Lack of the metabotropic glutamate receptor subtype 7 selectively impairs short-term working memory but not long-term memory. Behav Brain Res
ABSTRACT Metabotropic glutamate receptors (mGluRs), and in particular the mGluR group III receptors (subtypes 4, 6, 7, 8) are known to play a role in synaptic plasticity and learning. Here, we report the effect of mGluR7 gene ablation in different learning paradigms. In the acoustic startle response (ASR), no differences were seen between knockout (KO) mice and wildtype (WT) littermates in parameters including prepulse inhibition and habituation. In an open field test, no differences were seen between genotypes in motor activity, exploratory behaviour, and fearful behaviour. In a T-maze reinforced alternation working memory (WM) task, again no difference was seen between groups. However, when increasing the demands on working-memory in a 4-arm and 8-arm maze task, KO mice committed more WM errors than WT littermates thereby uncovering a highly significant difference between the two groups that persisted every day for the whole 9 days of the experiment. In a 4-arm maze with 2 arms baited, KO and wildtype mice committed the same number of LTM errors, whereas KOs committed more WM errors. Altogether, these findings suggest that a lack of mGluR7 mainly impairs short-term working but not long-term memory performance while having no effect on sensorimotor processing, non-associative learning, motor activity and spatial orientation. The effects on WM are task-dependent and become apparent in more complex but not simple learning tasks. We discuss how mGluR7 could influence WM.
Full-textDOI: · Available from: Christian Hölscher, Jan 13, 2014
- SourceAvailable from: Lucyna Pomierny-Chamioło
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- "Group Subtype Main signaling pathway Expression in mammalian CSN Knock-out phenotype I m G l u 1 R G q/11 PLC s Human: cerebellum N thalamus N frontal cortex, hippocampus N striatum, pons N cortical cortex and caudate/putamen (Toyohara et al., 2013) Rodents: olfactory bulb, thalamus, hippocampus (excluding the CA1 region), lateral septum, superior colliculus and cerebellum N dorsal striatum, hypothalamus, pallidum, ventral midbrain, cerebral cortex N amygdala, medial septum, nucleus accumbens and brainstem, pons (Ferraguti & Shigemoto, 2006; Olive, 2009) Monkey: cerebellum N thalamus N striatum, hippocampus, cerebral cortex and olfactory bulb N pons– medulla (Hostetler et al., 2011; Fujinaga et al., 2012) -Reduction of LTD amplitude, deficit of translation initiation due to deficiency in mGluR stimulation caused by reduced mGluR-Homer interaction (Gubellini et al., 2001; Ronesi & Huber, 2008) -Impaired motor coordination and spatial learning deficits; impaired cerebellar LTD and hippocampal mossy fiber LTP (Conquet et al., 1994) -Reduced hippocampal LTP and impairment in context-specific associative learning (Aiba et al., 1994) -Deficit in prepulse inhibition (Brody et al., 2003) -Loss of adaptability of horizontal eye movements (Shutoh et al., 2002) mGlu 5 R G q/11 PLC s Human: anterior cingulate cortex, prefrontal cortex, temporal cortex, caudate nucleus, putamen, ventral striatum, hippocampus, thalamus N cerebellum, pons (Kagedal et al., 2013) Rodent: olfactory nuclei, olfactory tubercle, dorsal striatum, nucleus accumbens, lateral septum, hippocampal formation (CA1–CA3, dentate gyrus), and inferior colliculus N cerebral cortex (expression more dense in superficial than in deeper layers), amygdala, caudal portions of the spinal trigeminal nucleus N hypothalamus, medial septum, ventral midbrain, pons, medulla, cerebellum (low level or absent) (Ferraguti & Shigemoto, 2006; Olive, 2009) Monkey: caudate, cingulate gyrus, thalamus N temporal cortex N cerebellum (Andersson et al., 2013) -Antidepressant-like phenotype (Li et al., 2006) -Absence of reinforcing and locomotor stimulant effects of cocaine (Chiamulera et al., 2001) -Absence of cocaine-induced increasing the AMPA/NMDA receptor excitatory post-synaptic current amplitude ratio in dopaminergic cells of the ventral tegmental area (Bird et al., 2010) -Less ethanol intake in conditioned place preference (Bird et al., 2008) II mGlu 2 R G i/o AC i Human: orbitofrontal cortex N parietal cortex N anterior cingulate N prefrontal cortex N hippocampus, occipital cortex N nucleus accumbens N caudate nucleus N cerebellum thalamus (Ghose et al., 2008) Rodent: cerebellar cortex, olfactory bulb (mitral cells), olfactory nucleus, entorhinal and parasubicular cortices N olfactory bulb (granule cells), neocortex, cingulate, retrosplenial and subicular cortices and the granule cells of the dentate gyrus, lateral, basolateral and basomedial amygdaloid nuclei, medial mammillary nucleus and anterior, ventrolateral, midline, intralaminar and centromedian parafascicular thalamic nuclei (Ohishi et al., 1998; Ferraguti & Shigemoto, 2006) -Initial hyperactivity in novel environment (Morishima et al., 2005) -Loss of mGluR 2/3 agonist-induced