Group II metabotropic glutamate receptors (mGluR2, encoded by Grm2, and mGluR3, encoded by Grm3) are inhibitory autoreceptors that negatively modulate the adenylate cyclase signaling cascade. Within the hippocampus, mGluR2 is believed to play a key role in the induction of long-term depression (LTD) at mossy fiber-CA3 synapses. Here, we used Grm2/3 double knockout (dko) mice to investigate to what extent group II mGluRs are necessary for mossy fiber LTD. Surprisingly, we found that these mice displayed prominent mossy fiber LTD. However, the induction of this form of LTD was sensitive to the external Ca(2+) concentration. Mossy fiber LTD in Grm2/3 dko mice was indistinguishable from that in wild-type mice at 4 mM Ca(2+) , but largely absent at 2 mM external Ca(2+) . Mossy fiber LTD in Grm2/3 dko mice was not blocked by the N-methyl-D-aspartic acid (NMDA) receptor antagonist D-AP5, confirming that the observed response did not reflect NMDA receptor-dependent LTD in contaminating associational-commissural fibers, and enabling us to use the NMDA receptor-mediated EPSC to monitor mossy fiber LTD. Using whole-cell recordings, we demonstrated that LTD of the NMDA receptor-mediated EPSC in Grm2/3 dko mice was not affected by intracellular application of BAPTA and CsF to block postsynaptic Ca(2+) and G-protein-mediated effects. This presynaptic LTD was, however, blocked by the AMPA/kainate receptor antagonist, NBQX. Thus, an activity-dependent, external Ca(2+) concentration-sensitive form of mossy fiber LTD can be induced in Grm2/3 dko mice. Two mGluR antagonists also failed to block mossy fiber LTD under 4 mM conditions in wild-type mice, strengthening the conclusion that group II mGluRs are not obligatory for mossy fiber LTD.
The amygdala is a component of the limbic system that is involved in emotional modulation of behaviour and learning and memory (LeDoux 2000). This structure is central for the acquisition, storage, and expression of conditioned fear memory (Lavond et al. 1993;LeDoux 1996;Davis 1997;McKernan and Shinnick-Gallagher 1997;Rogan et al. 1997;Fendt and Fanselow 1999). Synaptic inputs to the lateral nucleus of the amygdala (LA) from the thalamic medial geniculate nucleus (MGN) and from the auditory cortex are essential for the acquisition of this conditioning (LeDoux et al. 1990a;Romanski and LeDoux 1992;Campeau and Davis 1995). Synaptic transmission in the MGN to LA, is mediated by NMDA and non-NMDA receptors (Li et al. 1996;Weisskopf and LeDoux 1999;Zinebi et al. 2001).Kainate receptors are a family of glutamate receptors that can (postsynaptically) mediate synaptic transmission at some synapses, and (presynaptically) modulate transmitter release (see Rodríguez-Moreno and Sihra 2007a;Jane et al. 2009).In the modulatory context, kainate receptors have been implicated in the modulation of both glutamate and GABA release (see Rodríguez-Moreno and Sihra 2007a,b; Jane Received August 11, 2011; revised manuscript received January 11, 2012; accepted January 11, 2012.Address for correspondence and reprint requests to Dr Antonio Rodríguez-Moreno, Laboratory of Cellular Neuroscience and Plasticity, Department of Physiology, Anatomy and Cellular Biology, University Pablo de Olavide, Ctra. de Utrera, Km. 1, 41013, Sevilla, Spain. E-mail: arodmor@upo.es Abbreviations used: AMPA, a-amino-3-hydroxy-5-methylisoxazole-4-propionate; ATPA, (RS)-2-amino-3(3-hydroxy-5-tert-butylisoxazol-4-yl) propanoic acid; BAPTA, 1,2-bis(o-aminophenoxy)ethane-N,N,N¢, N¢-tetraacetic acid; CV, coefficient of variation; DPCPX, 8-cyclopentyl-1,3-dipropyl-7H-purine-2,6-dione; eEPSCs, evoked excitatory postsynaptic currents; KAR, kainate receptor; LA, lateral nucleus of the amygdala; LTP, long-term potentiation; MGN, medial geniculate nucleus; NBQX, 2,3-Dioxo-6-nitro-1,2,3,4-tetrahydrobenzo[f]quinoxaline-7-sulfonamide; PKA, protein kinase A; PKC, protein kinase C; PPR, pair pulse ratio. MéxicoAbstract Kainate receptors (KARs) have been described as modulators of synaptic transmission at different synapses. However, this role of KARs has not been well characterized in the amygdala. We have explored the effect of kainate receptor activation at the synapse established between fibers originating at medial geniculate nucleus and the principal cells in the lateral amygdala. We have observed an inhibition of evoked excitatory postsynaptic currents (eEPSCs) amplitude after a brief application of KARs agonists KA and ATPA. Paired-pulse recordings showed a clear pair pulse facilitation that was enhanced after KA or ATPA application. When postsynaptic cells were loaded with BAPTA, the depression of eEPSC amplitude observed after the perfusion of KAR agonists was not prevented. We have also observed that the inhibition of the eEPSCs by KARs agonists was prevented by pro...
