Physiological impact of CB1 receptor expression by hippocampal GABAergic interneurons

A subset of hippocampal GABAergic neurons, which are cholecystokinin-positive, highly express cannabinoid type 1 (CB1) receptors. Activation of these receptors inhibits GABA release and thereby limits inhibitory control. While genetic deletion of CB1 receptors from GABAergic neurons led to behavioural alterations and neuroinflammatory reactions, it remained unclear whether these changes in the knockout animals were a direct consequence of the enhanced transmitter release or reflected developmental deficits. The hippocampus is vital for the generation of spatial, declarative and working memory. Here, we addressed the question how CB1 receptors in GABAergic neurons influence hippocampal function. Patch clamp and field potential recordings in mice devoid of CB1 receptors in GABAergic neurons revealed an enhanced frequency and faster kinetics of spontaneous inhibitory postsynaptic currents in CA1 pyramidal neurons while tonic inhibition, paired-pulse facilitation and long-term potentiation in the hippocampus were not affected. Evaluation of cognitive functions demonstrated impaired acquisition of spatial memory and deficits in novel object recognition and partner recognition in the knockout mice, while working memory and spatial memory remained intact. The density of GABAergic neurons was also similar in knockout mice and their littermates, which argues against global deficits in hippocampal development. Together, these results suggest that CB1 receptors in GABAergic neurons influence specific aspects of neuronal excitability and hippocampal learning.

[1]  G. Perea,et al.  Endocannabinoids Induce Lateral Long-Term Potentiation of Transmitter Release by Stimulation of Gliotransmission. , 2015, Cerebral cortex.

[2]  T. Freund,et al.  GABAergic interneurons are the targets of cannabinoid actions in the human hippocampus , 2000, Neuroscience.

[3]  Peter Somogyi,et al.  Cell Type-Specific Long-Term Plasticity at Glutamatergic Synapses onto Hippocampal Interneurons Expressing either Parvalbumin or CB1 Cannabinoid Receptor , 2010, The Journal of Neuroscience.

[4]  I. Galve-Roperh,et al.  Endocannabinoids via CB1 receptors act as neurogenic niche cues during cortical development , 2012, Philosophical Transactions of the Royal Society B: Biological Sciences.

[5]  J. Haller,et al.  Stress-induced social avoidance A new model of stress-induced anxiety? , 2002, Physiology & Behavior.

[6]  I. Balderas,et al.  Consolidation and reconsolidation of object recognition memory , 2015, Behavioural Brain Research.

[7]  Malcolm W. Brown,et al.  Recognition memory: Material, processes, and substrates , 2010, Hippocampus.

[8]  Christopher Jarrold,et al.  Working Memory and the Hippocampus , 2011, Journal of Cognitive Neuroscience.

[9]  T. Freund,et al.  Role of endogenous cannabinoids in synaptic signaling. , 2003, Physiological reviews.

[10]  Klaus Obermayer,et al.  A Hippocampal Signature of Perceptual Learning in Object Recognition , 2015, Journal of Cognitive Neuroscience.

[11]  N. Hájos,et al.  Presynaptic Calcium Channel Inhibition Underlies CB1 Cannabinoid Receptor-Mediated Suppression of GABA Release , 2014, The Journal of Neuroscience.

[12]  K. Henke.  A model for memory systems based on processing modes rather than consciousness , 2010, Nature Reviews Neuroscience.

[13]  A. Takeda,et al.  Blockade of intracellular Zn2+ signaling in the dentate gyrus erases recognition memory via impairment of maintained LTP , 2015, Hippocampus.

[14]  N. Hájos,et al.  Anatomically heterogeneous populations of CB1 cannabinoid receptor‐expressing interneurons in the CA3 region of the hippocampus show homogeneous input–output characteristics , 2014, Hippocampus.

[15]  J. Seamans,et al.  Selective Roles for Hippocampal, Prefrontal Cortical, and Ventral Striatal Circuits in Radial-Arm Maze Tasks With or Without a Delay , 1997, The Journal of Neuroscience.

[16]  P. Castillo,et al.  Endocannabinoid Signaling and Synaptic Function , 2012, Neuron.

[17]  Attila Losonczy,et al.  Persistently active cannabinoid receptors mute a subpopulation of hippocampal interneurons. , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[18]  F. Gage,et al.  New neurons and new memories: how does adult hippocampal neurogenesis affect learning and memory? , 2010, Nature Reviews Neuroscience.

[19]  M. Korte,et al.  Cannabinoid CB1 Receptor Calibrates Excitatory Synaptic Balance in the Mouse Hippocampus , 2015, The Journal of Neuroscience.

[20]  P. Piazza,et al.  Bimodal control of stimulated food intake by the endocannabinoid system , 2010, Nature Neuroscience.

[21]  Gong-Wu Wang,et al.  Disconnection of the hippocampal–prefrontal cortical circuits impairs spatial working memory performance in rats , 2006, Behavioural Brain Research.

[22]  C. Wotjak,et al.  Cannabinoid receptor type 1 receptors on GABAergic vs. glutamatergic neurons differentially gate sex‐dependent social interest in mice , 2014, The European journal of neuroscience.

[23]  M. Roberto,et al.  Endocannabinoids restrict hippocampal long-term potentiation via CB1 , 2005, Neuropharmacology.

[24]  I. Módy,et al.  Cannabinoids inhibit hippocampal GABAergic transmission and network oscillations , 2000, The European journal of neuroscience.

[25]  C. Compagnucci,et al.  Type-1 (CB1) Cannabinoid Receptor Promotes Neuronal Differentiation and Maturation of Neural Stem Cells , 2013, PloS one.

