Lines of investigation
Since 1990, we have been working on the structure and function of glutamate receptors, the most important signaling system in the brain. We analyzed one important characteristic of neurotransmitter receptors: desensitization (Neuron 1992); defined its structural determinants (Neuron, 1998a) and the allosteric mechanism involved (Neuron, 2001), intrinsic to the NMDA type of glutamate receptors. We were first describing the existence in central neurons of functional kainate receptors (KARs), demonstrating that KAR proteins form functional receptor channels in hippocampal neurons (PNAS 1993) and providing the tool for further studies, the drug 2-3-benzodiazepine, GYKI 53655, which allowed their pharmacological isolation (Neuron 1995a). This finding paved the way for progress in the field. Our group was among the pioneers in applying single-cell RT-PCR (Neuron, 1995b) to study these receptors. We described their fundamental role in controlling neuronal tissue excitability and epileptogenesis (Neuron, 1997). Also demonstrated that KARs have a dual mechanism of signalling: as ion channels and triggering a second messenger cascade, involving a G-protein (Neuron, 1998b; PNAS, 2000). This and subsequent work (Neuron, 2003; EMBO J., 2007; J. Neurosci., 2013) put forward the new concept that ion channel-forming receptors are also able to signal through a G-protein, opening new vistas on the functional mechanisms of ionotropic glutamate receptors and provided strong evidence supporting their role in the maturation of neural circuits during development (J Neurosci., 2013). We have also identified some members of the KAR interactome (Neuron, 2009; J. Neurosci, 2013, J. Neurosci, 2015a) and provided fundaments on the structure of non-canonical signalling as we identified the Go alpha subunit and GluK1 subunit as natural partners for this activity.
All these data led us to conclude that KARs influence neuronal excitability and information transfer in the brain (see our 2013 Neuron review). However, the role played by KARs in brain physiology and even clearer in pathology is still much more poorly understood than that of other glutamate receptors. Our recent discovery that overexpressing one of the KAR high affinity subunits, GluK4, reproduces autism traits (J. Neurosci., 2015b) represents one of the most compelling demonstrations of their involvement in mental disease; but also that slightly altering the gain of particular synapses may significantly impact the behavior.
These results prompted us to propose the general objective of our current project: to get insights into the role played by KARs in the pathophysiology of brain diseases, in particular those related with the alteration of the mood. We have hypothesized that an excess of function of KARs, in particular GluK4, drastically affects circuit formation determining the functional state of particular brain nuclei and/or neuronal circuits, which further result in altered brain performance and therefore altered behavior. Indeed, in the past few years, the findings from genetics and brain-imaging studies support the idea that the mental disorders overlap. In summary, in the next few years we will try to bridge the gap between cellular and molecular properties of brain processes and behaviour in the hope that understanding of brain diseases requires the definition of the molecular, synaptic and cellular alterations underpinning the behavioural features that define the disease.
- Unbalanced dendritic inhibition of CA1 neurons drives spatial-memory deficits in the Ts2Cje Down syndrome model Valbuena S, García Á, Mazier W, Paternain AV, Lerma J Nature Communications 2019 10:4991 https://doi.org/10.1038/s41467-019-13004-9
- Increased Grik4 Gene Dosage Causes Imbalanced Circuit Output and Human Disease-Related Behaviors Arora V, Pecoraro V, Aller MI, Roman C, Paternain AV, Lerma J Cell Rep 2018 23(13):3827 https://doi.org/10.1016/j.celrep.2018.05.086
- Non-canonical Signaling, the Hidden Life of Ligand-Gated Ion Channels Valbuena S, Lerma J Neuron 2016 92(2):316 https://doi.org/10.1016/j.neuron.2016.10.016
- Synaptic Targeting of Kainate Receptors Palacios-Filardo J, Aller MI, Lerma J Cereb Cortex 2016 26(4):1464 https://doi.org/10.1093/cercor/bhu244
- Increased Dosage of High-Affinity Kainate Receptor Gene grik4 Alters Synaptic Transmission and Reproduces Autism Spectrum Disorders Features Aller MI, Pecoraro V, Paternain AV, Canals S, Lerma J J Neurosci 2015 35(40):13619 https://doi.org/10.1523/JNEUROSCI.2217-15.2015