The use of first and second generation antiepileptic drugs during pregnancy doubles the risk of major congenital malformations and other teratogenic defects. Lacosamide (LCM) is a third-generation antiepileptic drug that interacts with collapsing response mediator protein 2, a protein that has been associated with neurodevelopmental diseases like schizophrenia. The aim of this study was to test the potential teratogenic effects of LCM on developing embryos and its effects on behavioural/histological alterations in adult mice. We administered LCM to pregnant mice, assessing its presence, and that of related compounds, in the mothers’ serum and in embryonic tissues using liquid chromatography coupled to quadrupole/time of flight mass spectrometry detection. Embryo morphology was evaluated, and immunohistochemistry was performed on adult offspring. Behavioural studies were carried out during the first two postnatal weeks and on adult mice. We found a high incidence of embryonic lethality and malformations in mice exposed to LCM during embryonic development. Neonatal mice born to dams treated with LCM during gestation displayed clear psychomotor delay and behavioural and morphological alterations in the prefrontal cortex, hippocampus and amygdala that were associated with behaviours associated with schizophrenia spectrum disorders in adulthood. We conclude that LCM and its metabolites may have teratogenic effects on the developing embryos, reflected in embryonic lethality and malformations, as well as behavioural and histological alterations in adult mice that resemble those presented by patients with schizophrenia.
Excitatory amino acids (glutamate and aspartate) form the mainstay of synaptic transmission in the central nervous system. By the same token, dysfunctional, excitotoxic activity of excitatory amino acids can lead to and/or become instrumental in the progression of a number of neurological and neurodegenerative conditions. Dementia due to Alzheimer's disease (AD) is characterized by extracellular plaques containing amyloid (Aβ peptide) which, together with its disruption of dendritic morphology, affects glutamate (AMPA and NMDA) receptor function to alter glutamatergic transmission. The progressive neurodegeneration of nigrostriatal neurons in Parkinson's disease (PD) may in part arise as a result of overactivity of glutamatergic inputs from the cortex and subthalamic nuclei, presenting the utility of respective antagonism and agonism of stimulatory and inhibitory metabotropic glutamate receptors (mGluR) in PD therapeutics. Huntington's disease (HD) manifests as atrophy of the corpus striatum and cortex, with neurons containing the mutant huntingtin protein perhaps being more susceptible to excitotoxicity from corticostriatal inputs, as reflected by the NMDA receptor loss and interactions of huntingtin with facilitatory Group I mGluR. In schizophrenia, abnormalities in brain (dendritic) development and synaptic plasticity may precipitate the dysfunction of mesolimbic and mesocortical dopaminergic pathways. Here again, aberrations in glutamatergic transmission in the form of NMDA receptor hypofunction may underpin the pathophysiology, with inhibitory mGluR2/3 agonism presenting potential as a therapeutic recourse. Depression is classically attributed to defects in monoaminergic neurotransmission, but long-term changes in dendritic architecture in limbic areas arising from chronic stress may be subject to some influence of glucocorticoids on the glutamatergic input to hypothalamic neurons, and thus affect the hypothalamic/pituitary/adrenal axis and glucocorticoid secretion itself. Epilepsy is the perhaps the most clear example of excitatory transmission gone awry, with the manifest increases in cortical network activity during seizures. Increased glutamatergic activity is instrumental in the pathology, particularly given evidence of the convulsant associations of the kainate type glutamate receptors (KAR). Glutamatergic hyperactivity ultimately leads to excessive Ca2+ influx which can initiate the sequelae of events leading to neuronal damage and death. Thus the Ca2+-permeable NMDA plays a villain's role in excitotoxic culling of motor neurons seen in amytrophic lateral sclerosis (ALS) and indeed the necrotic death of neurons following stroke and cerebral ischaemia. However, it is now increasingly evident that AMPA receptors and KAR, with subunit compositions that permit Ca2+-permeability, may contribute significantly to neurodegenerative chaos when overactivated. Addressing the excitotoxic aspects of excitatory amino acids therefore represents a major challenge in any potential therapeutic intervention with a number of neuropathologies.
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