Antonio Rodríguez-Moreno

Presynaptic kainate receptor facilitation of glutamate release involves protein kinase A in the rat hippocampus

We have explored the mechanisms involved in the facilitation of glutamate release mediated by the activation of kainate receptors in the rat hippocampus using isolated nerve terminal (synaptosome) and slice preparations. In hippocampal nerve terminals, kainate (KA) produced an increase of glutamate release at concentrations of agonist ranging from 10 to 1000 μm. In hippocampal slices, KA at low nanomolar concentrations (20–50 nm) also produced an increase of evoked excitatory postsynaptic currents (eEPSCs) at mossy fibre–CA3 synapses. In both, synaptosomes and slices, the effect of KA was antagonized by CNQX, and persisted after pretreatment with a cocktail of antagonists for other receptors whose activation could potentially have produced facilitation of release. These data indicate that the facilitation of glutamate release observed is mediated by the activation of presynaptic glutamate receptors of the kainate type. Mechanistically, the observed effects of KA appear to be the same in synaptosomal and slice preparations. Thus, the effect of KA on glutamate release and mossy fibre–CA3 synaptic transmission was occluded by the stimulation of adenylyl cyclase by forskolin and suppressed by the inhibition of protein kinase A by H‐89 or Rp‐Br‐cAMP. We conclude that kainate receptors present at presynaptic terminals in the rat hippocampus mediate the facilitation of glutamate release through a mechanism involving the activation of an adenylyl cyclase–second messenger cAMP–protein kinase A signalling cascade.

An in vitro and in vivo study of early deficits in associative learning in transgenic mice that over‐express a mutant form of human APP associated with Alzheimer's disease

Transgenic mice over‐expressing a mutated form of the human amyloid precursor protein (APP, 695 isoform) bearing a mutation associated with Alzheimers disease (V642I, so‐called London mutation, hereafter APPLd2) and wild‐type controls were studied at age periods (3 and 10 months) prior to the overt development of neuritic amyloid plaques. Both 3‐ and 10‐month‐old APPLd2 mice had reflex eyelid responses like those of controls, but only younger mice were able to acquire a classical conditioning of eyelid responses in a trace paradigm. In vitro studies on hippocampal slices showed that 10‐month‐old APPLd2 mice also presented deficits in paired‐pulse facilitation and long‐term potentiation, but presented a normal synaptic activation of CA1 pyramidal cells by the stimulation of Schaffer collaterals. It is proposed that definite functional changes may appear well in advance of noticeable structural alterations in this animal model of Alzheimers disease, and that specific learning tasks could have a relevant diagnostic value.

Kainate receptors with a metabotropic modus operandi.

Kainate receptors (KARs), together with AMPA and NMDA, are typically described as ionotropic glutamate receptors. The functions of KARs have begun to be elucidated only in the last decade. Although some the actions of KARs are classically ionotropic, surprisingly others seem to involve the activation of second-messenger cascades and invoke metabotropic roles for this type of glutamate receptor. In this review, we describe these metabotropic actions of KARs in relation to the putative signalling cascades involved. Although it is still a mystery how KARs activate G proteins to stimulate second-messenger cascades, intriguingly, in very recent studies, specific subunits of KARs have been demonstrated to associate with G proteins. Altogether, the body of evidence supports the hypothesis that, together with the canonical ionotropic operation, KARs expedite long-lasting signalling by novel metabotropic modes of action.

Metabotropic actions of kainate receptors in the CNS

Kainate receptors (KARs), together with NMDA and α‐amino‐3‐hydroxy‐5‐methylisoxazole‐4‐propionate receptors (AMPA), are typically described as ionotropic glutamate receptors. Although ionotropic functions for KARs are beginning to be characterized in multiple brain regions, both, in the pre‐ and post‐synaptic compartments of the synapse, there is accumulating evidence that KARs mediate some of their effects without invoking ion‐fluxes. Thus, since 1998, when the first metabotropic action of KARs was described in the modulation of GABA release in hippocampal interneurons, there have been increasing reports that some of the functions of KARs involve the participation of intracellular signalling cascades and depend on G protein activation. These surprising observations, attesting metabotropic actions of KARs, akin to those usually attributed to seven transmembrane region G protein‐coupled receptors, make the physiological classification and description of glutamate receptors more complex. In the present review, we describe the metabotropic roles of KARs in the CNS and discuss the intriguing properties of this receptor which, structurally shows all the facets of a typical ionotropic receptor, but appears to express a metabotropic remit at some key synapses.

Kainate receptor-mediated presynaptic inhibition converges with presynaptic inhibition mediated by Group II mGluRs and long-term depression at the hippocampal mossy fiber-CA3 synapse

SummaryKainate receptors (KARs) effect depression of glutamate release at hippocampal mossy fiber-CA3 (MF-CA3) synapses by a metabotropic action involving adenylyl cyclase (AC) inhibition, cAMP reduction, and diminished protein kinase A (PKA) activation. Using hippocampal slices, we show here that KAR activation interferes with the depression of glutamate release produced by Group II metabotropic glutamate receptor stimulation and low frequency stimulation (LFS)-induced long-term depression (LTD), also expressed through presynaptic AC/cAMP/PKA at MF-CA3 synapses. The mutual occlusion of depression mediated by presynaptic KARs, Group II mGluR and LFS-induced LTD suggests their mechanistic convergence at the MF-CA3 synapse and thus invokes KARs in synaptic plasticity manifest in LTD.