reduction of spontaneous and phencyclidine-induced hyperlocomotion (Spooren et al., 2000) -Antidepressant-like phenotype (Morishima et al., 2005) -Impairment of hippocampal mossy fiber LTD (Yokoi et al., 1996) -Enhanced locomotor sensitization to cocaine and conditioned place preference; greater dopamine and glutamate release in response to cocaine (Morishima et al., 2005) mGlu 3 R G i/o AC i Human: neocortex (Brodmann area 7), caudate putamen, substantia nigra N hippocampus, amygdala, thalamus (Harrison et al., 2008) Rodent: cerebral cortex, dentate gyrus molecular layer, olfactory tubercle, nucleus of olfactory tract N hippocampus, striatum, thalamus, substantia nigra N cerebellum (Harrison et al., 2008) -Loss of anxiolytic effect of an mGluR2/3 agonist (Linden et al., 2005) -Increased hippocampal c-Fos expression at baseline (Linden et al., 2006) -Loss of mGluR2/3 agonist-induced neuroprotection by astrocytes against NMDA excitotoxicity (Corti et al., 2007a) -Increased level of hippocampal mGluR2 and NR2A mRNAs, and reduced GLAST and GLT-1 (Lyon et al., 2008) III mGlu 4 R G i/o AC i Human: anterior cingulate cortex, prefrontal cortex, temporal cortex, caudate nucleus, putamen, ventral striatum, hippocampus, thalamus N cerebellum, pons (Wu et al., 1998) Rodents: cerebellum, olfactory bulb N olfactory tubercle, cerebral cortex, lateral septum, striatum, basal ganglia, hippocampus (Corti et al., 2002; Pilc et al., 2008) -Impaired sensorimotor performance (Pekhletski et al., 1996) -Lack of motor stimulatory effect of ethanol (Blednov et al., 2004) -Increased anxiety in the open field and elevated zero maze as well as impaired sensorimotor function in young male mice (Davis et al., 2012) -Reduced anxiety in the open field and elevated zero maze as well as enhanced rotarod performance in young female mice (Davis et al., 2012) mGlu 6 R G i/o AC i Human: retina (Valerio et al., 2001) Rodent: retina (Valerio et al., 2001; Pilc et al., 2008) Monkey: retina (Vardi et al., 2002) -Impaired ability to detect visual contrasts and to respond rapidly to changes in light intensity in mice (Iwakabe et al., 1997; Nakanishi et al., 1998) -Five mGluR6 point mutations (P46L, G58R, G150S, C522Y, and E781K) lead to congenital stationary night blindness type 1 in humans (Beqollari et al., 2009) -Suppression of short-latency to light onset and revelation of long-latency ON responses in mice (Renteria et al., 2006) mGlu 7 R G i/o AC i Human: cerebral cortex, hippocampal formation and cerebellum cerebral N thalamus N the caudate– putamen (mRNA)(Makoff et al., 1996; Wu et al., 1998) Rodent: olfactory bulb, septum, locus coeruleus N olfactory tubercle, neocortex, CA1–CA3 regions of hippocampus, dentate gyrus, piriform cortex, striatum, nucleus accumbens, claustrum, hypothalamus, thalamus (Ferraguti & Shigemoto, 2006) -Antidepressant and anxiolytic-like phenotype (Cryan et al., 2003) -Dysregulation of the HPA-axis and increase hippocampal BDNF protein level (Mitsukawa et al., 2006) -Increased seizure susceptibility (Sansig et al., 2001) -increased alcohol consumption (Gyetvai et al., 2011) -Impairment of short-term working memory (Holscher et al., 2004) mGlu 8 R G i/o AC i Human caudate nucleus, putamen, parahippocampal gyrus N hippocampus N nucleus accumbens, locus coeruleus N hypothalamus N thalamus N substantia nigra N spinal cord (Wu et al., 1998; Robbins et al., 2007) Rodent olfactory bulbs, anterior olfactory nucleus, piriform cortex, entorhinal cortex, pontine nuclei, lateral reticular nucleus of the medulla oblongata (Pilc et al., 2008) -Increased anxiety (Duvoisin et al., 2005) -Deficits in learning tasks (Gerlai et al., 2002) BDNF—Brain Derived Neurotropic Factor; G i/o AC i —G i/o protein–coupled receptor that inhibits adenylyl cyclase activity; G q/11 PLC s-G q/11 protein–coupled receptor that stimulates phospholipase C; GLAST—glutamate/aspartate transporter (EAAT1); GLT-1—glutamate/aspartate transporter (EAAT2); HPA —hypothalamic-pituitary-adrenal axis; LTD —long-term depression; LTP —long-term potentiation. greatest density of mGlu 1 receptors (Ferraguti & Shigemoto, 2006; Olive, 2009; Fujinaga et al., 2012). 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ABSTRACT: Glutamatergic excitatory transmission is implicated in physiological and pathological conditions like learning, memory, neuronal plasticity and emotions, while glutamatergic abnormalities are reported in numerous neurological and psychiatric disorders, including neurodegenerative diseases, epilepsy, stroke, traumatic brain injury, depression, anxiety, schizophrenia and pain. Also, several lines of evidence have accumulated indicating a pivotal role for glutamatergic neurotransmission in mediating addictive behaviors. Among the proteins regulating glutamatergic transmission, the metabotropic glutamate receptors (mGluR) are being developed as pharmacological targets for treating many neuropsychiatric disorders, including drug addiction. In this review we describe the molecular structure of mGluRs and their distribution, physiology and pharmacology in the central nervous system, as well as their use as targets in preclinical studies of drug addiction.Pharmacology [?] Therapeutics 12/2013; 142(3). DOI:10.1016/j.pharmthera.2013.12.012 · 7.75 Impact Factor
