Cholecystokinin inhibits endocannabinoid-sensitive hippocampal IPSPs and stimulates others
Introduction
Cholecystokinin (CCK) is the most abundant neuropeptide in the central nervous system (CNS) (Beinfeld et al., 1981), and is highly expressed in a subset of GABAergic interneurons of the hippocampus (Dockray, 1976, Innis et al., 1979). CCK is released mainly as CCK8-S, and also, at low concentrations, as CCK4 or CCK8-U (Rehfeld, 1985). CCK-releasing interneurons in the hippocampus all contain GABA (Somogyi et al., 1984) and most express cannabinoid receptors (Katona et al., 1999, Freund, 2003). The axons of many CCK-positive neurons terminate on hippocampal pyramidal cell somata in stratum (s.) pyramidale and their proximal dendrites of s. radiatum (Freund and Buzsaki, 1996). Central (CCK2) receptors are widely distributed throughout the CNS (Zarbin et al., 1983) and modulate stress, anxiety and exploratory behaviors (Singh et al., 1991, Matto et al., 1997).
Physiological actions of CCK in the hippocampus have been attributed to CCK2 (Bohme et al., 1988, Carlberg et al., 1992); however CCK2 has not yet been localized to specific neuronal sub-types in hippocampus or elsewhere (cf. Mercer et al., 2000). Reports of CCK's physiological actions are inconsistent, with both excitation (Dodd and Kelly, 1979, Boden and Hill, 1988, Bohme et al., 1988, Shinohara and Kawasaki, 1997), and inhibition (MacVicar et al., 1987, Perez de la Mora et al., 1993) of pyramidal cells having been demonstrated. CCK may inhibit pyramidal cells indirectly (Perez de la Mora et al., 1993) by increasing GABA release from interneurons (Miller and Lupica, 1994, Miller et al., 1997, Ferraro et al., 1999, Deng and Lei, 2006). Some discrepancies have been ascribed to dosage and application method, or to different effects of CCK on interneurons and pyramidal cells (Miller et al., 1997). The close association of CCK only with certain interneurons suggests that some of the reported discrepancies in CCK effects might reflect its actions on distinct classes of interneurons (Freund and Buzsaki, 1996).
The primary aim of the present study was to test the hypothesis that CCK affects different interneurons in different ways, by using pharmacological tools to identify classes of interneuron outputs. Focusing on the rat hippocampal CA1 region, we show that CCK2 activation mediates the effects of CCK agonists, and directly stimulates persistent spontaneous (sIPSP) activity in control conditions. However, other sIPSPs are initiated in the presence of carbachol (CCh) and CCK2 activation inhibits the CCh-sIPSPs. This does not represent opposing effects of CCK and CCh on the same interneurons however, because the IPSPs in these two different conditions are sharply distinguished by their sensitivity to endocannabinoids, calcium channel antagonists, muscarinic agonists, and GABAB agonists. We also report the first evidence that endogenously released CCK suppresses CCh-sIPSPs. Our data are consistent with the hypothesis that the disparate actions of CCK on inhibition reflect opposite effects on distinct interneuron classes. Indeed, the pharmacological profiles of these two classes of sIPSPs correspond well with the properties of PV- and CCK-expressing interneurons as described in the literature (see Table 1). We suggest that CCK could thereby link the actions of different interneurons, a hypothesis that may have implications for understanding some of the oscillatory electrical activity in hippocampus (Buzsaki, 2002, Baraban and Tallent, 2004, Freund, 2003, Whittington and Traub, 2003).
Section snippets
Materials and methods
Male Sprague–Dawley rats, 5–7 weeks old (Charles River Laboratories) were deeply anaesthetized with halothane and decapitated in accordance with the guidelines set forth by the Institutional Animal Care and Use Committee of the University of Maryland, School of Medicine. The brain was rapidly removed from the skull and both hippocampi dissected free. Transverse hippocampal sections (400 μm thick) were cut on a Vibratome (Series 1000, Technical Products International). Slices were kept in a
CCK analogs initiate sIPSP activity in control conditions by activating CCK2
We used high resistance microelectrodes for pyramidal cell recording under current clamp conditions because the experiments, involving multiple pharmacological tests on single cells, demanded long-term (>2 hour), stable recording conditions. The advantages of these electrodes - less disruption of cell internal environment and long lasting maintenance of normal cell properties - outweighed the drawback of somewhat noisier recordings. With D-AP5 and NBQX present, the average pyramidal cell
Discussion
Despite the close association of CCK with GABAergic interneurons, prior reports of its actions on synaptic inhibition have not yielded a coherent picture. Our findings can reconcile some of the previous contradictory results, and in addition, suggest that CCK may mediate interactions between different classes of interneurons. The main observation was that CCK has opposite effects on two kinds of pyramidal cell sIPSPs, suppressing the endocannabinoid-sensitive, CCh-sIPSPs, but inducing the
Acknowledgements
We thank Scott Thompson, Celine Dinocourt, David Edwards, and Carlos Lafourcade for their comments on a draft of this manuscript. This work was supported by NIH grants NS30219 and DA140625 to B.E.A. M.A.K. was supported in part by the Cellular and Integrative Neurosciences Training Grant (NS07275) to the University of Maryland.