[26]  J. Trotter,et al.  The NG2 Protein Is Not Required for Glutamatergic Neuron-NG2 Cell Synaptic Signaling. , 2016, Cerebral cortex.

[27]  Alfonso Araque,et al.  Astrocytes in endocannabinoid signalling , 2014, Philosophical Transactions of the Royal Society B: Biological Sciences.

[28]  I. Soltesz,et al.  Distinct Endocannabinoid Control of GABA Release at Perisomatic and Dendritic Synapses in the Hippocampus , 2010, The Journal of Neuroscience.

[29]  A. Gaffuri,et al.  Type-1 Cannabinoid Receptor Signaling in Neuronal Development , 2012, Pharmacology.

[30]  A. Yonelinas.  The hippocampus supports high-resolution binding in the service of perception, working memory and long-term memory , 2013, Behavioural Brain Research.

[31]  Beat Lutz,et al.  The Endocannabinoid System Controls Key Epileptogenic Circuits in the Hippocampus , 2006, Neuron.

[32]  T. Teyler.  Long-term potentiation and memory. , 1987, International journal of neurology.

[33]  A. Yonelinas,et al.  Recollection and familiarity: Examining controversial assumptions and new directions , 2010, Hippocampus.

[34]  I. Soltesz,et al.  Postsynaptic origin of CB1‐dependent tonic inhibition of GABA release at cholecystokinin‐positive basket cell to pyramidal cell synapses in the CA1 region of the rat hippocampus , 2007, The Journal of physiology.

[35]  I. Galve-Roperh,et al.  Cannabinoid receptor signaling in progenitor/stem cell proliferation and differentiation. , 2013, Progress in lipid research.

[36]  Y. Ben-Ari,et al.  Altering cannabinoid signaling during development disrupts neuronal activity. , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[37]  J. Sweatt.  Hippocampal function in cognition , 2004, Psychopharmacology.

[38]  R. Jabs,et al.  Expression of the γ2-Subunit Distinguishes Synaptic and Extrasynaptic GABAA Receptors in NG2 Cells of the Hippocampus , 2013, The Journal of Neuroscience.

[39]  Joel L. Voss,et al.  Hippocampal contribution to implicit configuration memory expressed via eye movements during scene exploration , 2015, Hippocampus.

[40]  M. Parmentier,et al.  Enhanced long-term potentiation in mice lacking cannabinoid CB1 receptors , 1999, Neuroscience.

[41]  H. Eichenbaum,et al.  Interplay of Hippocampus and Prefrontal Cortex in Memory , 2013, Current Biology.

[42]  D. O'Leary,et al.  Requirement of cannabinoid CB1 receptors in cortical pyramidal neurons for appropriate development of corticothalamic and thalamocortical projections , 2010, The European journal of neuroscience.

[43]  G. Marsicano,et al.  Conditional cannabinoid receptor type 1 mutants reveal neuron subpopulation-specific effects on behavioral and neuroendocrine stress responses , 2008, Psychoneuroendocrinology.

[44]  Kuei Yuan Tseng,et al.  CB1 cannabinoid receptor stimulation during adolescence impairs the maturation of GABA function in the adult rat prefrontal cortex , 2014, Molecular Psychiatry.

[45]  Michela Matteoli,et al.  Hardwiring the Brain: Endocannabinoids Shape Neuronal Connectivity , 2007, Science.

[46]  A. Hoffman,et al.  Mechanisms of Cannabinoid Inhibition of GABAASynaptic Transmission in the Hippocampus , 2000, The Journal of Neuroscience.

[47]  N. Burgess,et al.  The hippocampus and memory: insights from spatial processing , 2008, Nature Reviews Neuroscience.

[48]  Beat Lutz,et al.  Role of CB1 cannabinoid receptors on GABAergic neurons in brain aging , 2011, Proceedings of the National Academy of Sciences.

[49]  A. Brusco,et al.  Prenatal exposure to the CB1 and CB2 cannabinoid receptor agonist WIN 55,212‐2 alters migration of early‐born glutamatergic neurons and GABAergic interneurons in the rat cerebral cortex , 2014, Journal of neurochemistry.

[50]  A. Bilkei-Gorzo,et al.  Dynorphins regulate the strength of social memory , 2014, Neuropharmacology.

[51]  A. Shetty,et al.  Aging in the rat hippocampus is associated with widespread reductions in the number of glutamate decarboxylase‐67 positive interneurons but not interneuron degeneration , 2004, Journal of neurochemistry.

[52]  T. Sakurai,et al.  Hypocretin/Orexin Neurons Contribute to Hippocampus-Dependent Social Memory and Synaptic Plasticity in Mice , 2013, The Journal of Neuroscience.

[53]  A. Romano,et al.  Nuclear factor kappa B-dependent Zif268 expression in hippocampus is required for recognition memory in mice , 2015, Neurobiology of Learning and Memory.

[54]  R. D'Hooge,et al.  Applications of the Morris water maze in the study of learning and memory , 2001, Brain Research Reviews.

[55]  G. Marsicano,et al.  Expression of the cannabinoid receptor CB1 in distinct neuronal subpopulations in the adult mouse forebrain , 1999, The European journal of neuroscience.

[56]  K. Mackie,et al.  Cannabinoid CB1 receptors are localized primarily on cholecystokinin-containing GABAergic interneurons in the rat hippocampal formation , 1999, Neuroscience.

[57]  V. Pickel,et al.  Decreased parvalbumin immunoreactivity in the cortex and striatum of mice lacking the CB1 receptor , 2011, Synapse.

[58]  R. Nicoll,et al.  Endocannabinoid Signaling in the Brain , 2002, Science.