Abstract
Cannabinoids impair hippocampus-dependent memory in both humans and animals, but the network mechanisms responsible for this effect are unknown. Here we show that the cannabinoids Δ9-tetrahydrocannabinol and CP55940 decreased the power of theta, gamma and ripple oscillations in the hippocampus of head-restrained and freely moving rats. These effects were blocked by a CB1 antagonist. The decrease in theta power correlated with memory impairment in a hippocampus-dependent task. By simultaneously recording from large populations of single units, we found that CP55940 severely disrupted the temporal coordination of cell assemblies in short time windows (<100 ms) yet only marginally affected population firing rates of pyramidal cells and interneurons. The decreased power of local field potential oscillations correlated with reduced temporal synchrony but not with firing rate changes. We hypothesize that reduced spike timing coordination and the associated impairment of physiological oscillations are responsible for cannabinoid-induced memory deficits.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 12 print issues and online access
$209.00 per year
only $17.42 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
Freund, T.F., Katona, I. & Piomelli, D. Role of endogenous cannabinoids in synaptic signaling. Physiol. Rev. 83, 1017–1066 (2003).
Ameri, A. The effects of cannabinoids on the brain. Prog. Neurobiol. 58, 315–348 (1999).
Ilan, A.B., Smith, M.E. & Gevins, A. Effects of marijuana on neurophysiological signals of working and episodic memory. Psychopharmacology (Berl.) 176, 214–222 (2004).
Curran, H.V., Brignell, C., Fletcher, S., Middleton, P. & Henry, J. Cognitive and subjective dose-response effects of acute oral delta 9-tetrahydrocannabinol (THC) in infrequent cannabis users. Psychopharmacology (Berl.) 164, 61–70 (2002).
Miller, L.L. & Branconnier, R.J. Cannabis: effects on memory and the cholinergic limbic system. Psychol. Bull. 93, 441–456 (1983).
Squire, L.R., Stark, C.E. & Clark, R.E. The medial temporal lobe. Annu. Rev. Neurosci. 27, 279–306 (2004).
Lichtman, A.H. & Martin, B.R. Delta 9-tetrahydrocannabinol impairs spatial memory through a cannabinoid receptor mechanism. Psychopharmacology (Berl.) 126, 125–131 (1996).
Lichtman, A.H., Dimen, K.R. & Martin, B.R. Systemic or intrahippocampal cannabinoid administration impairs spatial memory in rats. Psychopharmacology (Berl.) 119, 282–290 (1995).
Hampson, R.E. & Deadwyler, S.A. Role of cannabinoid receptors in memory storage. Neurobiol. Dis. 5, 474–482 (1998).
Buonamici, M., Young, G.A. & Khazan, N. Effects of acute delta 9-THC administration on EEG and EEG power spectra in the rat. Neuropharmacology 21, 825–829 (1982).
Constoe, P.F., Jones, B.C. & Chin, L. Delta-9-tetrahydrocannabinol, EEG and behavior:the importance of adaptation to the testing milieu. Pharmacol. Biochem. Behav. 3, 173–177 (1975).
Willinsky, M.D., Loizzo, A. & Longo, V.G. EEG spectral analysis for the evaluation of the central effects of delta6-tetrahydrocannabinol in rabbits. Psychopharmacologia 41, 123–126 (1975).
Hajos, N. et al. Cannabinoids inhibit hippocampal GABAergic transmission and network oscillations. Eur. J. Neurosci. 12, 3239–3249 (2000).
Buzsáki, G., Traub, R.D. & Pedley, T. The cellular synaptic generation of EEG. in Current Practice of Clinical Encephalography (eds. J.S. Ebersole and T.A. Pedley) 1–11 (Lippincott-Williams and Wilkins, Philadelphia, 2003).
Siapas, A.G., Lubenov, E.V. & Wilson, M.A. Prefrontal phase locking to hippocampal theta oscillations. Neuron 46, 141–151 (2005).
Lee, H., Simpson, G.V., Logothetis, N.K. & Rainer, G. Phase locking of single neuron activity to theta oscillations during working memory in monkey extrastriate visual cortex. Neuron 45, 147–156 (2005).
Hasselmo, M.E., Bodelon, C. & Wyble, B.P. A proposed function for hippocampal theta rhythm: separate phases of encoding and retrieval enhance reversal of prior learning. Neural Comput. 14, 793–817 (2002).
