigated the susceptibility of 5-HTR expression in the embryonic mouse telencephalon to chronic and acute perturbations of 5-HT levels and examined the effects of altered 5-HT4R expression on the synaptic structure of the mPFC-DRN projection. These studies demonstrated (i) that acute and chronic perturbations of 5-HT levels affect the expression of 5-HT1AR, 5-HT2AR, and 5-HT4R in the embryonic forebrain and (ii) that altered 5-HT4R expression affects the development of the synaptic connectivity between mPFC terminals and DRN serotonergic neurons. These findings suggest that prenatal serotonergic perturbations can strongly influence the development of the prefrontal control of 5-HT signaling and have long-term consequences for behavioral responses later in life