Abstract
Episodic memory, a fundamental component of human cognition, is significantly impaired in autism. We believe we report the first evidence for this problem in the Fmr1-knockout (KO) mouse model of Fragile X syndrome and describe potentially treatable underlying causes. The hippocampus is critical for the formation and use of episodes, with semantic (cue identity) information relayed to the structure via the lateral perforant path (LPP). The unusual form of synaptic plasticity expressed by the LPP (lppLTP) was profoundly impaired in Fmr1-KOs relative to wild-type mice. Two factors contributed to this defect: (i) reduced GluN1 subunit levels in synaptic NMDA receptors and related currents, and (ii) impaired retrograde synaptic signaling by the endocannabinoid 2-arachidonoylglycerol (2-AG). Studies using a novel serial cue paradigm showed that episodic encoding is dependent on both the LPP and the endocannabinoid receptor CB1, and is strikingly impaired in Fmr1-KOs. Enhancing 2-AG signaling rescued both lppLTP and learning in the mutants. Thus, two consequences of the Fragile-X mutation converge on plasticity at one site in hippocampus to prevent encoding of a basic element of cognitive memory. Collectively, the results suggest a clinically plausible approach to treatment.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 12 print issues and online access
$259.00 per year
only $21.58 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Hampton RR, Schwartz BL. Episodic memory in nonhumans: what, and where, is when? Curr Opin Neurobiol 2004; 14: 192–197.
Tulving E. Episodic and semantic memory. In: Tulving E, Donaldson W (eds). Organization of Memory. Academic Press: New York, NY, USA, 1972, pp 381–403.
Grober E, Hall CB, Lipton RB, Zonderman AB, Resnick SM, Kawas C. Memory impairment, executive dysfunction, and intellectual decline in preclinical Alzheimer's disease. J Int Neuropsychol Soc 2008; 14: 266–278.
Leyhe T, Muller S, Milian M, Eschweiler GW, Saur R. Impairment of episodic and semantic autobiographical memory in patients with mild cognitive impairment and early Alzheimer's disease. Neuropsychologia 2009; 47: 2464–2469.
Xie SX, Libon DJ, Wang X, Massimo L, Moore P, Vesely L et al. Longitudinal patterns of semantic and episodic memory in frontotemporal lobar degeneration and Alzheimer's disease. J Int Neuropsychol Soc 2010; 16: 278–286.
Schneider A, Hagerman RJ, Hessl D. Fragile X syndrome — from genes to cognition. Dev Disabil Res Rev 2009; 15: 333–342.
Gaigg SB, Bowler DM, Ecker C, Calvo-Merino B, Murphy DG. Episodic recollection difficulties in ASD result from atypical relational encoding: behavioral and neural evidence. Autism Res 2015; 8: 317–327.
Crane L, Goddard L. Episodic and semantic autobiographical memory in adults with autism spectrum disorders. J Autism Dev Disord 2008; 38: 498–506.
Crane L, Lind SE, Bowler DM. Remembering the past and imagining the future in autism spectrum disorder. Memory 2013; 21: 157–166.
Gaigg SB, Bowler DM, Gardiner JM. Episodic but not semantic order memory difficulties in autism spectrum disorder: evidence from the Historical Figures Task. Memory 2014; 22: 669–678.
Hare DJ, Mellor C, Azmi S. Episodic memory in adults with autistic spectrum disorders: recall for self- versus other-experienced events. Res Dev Disabil 2007; 28: 317–329.
Lind SE, Williams DM, Bowler DM, Peel A. Episodic memory and episodic future thinking impairments in high-functioning autism spectrum disorder: an underlying difficulty with scene construction or self-projection? Neuropsychology 2014; 28: 55–67.
Souchay C, Guillery-Girard B, Pauly-Takacs K, Wojcik DZ, Eustache F. Subjective experience of episodic memory and metacognition: a neurodevelopmental approach. Front Behav Neurosci 2013; 7: 212.
Burgess N, Maguire EA, O'Keefe J. The human hippocampus and spatial and episodic memory. Neuron 2002; 35: 625–641.
Dickerson BC, Eichenbaum H. The episodic memory system: neurocircuitry and disorders. Neuropsychopharmacology 2010; 35: 86–104.
Wixted JT, Squire LR, Jang Y, Papesh MH, Goldinger SD, Kuhn JR et al. Sparse and distributed coding of episodic memory in neurons of the human hippocampus. Proc Natl Acad Sci USA 2014; 111: 9621–9626.
