Activity-Dependent Reconnection of Adult-Born Dentate Granule Cells in a Mouse Model of Frontotemporal Dementia

Frontotemporal dementia (FTD) is characterized by neuronal loss in the frontal and temporal lobes of the brain. Here, we provide the first evidence of striking morphological alterations in dentate granule cells (DGCs) of FTD patients and in a mouse model of the disease, Tau VLW mice. Taking advantage of the fact that the hippocampal dentate gyrus (DG) gives rise to newborn DGCs throughout the lifetime in rodents, we used RGB retroviruses to study the temporary course of these alterations in newborn DGCs of female Tau VLW mice. In addition, retroviruses that encode either PSD95:GFP or Syn:GFP revealed striking alterations in the afferent and efferent connectivity of newborn Tau VLW DGCs, and monosynaptic retrograde rabies virus tracing showed that these cells are disconnected from distal brain regions and local sources of excitatory innervation. However, the same cells exhibited a predominance of local inhibitory innervation. Accordingly, the expression of presynaptic and postsynaptic markers of inhibitory synapses was markedly increased in the DG of Tau VLW mice and FTD patients. Moreover, an increased number of neuropeptide Y-positive interneurons in the DG correlated with a reduced number of activated egr-1 + DGCs in Tau VLW mice. Finally, we tested the therapeutic potential of environmental enrichment and chemoactivation to reverse these alterations in mice. Both strategies reversed the morphological alterations of newborn DGCs and partially restored their connectivity in a mouse model of the disease. Moreover, our data point to remarkable morphological similarities between the DGCs of Tau VLW mice and FTD patients.Fil: Terreros Roncal, Julia. Universidad Autónoma de Madrid. Facultad de Ciencias; EspañaFil: Flor García, Miguel. Universidad Autónoma de Madrid. Facultad de Ciencias; EspañaFil: Moreno Jiménez, Elena P.. Universidad Autónoma de Madrid. Facultad de Ciencias; EspañaFil: Pallas Bazarra, Noemí. Universidad Autónoma de Madrid. Facultad de Ciencias; EspañaFil: Rábano, Alberto. No especifíca;Fil: Sah, Nirnath. National Institutes of Health; Estados UnidosFil: Van Praag, Henriette. National Institutes of Health; Estados UnidosFil: Giacomini, Damiana Paula. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones Bioquímicas de Buenos Aires. Fundación Instituto Leloir. Instituto de Investigaciones Bioquímicas de Buenos Aires; ArgentinaFil: Schinder, Alejandro Fabián. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones Bioquímicas de Buenos Aires. Fundación Instituto Leloir. Instituto de Investigaciones Bioquímicas de Buenos Aires; ArgentinaFil: Ávila, Jesús. Universidad Autónoma de Madrid. Facultad de Ciencias; EspañaFil: Llorens Martín, Maria. Universidad Autónoma de Madrid. Facultad de Ciencias; Españ

Transition in subicular burst firing neurons from epileptiform activity to suppressed state by feedforward inhibition

The subiculum, a para-hippocampal structure positioned between the cornu ammonis 1 subfield and the entorhinal cortex, has been implicated in temporal lobe epilepsy in human patients and in animal models of epilepsy. The structure is characterized by the presence of a significant population of burst firing neurons that has been shown previously to lead epileptiform activity locally. Phase transitions in epileptiform activity in neurons following a prolonged challenge with an epileptogenic stimulus has been shown in other brain structures, but not in the subiculum. Considering the importance of the subicular burst firing neurons in the propagation of epileptiform activity to the entorhinal cortex, we have explored the phenomenon of phase transitions in the burst firing neurons of the subiculum in an in vitro rat brain slice model of epileptogenesis. Whole-cell patch-clamp and extracellular field recordings revealed a distinct phenomenon in the subiculum wherein an early hyperexcitable state was followed by a late suppressed state upon continuous perfusion with epileptogenic 4-aminopyridine and magnesium-free medium. The suppressed state was characterized by inhibitory post-synaptic potentials in pyramidal excitatory neurons and bursting activity in local fast-spiking interneurons at a frequency of 0.1-0.8Hz. The inhibitory post-synaptic potentials were mediated by GABA(A) receptors that coincided with excitatory synaptic inputs to attenuate action potential discharge. These inhibitory post-synaptic potentials ceased following a cut between the cornu ammonis 1 and subiculum. The suppression of epileptiform activity in the subiculum thus represents a homeostatic response towards the induced hyperexcitability. Our results suggest the importance of feedforward inhibition in exerting this homeostatic control

Tonic current through GABAA receptors and hyperpolarization-activated cyclic nucleotide-gated channels modulate resonance properties of rat subicular pyramidal neurons

The subiculum, considered to be the output structure of the hippocampus, modulates information flow from the hippocampus to various cortical and sub-cortical areas such as the nucleus accumbens, lateral septal region, thalamus, nucleus gelatinosus, medial nucleus and mammillary nuclei. Tonic inhibitory current plays an important role in neuronal physiology and pathophysiology by modulating the electrophysiological properties of neurons. While the alterations of various electrical properties due to tonic inhibition have been studied in neurons from different regions, its influence on intrinsic subthreshold resonance in pyramidal excitatory neurons expressing hyperpolarization-activated cyclic nucleotide-gated (HCN) channels is not known. Using pharmacological agents, we show the involvement of alpha 5 beta gamma GABA(A) receptors in the picrotoxin-sensitive tonic current in subicular pyramidal neurons. We further investigated the contribution of tonic conductance in regulating subthreshold electrophysiological properties using current clamp and dynamic clamp experiments. We demonstrate that tonic GABAergic inhibition can actively modulate subthreshold properties, including resonance due to HCN channels, which can potentially alter the response dynamics of subicular pyramidal neurons in an oscillating neuronal network

Topoisomerase 3β knockout mice show transcriptional and behavioural impairments associated with neurogenesis and synaptic plasticity

Topoisomerase 3β (Top3β) solves topological stress in DNA or RNA metabolism and its mutations are linked to mental disorders. Here, the authors describe transcriptional and behavioural impairments in Top3β-knockout mice and show that these are linked to impaired neurogenesis and synaptic plasticity