Temporal lobe epilepsy is associated with hippocampal sclerosis, which is characterized by specific patterns of neuronal loss along hippocampal subfields from the CA1 to CA3/4 areas. Mechanisms underlying such a cell-type specificity remain unknown. We discovered that a subtype ot pyramidal neurons (superficial CA1 cells) are overactive in epileptic rodents (Cid, Marquez-Galera et al., Cell reports 2021). Pseudotemporal analysis of single-cell transcriptional responses reveal separated trajectories from health to epilepsy across cell types and identify a subset of superficial cells undergoing a later stage in neurodegeneration. Our findings indicate that sublayer- and cell-type-specific changes associated with selective CA1 neuronal damage contribute to progression of hippocampal sclerosis.

The proximodistal axis is considered a major organizational principle of the hippocampus. The CA2 region apparently breaks this rule. We discovered that CA2 is organized around the limit of the mossy fibers (Fernandez-Lamo et al., Cell Reports 2019). We found a characteristic molecular gradient within CA2 and marked proximodistal trends of synaptic activity and phase-locked theta and gamma firing.  Our data suggest that the structure and function of CA2 are distributed along the proximodistal hippocampal axis.

Recently, we discovered that deep and superficial CA1 pyramidal cells participate differentially during sharp-wave ripples (Valero et al Nat Neu 2015). Using unsupervised clustering of ripple events, we next disclosed a mechanism determining firing selectivity and its distorsion in the epileptic hippocampus (Valero et al. Neuron 2017). Our data support the idea of a strong regionalization of hippocampal function during basic processes underlying memory consolidation, which is a major research line today in our lab.

Fast ripples are high-frequency oscillations (HFOs) >250 Hz recorded in epileptogenic hippocampal regions. In 2007, we proposed a mechanism by which fast ripples emerge from the pathological desynchronization of neuronal firing (Foffani et al. Neuron 2007). Later in 2010, we developed the out-of-phase firing hypothesis which is now accepted as a major mechanism of pathological HFOs (Ibarz et al. JNeurosc 2010). More recently, using unsupervised learning we disclosed synaptic mechanisms underlying firing selectivity collapse during fast ripples (Valero et al. Neuron 2017).

Generation of population activities such as hippocampal sharp wave ripples and epileptiform discharges follows an emergent dynamics. During my postdoc, we discovered that population discharges are initiated at a threshold level of population firing after recovery from a previous event (de la Prida et al., Neuron 2016). Each population discharge follows an active buildup period when synaptic recruitment and cell firing increase to threshold levels. Firing of densely connected individual hub cells can advance the onset of population events by increasing population firing to suprathreshold values. We proposed a theoretical framework to understand sharp-wave ripple emergence.

The idea of a critical period in hippocampal postnatal development characterized by hyperexcitability was a major research line in the 90s. Giant Depolarizing Potentials (GDPs) represent a prominent population event recorded in vitro and in vivo. During my PhD Thesis, I studied the microcircuit dynamics and cell type contribution to GDPs. They were considered to be generated in the CA3 hippocampal region. I discovered they were actually ubiquitous at any hippocampal area (Menendez de la Prida et al., EJN 1998), and generated by small pieces of tissue provided they contain a minimal network following a threshold dynamics (Menendez de la Prida, J Neurophysiol 1999; Physical Rev. E 1999). Using simultaneous intracellular recordings, I started exploring the contribution of different cell types to the initiation and triggering of population events (Menendez de la Prida and Sanchez-Andres, Neuroscience 2000).