Reagh ZM, Yassa MA. Object and spatial mnemonic interference differentially engage lateral and medial entorhinal cortex in humans. Proc Natl Acad Sci USA 2014; 111: E4264–E4273.
Wang W, Trieu BH, Palmer LC, Jia Y, Pham DT, Jung KM et al. A primary cortical input to hippocampus expresses a pathway-specific and endocannabinoid-dependent form of long-term potentiation. eNeuro 2016; 3: ENEURO.0160-16.2016.
Devane WA, Hanus L, Breuer A, Pertwee RG, Stevenson LA, Griffin G et al. Isolation and structure of a brain constituent that binds to the cannabinoid receptor. Science 1992; 258: 1946–1949.
Stella N, Schweitzer P, Piomelli D. A second endogenous cannabinoid that modulates long-term potentiation. Nature 1997; 388: 773–778.
Dolen G, Bear MF. Role for metabotropic glutamate receptor 5 (mGluR5) in the pathogenesis of fragile X syndrome. J Physiol 2008; 586: 1503–1508.
Bhakar AL, Dolen G, Bear MF. The pathophysiology of fragile X (and what it teaches us about synapses). Annu Rev Neurosci 2012; 35: 417–443.
Santoro MR, Bray SM, Warren ST. Molecular mechanisms of fragile X syndrome: a twenty-year perspective. Annu Rev Pathol 2012; 7: 219–245.
Bramham CR, Sarvey JM. Endogenous activation of mu and delta-1 opioid receptors is required for long-term potentiation induction in the lateral perforant path: dependence on GABAergic inhibition. J Neurosci 1996; 16: 8123–8131.
Breindl A, Derrick BE, Rodriguez SB, Martinez JL Jr. Opioid receptor-dependent long-term potentiation at the lateral perforant path-CA3 synapse in rat hippocampus. Brain Res Bull 1994; 33: 17–24.
Wadell PM, Hagerman RJ, Hessl DR. Fragile X syndrome: psychiatric manifestations, assessment and emerging therapies. Curr Psychiatry Rev 2013; 9: 53–58.
Yu TW, Berry-Kravis E. Autism and fragile X syndrome. Semin Neurol 2014; 34: 258–265.
Trieu BH, Kramar EA, Cox CD, Jia Y, Wang W, Gall CM et al. Pronounced differences in signal processing and synaptic plasticity between piriform-hippocampal network stages: a prominent role for adenosine. J Physiol 2015; 593: 2889–2907.
Christie BR, Abraham WC. Differential regulation of paired-pulse plasticity following LTP in the dentate gyrus. Neuroreport 1994; 5: 385–388.
Seese RR, Babayan AH, Katz AM, Cox CD, Lauterborn JC, Lynch G et al. LTP induction translocates cortactin at distant synapses in wild-type but not Fmr1 knock-out mice. J Neurosci 2012; 32: 7403–7413.
Kahlfuss S, Simma N, Mankiewicz J, Bose T, Lowinus T, Klein-Hessling S et al. Immunosuppression by N-methyl-D-aspartate receptor antagonists is mediated through inhibition of Kv1.3 and KCa3.1 channels in T cells. Mol Cell Biol 2014; 34: 820–831.
Larsen RS, Corlew RJ, Henson MA, Roberts AC, Mishina M, Watanabe M et al. NR3A-containing NMDARs promote neurotransmitter release and spike timing-dependent plasticity. Nat Neurosci 2011; 14: 338–344.
Zhang J, Diamond JS. Subunit- and pathway-specific localization of NMDA receptors and scaffolding proteins at ganglion cell synapses in rat retina. J Neurosci 2009; 29: 4274–4286.
Takahashi H, Arstikaitis P, Prasad T, Bartlett TE, Wang YT, Murphy TH et al. Postsynaptic TrkC and presynaptic PTPsigma function as a bidirectional excitatory synaptic organizing complex. Neuron 2011; 69: 287–303.
Seese RR, Chen LY, Cox CD, Schulz D, Babayan AH, Bunney WE et al. Synaptic abnormalities in the infralimbic cortex of a model of congenital depression. J Neurosci 2013; 33: 13441–13448.
Jung KM, Clapper JR, Fu J, D'Agostino G, Guijarro A, Thongkham D et al. 2-arachidonoylglycerol signaling in forebrain regulates systemic energy metabolism. Cell Metab 2012; 15: 299–310.
Jung KM, Astarita G, Zhu C, Wallace M, Mackie K, Piomelli D. A key role for diacylglycerol lipase-alpha in metabotropic glutamate receptor-dependent endocannabinoid mobilization. Mol Pharmacol 2007; 72: 612–621.