Buzsaki, G. The hippocampo-neocortical dialogue. Cereb. Cortex 6, 81–92 (1996).
Kudrimoti, H.S., Barnes, C.A. & McNaughton, B.L. Reactivation of hippocampal cell assemblies: effects of behavioral state, experience and EEG dynamics. J. Neurosci. 19, 4090–4101 (1999).
Chrobak, J.J. & Buzsaki, G. High-frequency oscillations in the output networks of the hippocampal-entorhinal axis of the freely behaving rat. J. Neurosci. 16, 3056–3066 (1996).
Csicsvari, J., Hirase, H., Mamiya, A. & Buzsaki, G. Ensemble patterns of hippocampal CA3-CA1 neurons during sharp wave-associated population events. Neuron 28, 585–594 (2000).
Nunez, P.L. et al. EEG coherency. I: Statistics, reference electrode, volume conduction, Laplacians, cortical imaging, and interpretation at multiple scales. Electroencephalogr. Clin. Neurophysiol. 103, 499–515 (1997).
Destexhe, A., Rudolph, M. & Pare, D. The high-conductance state of neocortical neurons in vivo. Nat. Rev. Neurosci. 4, 739–751 (2003).
Hampson, R.E. & Deadwyler, S.A. Cannabinoids reveal the necessity of hippocampal neural encoding for short-term memory in rats. J. Neurosci. 20, 8932–8942 (2000).
Lisman, J.E. Bursts as a unit of neural information: making unreliable synapses reliable. Trends Neurosci. 20, 38–43 (1997).
Harris, K.D., Hirase, H., Leinekugel, X., Henze, D.A. & Buzsaki, G. Temporal interaction between single spikes and complex spike bursts in hippocampal pyramidal cells. Neuron 32, 141–149 (2001).
Freund, T.F. & Buzsaki, G. Interneurons of the hippocampus. Hippocampus. 6, 347–470 (1996).
Robson, P. Therapeutic aspects of cannabis and cannabinoids. Br. J. Psychiatry. 178, 107–115 (2001).
Pisanu, A., Acquas, E., Fenu, S. & Di Chiara, G. Modulation of Δ9-THC-induced increase of cortical and hippocampal acetylcholine release by μ opioid and D1 dopamine receptors. Neuropharmacology 50, 661–670 (2006).
Tzavara, E.T., Wade, M. & Nomikos, G.G. Biphasic effects of cannabinoids on acetylcholine release in the hippocampus: site and mechanism of action. J. Neurosci. 23, 9374–9384 (2003).
Egashira, N. et al. Involvement of 5-hydroxytryptamine neuronal system in Δ9-tetrahydrocannabinol-induced impairment of spatial memory. Eur. J. Pharmacol. 445, 221–229 (2002).
Bland, B.H. The physiology and pharmacology of hippocampal formation theta rhythms. Prog. Neurobiol. 26, 1–54 (1986).
Behrens, C.J., van den Boom, L.P., de, H.L., Friedman, A. & Heinemann, U. Induction of sharp wave-ripple complexes in vitro and reorganization of hippocampal networks. Nat. Neurosci. 8, 1560–1567 (2005).
Klausberger, T. et al. Complementary roles of cholecystokinin- and parvalbumin-expressing GABAergic neurons in hippocampal network oscillations. J. Neurosci. 25, 9782–9793 (2005).
Csicsvari, J., Jamieson, B., Wise, K.D. & Buzsaki, G. Mechanisms of gamma oscillations in the hippocampus of the behaving rat. Neuron. 37, 311–322 (2003).
Fisahn, A., Pike, F.G., Buhl, E.H. & Paulsen, O. Cholinergic induction of network oscillations at 40 Hz in the hippocampus in vitro. Nature. 394, 186–189 (1998).
Buzsaki, G. Theta oscillations in the hippocampus. Neuron. 33, 325–340 (2002).
Kawamura, Y. et al. The CB1 cannabinoid receptor is the major cannabinoid receptor at excitatory presynaptic sites in the hippocampus and cerebellum. J. Neurosci. 26, 2991–3001 (2006).
Takahashi, K.A. & Castillo, P.E. The CB1 cannabinoid receptor mediates glutamatergic synaptic suppression in the hippocampus. Neuroscience 139, 795–802 (2006).
Katona, I. et al. Molecular composition of the endocannabinoid system at glutamatergic synapses. J. Neurosci. 26, 5628–5637 (2006).