Presynaptic kainate receptor-mediated facilitation of glutamate release involves Ca2+–calmodulin and PKA in cerebrocortical synaptosomes

We have explored the mechanisms involved in the facilitation of glutamate release mediated by the activation of kainate receptors (KARs) in the cortex using isolated nerve terminals (synaptosomes). Kainate (KA) produced an increase on glutamate release at 100 μM. The effect of KA was antagonized by NBQX (with AMPA receptors blocked by GYKI53655). This facilitation was suppressed by the inhibition of PKA activation by Rp‐Br‐cAMP and H‐89. Moreover, the facilitation of glutamate release mediated by KAR requires the mobilization of intrasynaptosomal Ca2+ stores and the formation of a Ca2+–calmodulin complex. We conclude that KARs present on presynaptic terminals in the neocortex mediate the facilitation of glutamate release through a mechanism involving an increase in cytosolic Ca2+ to activate a Ca2+–calmodulin–AC/cAMP/PKA signaling cascade.

Kainate Receptors Multiple Roles in Neuronal Plasticity

Ionotropic glutamate receptors of the N-methyl-d-aspartate (NMDA)- and AMPA-type, as well as metabotropic glutamate receptors have been extensively invoked in plasticity. Until relatively recently, however, kainate-type receptors (KARs) had been the most elusive to study because of the lack of appropriate pharmacological tools to specifically address their roles. With the development of selective glutamate receptor antagonists, and knockout mice with specific KAR subunits deleted, the functions of KARs in neuromodulation and synaptic transmission, together with their involvement in some types of plasticity, have been extensively probed in the central nervous system. In this review, we summarize the findings related to the roles of KARs in short- and long-term forms of plasticity, primarily in the hippocampus, where KAR function and synaptic plasticity have received avid attention.

Presynaptic kainate receptor-mediated facilitation of glutamate release involves Ca2+ -calmodulin at mossy fiber-CA3 synapses.

J. Neurochem. (2012) 122, 891–899.

Dendritic morphology changes in neurons from the prefrontal cortex, hippocampus and nucleus accumbens in rats after lesion of the thalamic reticular nucleus

Several studies in rodents have shown that dysfunctions of the thalamic reticular nucleus (TRN) result in deficits of sensory gating and attentional processes, two core features of schizophrenia. TRN receives inputs from the prefrontal cortex (PFC) and hippocampal formation, two structures which send excitatory projections to the nucleus accumbens (NAcc) and are interconnected with the basolateral amygdala (BLA). Here we determined whether (and which) changes occurred four weeks after a TRN lesion in the dendritic morphology of pyramidal neurons of layers 3 and 5 of the PFC, neurons of ventral and dorsal hippocampus, BLA, and the medium spiny neurons of the NAcc. Dendritic morphology and characteristics were measured by using Golgi-Cox procedure followed by Sholl analysis. We also evaluated the effects of TRN lesion on exploratory behavior assessed by hole-board test and locomotor activity induced by a novel environment. We found that TRN damage induced a reduction in the exploratory behavior measured by hole-board test with neuronal hypotrophy in PFC (layer 5), CA1 ventral hippocampus and NAcc neurons. Taken together, these data suggest that the behavioral and morphological effects of TRN lesion are, at least partially, mediated by limbic subregions with possible consequences for schizophrenia-related behaviors.

Chronic administration of resveratrol prevents morphological changes in prefrontal cortex and hippocampus of aged rats.

Resveratrol may induce its neuroprotective effects by reducing oxidative damage and chronic inflammation apart from improving vascular function and activating longevity genes, it also has the ability to promote the activity of neurotrophic factors. Morphological changes in dendrites of the pyramidal neurons of the prefrontal cortex (PFC) and hippocampus have been reported in the brain of aging humans, or in humans with neurodegenerative diseases such as Alzheimers disease. These changes are reflected particularly in the decrement of both the dendritic tree and spine density. Here we evaluated the effect of resveratrol on the dendrites of pyramidal neurons of the PFC (Layers 3 and 5), CA1‐ and CA3‐dorsal hippocampus (DH) as well as CA1‐ventral hippocampus, dentate gyrus (DG), and medium spiny neurons of the nucleus accumbens of aged rats. 18‐month‐old rats were administered resveratrol (20 mg/kg, orally) daily for 60 days. Dendritic morphology was studied by the Golgi‐Cox stain procedure, followed by Sholl analysis on 20‐month‐old rats. In all resveratrol‐treated rats, a significant increase in dendritic length and spine density in pyramidal neurons of the PFC, CA1, and CA3 of DH was observed. Interestingly, the enhancement in dendritic length was close to the soma in pyramidal neurons of the PFC, whereas in neurons of the DH and DG, the increase in dendritic length was further from the soma. Our results suggest that resveratrol induces modifications of dendritic morphology in the PFC, DH, and DG. These changes may explain the therapeutic effect of resveratrol in aging and in Alzheimers disease. Synapse, 2016.