Eadie BD, Cushman J, Kannangara TS, Fanselow MS, Christie BR. NMDA receptor hypofunction in the dentate gyrus and impaired context discrimination in adult Fmr1 knockout mice. Hippocampus 2012; 22: 241–254.
Yun SH, Trommer BL. Fragile X mice: reduced long-term potentiation and N-Methyl-D-Aspartate receptor-mediated neurotransmission in dentate gyrus. J Neurosci Res 2011; 89: 176–182.
Bostrom CA, Majaess NM, Morch K, White E, Eadie BD, Christie BR. Rescue of NMDAR-dependent synaptic plasticity in Fmr1 knock-out mice. Cereb Cortex 2015; 25: 271–279.
Zhang F, Wang LP, Boyden ES, Deisseroth K. Channelrhodopsin-2 and optical control of excitable cells. Nat Methods 2006; 3: 785–792.
Roy DS, Arons A, Mitchell TI, Pignatelli M, Ryan TJ, Tonegawa S. Memory retrieval by activating engram cells in mouse models of early Alzheimer's disease. Nature 2016; 531: 508–512.
Hanse E, Gustafsson B. Long-term potentiation and field EPSPs in the lateral and medial perforant paths in the dentate gyrus in vitro: a comparison. Eur J Neurosci 1992; 4: 1191–1201.
Jia Y, Gall CM, Lynch G. Presynaptic BDNF promotes postsynaptic long-term potentiation in the dorsal striatum. J Neurosci 2010; 30: 14440–14445.
Kim WR, Lee JW, Sun W, Lee SH, Choi JS, Jung MW. Effect of dentate gyrus disruption on remembering what happened where. Front Behav Neurosci 2015; 9: 170.
Wilson DI, Watanabe S, Milner H, Ainge JA. Lateral entorhinal cortex is necessary for associative but not nonassociative recognition memory. Hippocampus 2013; 23: 1280–1290.
Dong S, Allen JA, Farrell M, Roth BL. A chemical-genetic approach for precise spatio-temporal control of cellular signaling. Mol Biosyst 2010; 6: 1376–1380.
Zhu H, Roth BL. Silencing synapses with DREADDs. Neuron 2014; 82: 723–725.
Zhu H, Pleil KE, Urban DJ, Moy SS, Kash TL, Roth BL. Chemogenetic inactivation of ventral hippocampal glutamatergic neurons disrupts consolidation of contextual fear memory. Neuropsychopharmacology 2014; 39: 1880–1892.
Robinson S, Todd TP, Pasternak AR, Luikart BW, Skelton PD, Urban DJ et al. Chemogenetic silencing of neurons in retrosplenial cortex disrupts sensory preconditioning. J Neurosci 2014; 34: 10982–10988.
Lopez AJ, Kramar E, Matheos DP, White AO, Kwapis J, Vogel-Ciernia A et al. Promoter-specific effects of DREADD modulation on hippocampal synaptic plasticity and memory formation. J Neurosci 2016; 36: 3588–3599.
Stachniak TJ, Ghosh A, Sternson SM. Chemogenetic synaptic silencing of neural circuits localizes a hypothalamus—>midbrain pathway for feeding behavior. Neuron 2014; 82: 797–808.
Mahler SV, Vazey EM, Beckley JT, Keistler CR, McGlinchey EM, Kaufling J et al. Designer receptors show role for ventral pallidum input to ventral tegmental area in cocaine seeking. Nat Neurosci 2014; 17: 577–585.
Eldridge MA, Lerchner W, Saunders RC, Kaneko H, Krausz KW, Gonzalez FJ et al. Chemogenetic disconnection of monkey orbitofrontal and rhinal cortex reversibly disrupts reward value. Nat Neurosci 2016; 19: 37–39.
Lex B, Hauber W. Disconnection of the entorhinal cortex and dorsomedial striatum impairs the sensitivity to instrumental contingency degradation. Neuropsychopharmacology 2010; 35: 1788–1796.
Witter MP. Organization of the entorhinal-hippocampal system: a review of current anatomical data. Hippocampus 1993; 3: 33–44.
Colgin LL, Kramar EA, Gall CM, Lynch G. Septal modulation of excitatory transmission in hippocampus. J Neurophysiol 2003; 90: 2358–2366.
Gulyas AI, Cravatt BF, Bracey MH, Dinh TP, Piomelli D, Boscia F et al. Segregation of two endocannabinoid-hydrolyzing enzymes into pre- and postsynaptic compartments in the rat hippocampus, cerebellum and amygdala. Eur J Neurosci 2004; 20: 441–458.