Hoffman, A.F., Riegel, A.C. & Lupica, C.R. Functional localization of cannabinoid receptors and endogenous cannabinoid production in distinct neuron populations of the hippocampus. Eur. J. Neurosci. 18, 524–534 (2003).
Traub, R.D., Whittington, M.A., Stanford, I.M. & Jefferys, J.G. A mechanism for generation of long-range synchronous fast oscillations in the cortex. Nature 383, 621–624 (1996).
Givens, B.S. & Olton, D.S. Cholinergic and GABAergic modulation of medial septal area: effect on working memory. Behav. Neurosci. 104, 849–855 (1990).
Mizumori, S.J., Perez, G.M., Alvarado, M.C., Barnes, C.A. & McNaughton, B.L. Reversible inactivation of the medial septum differentially affects two forms of learning in rats. Brain Res. 528, 12–20 (1990).
Olpe, H.-R., Glatt, A. & Bencze, W. Electrophysiological manifestations of supraspinal actions of baclofen. Brain Res. Bull. 5, 507–511 (1980).
Konig, P., Engel, A.K. & Singer, W. Integrator or coincidence detector? The role of the cortical neuron revisited. Trends Neurosci. 19, 130–137 (1996).
Monory, K. et al. The endocannabinoid system controls key epileptogenic circuits in the hippocampus. Neuron 51, 455–466 (2006).
Marsicano, G. et al. CB1 cannabinoid receptors and on-demand defense against excitotoxicity. Science 302, 84–88 (2003).
Bernard, C. et al. Altering cannabinoid signaling during development disrupts neuronal activity. Proc. Natl. Acad. Sci. USA 102, 9388–9393 (2005).
Hazan, L., Zugaro, M. & Buzsaki, G. Klusters, NeuroScope, NDManager: a free software suite for neurophysiological data processing and visualization. J. Neurosci. Methods 155, 207–216 (2006).
Acknowledgements
We thank C. Geisler, K.D. Harris, H. Hirase, A. Sirota and M. Zugaro for their help with data analysis and A. Amarasingham, S.A. Deadwyler, K. Diba and O.J. Manzoni for comments on earlier versions of this manuscript. Supported by grants from the NIH (G.B.: NS34994, NS43157, MH54671; B.L.M.: NS20331) and the Human Science Program Organization and the European Molecular Biology Organization (D.R.).
Author information
Authors and Affiliations
Contributions
D.R. conducted the recordings in head-restrained, anesthetized and freely moving (n= 3) rats and did most of the data analysis. S.M.M. conducted recordings in freely moving rats (n= 2) and designed the covariance analysis test. P.E.R.-O. participated in the recordings of two freely moving rats. A.T. conducted and B.L.M. supervised the Δ9-THC experiments. G.B. supervised the project and cowrote the manuscript with D.R. and S.M.M.
Corresponding author
Ethics declarations
Competing interests
The authors declare no competing financial interests.
Supplementary information
Supplementary Fig. 1
The CB1 receptor antagonist SR141716A (1.5 mg kg−1) did not significantly affect network properties or firing patterns of single neurons. (PDF 6318 kb)
Supplementary Fig. 2
Parallel recording and clustering of unit activity in the CA1 pyramidal layer by an 8-shank, 64-site silicon probe. (PDF 2116 kb)
Supplementary Fig. 3
Effect of CP55940 on interspike intervals distribution (ISI) of hippocampal CA1 cells. (PDF 45 kb)
Supplementary Fig. 4
Cannabinoid-induced alteration of firing patterns of hippocampal cells. (PDF 148 kb)
Rights and permissions
About this article
Cite this article
Robbe, D., Montgomery, S., Thome, A. et al. Cannabinoids reveal importance of spike timing coordination in hippocampal function. Nat Neurosci 9, 1526–1533 (2006). https://doi.org/10.1038/nn1801
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/nn1801
This article is cited by
-
Endogenous cannabinoids in the piriform cortex tune olfactory perception
Nature Communications (2024)
-
Endocannabinoids at the synapse and beyond: implications for neuropsychiatric disease pathophysiology and treatment
Neuropsychopharmacology (2023)
-
Hippocampal circuit dysfunction in psychosis
Translational Psychiatry (2022)
-
Increased 2-arachidonoyl-sn-glycerol levels normalize cortical responses to sound and improve behaviors in Fmr1 KO mice
Journal of Neurodevelopmental Disorders (2021)
-
An emergent neural coactivity code for dynamic memory
Nature Neuroscience (2021)