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Lack of the metabotropic glutamate receptor subtype 7 selectively impairs short-term working memory but not long-term memory. Behav Brain Res

Department of Cognitive Neuroscience, University of Tübingen, Auf der Morgenstelle 28, Germany.
Behavioural Brain Research (Impact Factor: 3.39). 11/2004; 154(2):473-81. DOI: 10.1016/j.bbr.2004.03.015
Source: PubMed

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.

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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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