Zhu H, Roth BL. DREADD: a chemogenetic GPCR signaling platform. Int J Neuropsychopharmacol 2014; 18: pyu007.
Sternson SM, Roth BL. Chemogenetic tools to interrogate brain functions. Annu Rev Neurosci 2014; 37: 387–407.
Davachi L, DuBrow S. How the hippocampus preserves order: the role of prediction and context. Trends Cogn Sci 2015; 19: 92–99.
Devito LM, Eichenbaum H. Memory for the order of events in specific sequences: contributions of the hippocampus and medial prefrontal cortex. J Neurosci 2011; 31: 3169–3175.
Manns JR, Howard MW, Eichenbaum H. Gradual changes in hippocampal activity support remembering the order of events. Neuron 2007; 56: 530–540.
Hermann BP, Seidenberg M, Wyler A, Davies K, Christeson J, Moran M et al. The effects of human hippocampal resection on the serial position curve. Cortex 1996; 32: 323–334.
Bowler DM, Limoges E, Mottron L. Different verbal learning strategies in autism spectrum disorder: evidence from the Rey Auditory Verbal Learning Test. J Autism Dev Disord 2009; 39: 910–915.
Ghosh A, Michalon A, Lindemann L, Fontoura P, Santarelli L. Drug discovery for autism spectrum disorder: challenges and opportunities. Nat Rev Drug Discov 2013; 12: 777–790.
Maurin T, Zongaro S, Bardoni B. Fragile X Syndrome: from molecular pathology to therapy. Neurosci Biobehav Rev 2014; 46(Pt 2): 242–255.
Richter JD, Bassell GJ, Klann E. Dysregulation and restoration of translational homeostasis in fragile X syndrome. Nat Rev Neurosci 2015; 16: 595–605.
McNaughton CH, Moon J, Strawderman MS, Maclean KN, Evans J, Strupp BJ. Evidence for social anxiety and impaired social cognition in a mouse model of fragile X syndrome. Behav Neurosci 2008; 122: 293–300.
Santos AR, Kanellopoulos AK, Bagni C. Learning and behavioral deficits associated with the absence of the fragile X mental retardation protein: what a fly and mouse model can teach us. Learn Mem 2014; 21: 543–555.
Saario SM, Laitinen JT. Therapeutic potential of endocannabinoid-hydrolysing enzyme inhibitors. Basic Clin Pharmacol Toxicol 2007; 101: 287–293.
Davis KL, Mohs RC. Enhancement of memory processes in Alzheimer's disease with multiple-dose intravenous physostigmine. Am J Psychiatry 1982; 139: 1421–1424.
Francis PT, Palmer AM, Snape M, Wilcock GK. The cholinergic hypothesis of Alzheimer's disease: a review of progress. J Neurol Neurosurg Psychiatry 1999; 66: 137–147.
Acknowledgments
This research was funded by National Institutes of Health grants NS045260, NS085709 and HD089491 to CMG and GL, and DA-012413 and DA031387 to DP, Department of Defense Multidisciplinary University Research Initiative Grant N00014-101-0072 from the Office of Naval Research to GL; UL1 TR001414 fellowship to BMC, and National Science Foundation fellowship DGE0808392 to CDC.
Author information
Authors and Affiliations
Corresponding authors
Ethics declarations
Conflict of Interest
The authors declare no conflict of interest.
Electronic supplementary material
Rights and permissions
About this article
Cite this article
Wang, W., Cox, B.M., Jia, Y. et al. Treating a novel plasticity defect rescues episodic memory in Fragile X model mice. Mol Psychiatry 23, 1798–1806 (2018). https://doi.org/10.1038/mp.2017.221
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/mp.2017.221
This article is cited by
-
Neurotrophin-3 from the dentate gyrus supports postsynaptic sites of mossy fiber-CA3 synapses and hippocampus-dependent cognitive functions
Molecular Psychiatry (2024)
-
Fmr1-KO mice failure to detect object novelty associates with a post-test decrease of structural and synaptic plasticity upstream of the hippocampus
Scientific Reports (2023)
-
Endocannabinoids at the synapse and beyond: implications for neuropsychiatric disease pathophysiology and treatment
Neuropsychopharmacology (2023)
-
Anandamide and 2-arachidonoylglycerol differentially modulate autistic-like traits in a genetic model of autism based on FMR1 deletion in rats
Neuropsychopharmacology (2023)
-
Increased 2-arachidonoyl-sn-glycerol levels normalize cortical responses to sound and improve behaviors in Fmr1 KO mice
Journal of Neurodevelopmental Disorders (2021)