References (62)
- et al.
Interneuronal neuropeptides – endogenous regulators of neuronal excitability
Trends in Neurosciences
(2004) - et al.
The distribution of cholecystokinin immunoreactivity in the central nervous system of the rat as determined by radioimmunoassay
Brain Research
(1981) - et al.
A novel network of multipolar bursting interneurons generates theta frequency oscillations in neocortex
Neuron
(2003) - et al.
Effects of cholecystokinin and pentagastrin on rat hippocampal neurons maintained in vitro
Neuropeptides
(1988) - et al.
Excitatory effects of cholecystokinin in rat hippocampal slices inhibits potassium-evoked cholecystokinin release, a possible mechanism contributing to the spatial memory defects produced by cannabinoids
Brain Research
(1988) Theta oscillations in the hippocampus
Neuron
(2002)- et al.
Synaptic effects of identified interneurons innervating both interneurons and pyramidal cells in the rat hippocampus
Neuroscience
(1997) Interneuron diversity series: rhythm and mood in perisomatic inhibition
Trends in Neurosciences
(2003)- et al.
Local and diffuse synaptic actions of GABA in the hippocampus
Neuron
(1993) - et al.
Inhibition of synaptic transmission in the hippocampus by cholecystokinin (CCK) and its antagonism by a CCK analog (CCK-27-33)
Brain Research
(1987)
Muscarinic facilitation of the occurrence of depolarization-induced suppression of inhibition in rat hippocampus
Neuroscience
The effects of cholecystokinin A and B receptor antagonists on exploratory behaviour in the elevated zero-maze in rat
Neuropharmacology
Direct visualization of cholecystokinin subtype2 receptors in rat central nervous system using anti-peptide antibodies
Neuroscience Letters
A simple chamber for recording from submerged brain slices
Journal of Neuroscience Methods
Distinct properties of carbachol- and DHPG- induced network oscillations in hippocampal slices
Neuropharmacology
Either N- or P-type calcium channels mediate GABA release at distinct hippocampal inhibitory synapses
Neuron
Electrophysiological changes in rat hippocampal pyramidal neurons produced by cholecystokinin octapeptide
Neuroscience
Immunohistochemical distribution of cannabinoid CB1 receptors in the rat central nervous system
Neuroscience
Interneuron Diversity series: Inhibitory interneurons and network oscillations in vitro
Trends in Neurosciences
Presynaptic specificity of endocannabinoid signaling in the hippocampus
Neuron
Retrograde signaling in depolarization-induced suppression of inhibition in rat hippocampal CA1 cells
Journal of Physiology (London)
The synaptic basis of GABAA(slow)
Journal of Neuroscience
Autoradiographic localization of cholecystokinin A and B receptors in rat brain using [125I]d-Tyr25 (Nle28,31)-CCK 25-33S
European Journal of Neuroscience
Cholinergic induction of theta-frequency oscillations in hippocampal inhibitory interneurons and pacing of pyramidal cell firing
Journal of Neuroscience
Cholinergic modulation of hippocampal cells and circuits
Journal of Physiology (London)
Synchronization of neuronal activity in hippocampus by individual GABAergic interneurons
Nature
Cholecystokinin depolarizes rat thalamic reticular neurons by suppressing a K+ conductance
Journal of Neurophysiology
Bi-directional modulation of GABAergic transmission by cholecystokinin in hippocampal dentate gyrus granule cells of juvenile rats
Journal of Physiology
Immunochemical evidence of cholecystokinin-like peptides in the brain
Nature
Excitation of CA1 pyramidal neurones of the hippocampus by the tetra- and octapeptide C-terminal fragments of cholecystokinin
Journal of Physiology
Quantal analysis of inhibitory synaptic transmission in the dentate gyrus of rat hippocampal slices: a patch-clamp study
Journal of Physiology
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