S130 S.12. Junior Scientists symposium − New targets for treating depression and anxiety: preclinical and clinical studies

despair in the FST, as suggested by comparable latency andimmobility on both days of testing. By transgenically expressinga GFP-tagged GluA1-subunit in the GluA1 knockout backgroundwe were able to rescue this deficit.Taken together, this study provides evidence that hippocampal

GluA1-containing AMPA receptors and their interaction withPDZ-domain proteins are critical for the induction of learnedbehavioural despair, thereby linking mechanisms of hippocam-pal GluA1-dependent synaptic plasticity with the pathophysiol-ogy of depression. In conclusion, modulation of specific PDZ-interactions in the glutamatergic postsynapse might provide apromising target for the treatment of depression and other psy-chiatric disorders and will be the target of future studies.

References

[1] Skolnick P, Popik P, Trullas R. Glutamate-based antidepressants: 20years on. Trends in Pharmacological Sciences 2009; 30: 563−9.

[2] Duman RS, Voleti B. Signaling pathways underlying the pathophysi-ology and treatment of depression: novel mechanisms for rapid-actingagents. Trends in Neurosciences 2012; 35: 47−56.

[3] Freudenberg F, Marx V, Mack V, Layer LE, Klugmann M, Seeburg PH,Sprengel R, Celikel T. Neurobiology of Disease GluA1 and its PDZ-interaction: A role in experience-dependent behavioral plasticity in theforced swim test. Neurobiology of Disease 2013; 52: 160−7.

Disclosure statement: This study has been supported in part by the Univer-sity of Heidelberg (University Grant GC791 F.F.) Alexander von Humboldtfoundation (F.F., T.C.), DFG: SFB636.A4 (R.S.), Volkswagen foundation:Dynamik und Adaptivitat neuronaler Systeme and the European Com-mission, EUSynapse project LSHM-CT-2005–019055 (P.H.S.), WhitehallFoundation (T.C.) and Sloan Foundation (T.C.). Volker Mack is an employeeof Evotec AG, Liliana E. Layer is an employee of PromoCell GmbH. At thetime research for this manuscript was conducted they were not involved withtheir respective companies. All other authors declare no conflict of interest.The presented data has in part been published: Freudenberg, F. et al. (2013).GluA1 and its PDZ-interaction: A role in experience-dependent behavioralplasticity in the forced swim test. Neurobiology of Disease, 52, 160–167.

S.12.05 Serotonin regulates hippocampal synaptic

plasticity and object memory in mice

S. Fernandez1 °, A. Gruart2, J.M. Delgado2, P. Gaspar1 1Institutdu Fer a Moulin, UMR-S 839 INSERM/UPMC, Paris, France;2Pablo Olavide University, Neuroscience Division, Seville, Spain

Low levels of serotonin (5-HT) have been associated with thelearning and memory deficits seen in Alzheimer’s disease, autismand major depression [1]. Studies performed in healthy volunteershave shown that 5-HT depletion disrupts consolidation of newinformation, specifically in tasks involving delayed recall and/orrecognition of visually-presented words, spoken words, picturesor abstract figures [1]. Despite this evidence, the mechanismby which 5-HT regulates learning and memory function is notclear. We used a genetic model of 5-HT depletion, Pet1 knock-out mice (Pet1 KO), to study the role of 5-HT in learning andmemory function. In these mice, brain 5-HT levels are reducedin the cortex and the hippocampus [2]. Pet1 KO mice are capableof acquiring operant and associative learning, but fail to recallfamiliarization with objects. The object recognition test is usedto measure hippocampal-dependent declarative memory and Pet1KO mice consistently failed to spend more time exploring thenovel object, suggesting impairment in recognition memory.This phenotype was reversed if 5-HT levels were previously

incremented in the brain by administration of a 5-HT precursor.Consolidation of object memory involves synaptic long-term po-tentiation (LTP) across the CA3-CA1 hippocampal pathway. We

performed in vivo hippocampal recordings in mice performing theobject memory task. In Pet1 KO mice, experience-dependent LTPwas exaggerated, possibly explaining the aberration seen in objectrecognition. These results established a direct link between 5-HTdepletion, memory impairment and synaptic plasticity deficits.

References

[1] Schmitt, J.A., Wingen, M., Ramaekers, J.G., Evers, E.A., Riedel, W.J.2006. 5-HT and human cognitive performance. Curr Pharm Des 12,2473−86.

[2] Kiyasova, V., Fernandez, S.P., Laine, J., Stankovski, L., Muzerelle, A.,Doly, S., Gaspar, P., 2011. A Genetically Defined Morphologically andFunctionally Unique Subset of 5-HT Neurons in the Mouse RapheNuclei. J Neurosci 31, 2756−68.

Disclosure statement: this research is funded by the Fondation pour laRecherche Medicale, Fondation Jerome Lejeune and the Federation pour laRecherche sur le Cerveau.

S.12.06 Corticotropin releasing hormone and

serotonin − the neuropsychopharmacology of

fear learning deficit from rodents to humans

I. Heitland1 °, L. Groenink2, E.Y. Bijlsma2, R.S. Oosting2,J.M.P. Baas1 1Utrecht University, Department of ExperimentalPsychology & Psychopharmacology, Utrecht, The Netherlands;2Utrecht Institute of Pharmaceutical Sciences, Department ofPsychopharmacology, Utrecht, The Netherlands

Introduction: From an evolutionary perspective, the acquisitionof fear responses enables organisms to respond appropriately topredictors of aversive events. Our previous work has demonstratedthat failure to condition to a specific threat cue results in anincrease in conditioned fear to the context because the threatremains unpredictable [1]. This mechanism may model a pathwayto chronic states of anxiety [2]. Recent preclinical data fromcollaborators suggests that the interplay between brain serotonin(5-HT) and corticotropin releasing hormone (CRH) systems iscrucial in successful fear acquisition [3].

Methods: To translate these preclinical findings, we recruited150 healthy human subjects that underwent a cue and context fearconditioning procedure in a virtual environment. All participantswere genotyped for common polymorphisms within regulatoryregions of the serotonin transporter (5-HTTLPR) and the CRHreceptor 1 (CRHR1). These polymorphisms have previously beenlinked to panic disorder (CRHR1 [rs878886] G-allele) and anxioussymptomology and personality (5-HTTLPR short allele), respec-tively. As in the rodent experiment, the fear potentiated startle wasrecorded to assess fear conditioned responses to the threat cue andthreat context.

Results: Uninstructed fear acquisition to the threat cue wassignificantly affected by CRHR1 genotype: G-allele carriers ofrs878886 failed to discriminate between the threat cue and context.Moreover, subjects carrying the risk-alleles of both genotypes(CRHR1 and 5-HTTLPR) displayed increased contextual condi-tioned responses.

Conclusion: Hence, genetic variation in these transmitter sys-tems may confer a risk for maladaptive acquisition of fear asso-ciations, which may constitute a pathway to pathological fear.

References

[1] Baas JM, van Ooijen L, Goudriaan A, Kenemans JL (2008) Failure tocondition to a cue is associated with sustained contextual fear. ActaPsychol (Amst) 127: 581–592.

[2] Grillon C (2002) Associative learning deficits increase symptoms ofanxiety in humans. Biol Psychiatry 51: 851–858.