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- "ed synaptic plasticity also requires activation of group I mGlus ( Popkirov and Manahan - Vaughan , 2011 ) as do theta - gamma oscillations in the hippocampus ( Bikbaev et al . , 2008 ) . Intriguingly , group II and II mGlu receptors , that are critically required for LTD but not LTP , appear to be highly important for long - term spatial memory ( Holscher et al . , 2004 , 2005 ; Altinbilek and Manahan - Vaughan , 2009 ) that is linked to motivation ( Lyon et al . , 2011b ) . Given recent reports of a role for LTD in spatial context learning ( Kemp and Manahan - Vaughan , 2007 ) , these observations should open up new avenues in the development of strategies to address brain diseases that relate to defi"
ABSTRACT: Storage and processing of information at the synaptic level is enabled by the ability of synapses to persistently alter their efficacy. This phenomenon, known as synaptic plasticity, is believed to underlie multiple forms of long-term memory in the mammalian brain. It has become apparent that the metabotropic glutamate (mGlu) receptor is critically required for both persistent forms of memory and persistent synaptic plasticity. Persistent forms of synaptic plasticity comprise long-term potentiation (LTP) and long-term depression (LTD) that last at least for 4 h but can be followed in vivo for days and weeks. These types of plasticity are believed to be analogous to forms of memory that persist for similar time-spans. The mGlu receptors are delineated into three distinct groups based on their G-protein coupling and agonist affinity and also exercise distinct roles in the way they regulate both long-term plasticity and long-term hippocampus-dependent memory. Here, the mGlu receptors will be reviewed both in general, and in the particular context of their role in persistent (>4 h) forms of hippocampus-dependent synaptic plasticity and memory, as well as forms of synaptic plasticity that have been shown to be directly regulated by memory events. This article is part of a Special Issue entitled 'mGluR'.Neuropharmacology 06/2012; 66. DOI:10.1016/j.neuropharm.2012.06.005 · 4.82 Impact Factor
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- "Taken together, these data suggest that mGluR7 knockout mice have impaired reference memory acquisition and spatial working memory, and a dysfunctional glutamatergic signalling particularly in the hippocampus and prefrontal cortex where mGluR7 are expressed has been hypothesized to cause these deficits. Performances in complex working memory tasks such as 8-arm radial maze task were also impaired in mGluR7 knockout mice . Interestingly, the working memory deficit was associated with an increased hippocampal theta power while performing the task, which was suggested to reflect a lack of modulation of local inhibition, in turn leading to decreased neuronal firing threshold and altered spike timing . "
ABSTRACT: Glutamate is the main excitatory neurotransmitter in the central nervous system (CNS) and is a major player in complex brain functions. Glutamatergic transmission is primarily mediated by ionotropic glutamate receptors, which include NMDA, AMPA and kainate receptors. However, glutamate exerts modulatory actions through a family of metabotropic G-protein-coupled glutamate receptors (mGluRs). Dysfunctions of glutamatergic neurotransmission have been implicated in the etiology of several diseases. Therefore, pharmacological modulation of ionotropic glutamate receptors has been widely investigated as a potential therapeutic strategy for the treatment of several disorders associated with glutamatergic dysfunction. However, blockade of ionotropic glutamate receptors might be accompanied by severe side effects due to their vital role in many important physiological functions. A different strategy aimed at pharmacologically interfering with mGluR function has recently gained interest. Many subtype selective agonists and antagonists have been identified and widely used in preclinical studies as an attempt to elucidate the role of specific mGluRs subtypes in glutamatergic transmission. These studies have allowed linkage between specific subtypes and various physiological functions and more importantly to pathological states. This article reviews the currently available knowledge regarding the therapeutic potential of targeting mGluRs in the treatment of several CNS disorders, including schizophrenia, addiction, major depressive disorder and anxiety, Fragile X Syndrome, Parkinson's disease, Alzheimer's disease and pain.DNA research: an international journal for rapid publication of reports on genes and genomes 03/2012; 10(1):12-48. DOI:10.2174/157015912799362805 · 2.35 Impact Factor