Biology subjects

Metodieva, V. D.

Publications and source records attributed to Metodieva, V. D..

5 recordsLinked to original sources

bioRxiv2025

Calbindin-containing CA1 pyramidal cells support cognitive flexibility in spatial task in mice

The hippocampus, and particularly the dorsal CA1, is essential for spatial memory consolidation through sharp-wave ripple events (SWRs) that enable the transfer of information to cortical areas. Within the dorsal CA1, distinct pyramidal cell sub-populations of the deep and superficial layer may play distinct roles in the processing and updating of spatial information. Using a Cre-dependent mouseline, we were able to precisely target the superficial, Calbindin (CALB1+) PCs of the CA1. This allowed us to gain a deeper understanding of the connectivity of CALB1+ CA1 PCs to their SWR-propagating excitatory output partners within the Subiculum (SUB), the burst-firing SUB PCs and their functional relevance in spatial memory consolidation and recall. Retrograde rabies tracing revealed heterogeneous innervation of the VGlut2+ bursting PCs by both CA1 PC sub-layers, and showed that the majority of presynaptic inputs are located in the superficial CA1 PC layer. We were able to observe that this anatomically confirmed connection between CALB1+ CA1 PCs and both SUB PC subtypes is able to induce spiking more reliably in burst- than regular-firing SUB PCs. CNO-induced inhibition in a Barnes Maze task revealed that the experimental group showed reduced cognitive flexibility and were slower to adapt to re-location of the goal when CALB1+ CA1 PCs were inhibited during the recall (test), while both groups behaved similarly when consolidation was manipulated (training). Inhibition did not impact overall learning, strategy development or locomotor control. This suggests that CALB1+ CA1 PCs preferentially connect to bursting SUB PCs, and support cognitive flexibility needed to adapt to a changing environment, adding further proof to the functional relevance of laminar segregation of the CA1 and the hippocampus in spatial memory processes.

neuroscience↗

bioRxiv2024

Sub-type specific connectivity between CA3 pyramidal neurons may underlie their sequential activation during sharp waves

The CA3 region of the hippocampus is the major site of sharp wave initiation, and a brain region crucially involved in learning and memory. Highly recurrent connectivity within its excitatory network is thought to underlie processes involved in memory formation. Recent work has indicated that distinct subpopulations of pyramidal neurons within this region may contribute differently to network activity, including sharp waves, in CA3. Exactly how these contributions may arise is not yet known. Here, we disentangle the local connectivity between two distinct CA3 cell types: thorny and athorny pyramidal cells. We find an asymmetry in the connectivity between these two populations, with athorny cells receiving strong input from both athorny and thorny cells. Conversely, the thorny cell population receives very little input from the athorny population. Computational modeling suggests that this connectivity scheme may determine the sequential activation of these cell types during large network events such as sharp waves.

neuroscience↗

bioRxiv2024

Disruption of autism-associated Pcdh9 gene leads to transcriptional alterations, synapses overgrowth and aberrant excitatory transmission in the CA1

Protocadherins are cell adhesion molecules with crucial role in cell-cell contacts, whose mutations or altered expression have been implicated in multiple brain disorders. In particular, growing evidence links genetic alterations in Protocadherin 9 (PCDH9) gene with Autism Spectrum Disorder (ASD) and Major Depression Disorder (MDD). Furthermore, Pcdh9 deletion induces neuronal defects in the mouse somatosensory cortex, accompanied by sensorimotor and memory impairment. However, the synaptic and molecular mechanisms underlying Pcdh9 physiological function and its involvement in brain pathology remain largely unknown. To this aim, we conducted a comprehensive investigation of PCDH9 role in the mouse hippocampus at the ultrastructural, biochemical, transcriptomic, electrophysiological and network level. We show that PCDH9 mainly localizes at glutamatergic synapses and its expression peaks in the first week after birth, a crucial time window for synaptogenesis. Strikingly, Pcdh9 KO neurons exhibit oversized presynaptic terminal and postsynaptic density (PSD) in the CA1. Synapse overgrowth is sustained by the broad up-regulation of synaptic genes and the dysregulation of key drivers of synapse morphogenesis, as revealed by single-nucleus RNAseq. Synaptic and transcriptional defects are accompanied by increased EPSC frequency and disturbances in the hippocampal network activity of Pcdh9 KO mice. In conclusion, our work indicates that Pcdh9 regulates the morphology and function of excitatory synapses in the CA1, thereby affecting glutamatergic transmission in hippocampal circuitries.

neuroscience↗

bioRxiv2022

Human voltage-gated Na+ and K+ channel properties underlie sustained fast AP signaling

Human cortical pyramidal neurons are large, have extensive dendritic trees, and yet have surprisingly fast input-output properties: rapid subthreshold synaptic membrane potential changes are reliably encoded in timing of action potentials (APs). Here, we tested whether biophysical properties of voltage-gated sodium (Na+) and potassium (K+) currents in human pyramidal neurons can explain their fast input-output properties. Human Na+ and K+ currents exhibited more depolarized voltage-dependence, slower inactivation and faster recovery from inactivation compared with their mouse counterparts. Computational modeling showed that despite lower Na+ channel densities in human neurons, the biophysical properties of Na+ channels resulted in higher channel availability and contributed to fast AP kinetics stability. Finally, human Na+ channel properties also resulted in a larger dynamic range for encoding of subthreshold membrane potential changes. Thus, biophysical adaptations of voltage-gated Na+ and K+ channels enable fast input-output properties of large human pyramidal neurons. One-Sentence SummaryBiophysical properties of Na+ and K+ ion channels enable human neurons to reliably encode fast inputs into output.

neuroscience↗

bioRxiv2022

Structural and functional specializations of human fast spiking neurons support fast cortical signaling

Fast spiking interneurons (FSINs) provide fast inhibition that synchronizes neuronal activity and is critical for cognitive function. Fast synchronization frequencies are evolutionary conserved in the expanded human neocortex, despite larger neuron-to-neuron distances that challenge fast input-output transfer functions of FSINs. Here, we test in human neurons from neurosurgery tissue which mechanistic specializations of human FSINs explain their fast-signaling properties in human cortex. With morphological reconstructions, multi-patch recordings, and biophysical modeling we find that despite three-fold longer dendritic path, human FSINs maintain fast inhibition between connected pyramidal neurons through several mechanisms: stronger synapse strength of excitatory inputs, larger dendrite diameter with reduced complexity, faster AP initiation, and faster and larger inhibitory output, while Na+ current activation/inactivation properties are similar. These adaptations underlie short input-output delays in fast inhibition of human pyramidal neurons through FSINs, explaining how cortical synchronization frequencies are conserved despite expanded and sparse network topology of human cortex. Teaser/one-sentence summarySpecializations of fast spiking human neurons ensure fast signaling in human cortex.

neuroscience↗