Biology subjects

Racca, C.

Publications and source records attributed to Racca, C..

3 recordsLinked to original sources

bioRxiv2024

The correct temporal connectivity of the DG CA3 circuits involved in declarative memory processes depends on Vangl2-dependent planar cell polarity signaling

In the hippocampus, dentate gyrus granule cells connect to CA3 pyramidal cells via their axons, the mossy fibers (Mf). The synaptic terminals of Mfs (Mf boutons, MfBs) form large and complex synapses with thorny excrescences (TE) on the proximal dendrites CA3 pyramidal cells (PCs). MfB/TE synapses have distinctive "detonator" properties due to low intitial release probability and large presynaptic facilitation. The molecular mechanisms shaping the morpho-functional properties of MfB/TE synapses are still poorly understood, though alterations in their morphology are associated with Down syndrome, intellectual disabilities, and Alzheimers disease. Here, we identify the core PCP gene Vangl2 as essential to the morphogenesis and function of MfB/TE synapses. Vangl2 colocalises with the presynaptic heparan sulfate proteoglycan glypican 4 (GPC4) to stabilise the postsynaptic orphan receptor GPR158. Embryonic loss of Vangl2 disrupts the morphology of MfBs and TEs, impairs ultrastructural and molecular organisation, resulting in defective synaptic transmission and plasticity. In adult, the early loss of Vangl2 results in a number of hippocampus-dependent memory deficits including characteristic flexibility of declarative memory, organisation and retention of working/ everyday-like memory. These deficits also lead to abnormal generalisation of memories to salient cues and diminished ability to form detailed contextual memories. Together, these results establish Vangl2 as a key regulator of DG-CA3 connectivity and functions. HighlightsO_LIVangl2 is a key regulator of MfB/TE synapses morphogenesis and plasticity in CA3 C_LIO_LIVangl2-mediated GPC4-GPR158 interaction maintains MfB-TE pre-synaptic morphology and function C_LIO_LIVangl2 deletion affects declarative memory in adult mice C_LIO_LIVangl2 function is necessary for contextual learning and its loss leads toa maladaptive fear memory for salient cues C_LI

neuroscience↗

bioRxiv2021

Ultrastructural readout of in vivo synaptic activity for functional connectomics.

Large-volume ultrastructural mapping approaches yield detailed circuit wiring diagrams but lack an integrated synaptic activity readout which is essential for functional interpretation of the connectome. Here we resolve this limitation by combining functional synaptic labelling in vivo with focused ion-beam scanning electron microscopy (FIBSEM) and machine learning-based segmentation. Our approach generates high-resolution near-isotropic three-dimensional readouts of activated vesicle pools across large populations of individual synapses in a volume of tissue, opening the way for detailed functional connectomics studies. We apply this method to measure presynaptic activity in an ultrastructural context in synapses activated by sensory input in primary visual cortex in awake head-fixed mice, showing that the numbers of recycling and non-recycling vesicles approximate to a lognormal distribution across a large number of synapses. We also demonstrate that neighbouring boutons of the same axon, which share the same spiking activity, can differ greatly in their presynaptic release probability.

neuroscience↗

bioRxiv2021

PV-specific loss of the transcriptional coactivator PGC-1α slows down the evolution of epileptic activity in an acute ictogenic model.

The transcriptional coactivator, PGC-1 (peroxisome proliferator activated receptor gamma coactivator 1), plays a key role coordinating energy requirement within cells. Its importance is reflected in the growing number of psychiatric and neurological conditions that have been associated with reduced PGC-1 levels. In cortical networks, PGC-1 is required for the induction of parvalbumin (PV) expression in interneurons, and PGC-1 deficiency affects synchronous GABAergic release. It is unknown, however, how this affects cortical excitability. We show here that knocking down PGC-1 specifically in the PV-expressing cells (PGC-1PV-/-), blocks the activity-dependent regulation of the synaptic proteins, SYT2 and CPLX1. More surprisingly, this cell-class specific knock-out of PGC-1 appears to have a novel anti-epileptic effect, as assayed in brain slices bathed in 0 Mg2+ media. The rate of pre-ictal discharges developed approximately equivalently in wild-type and PGC-1PV-/- brain slices, but the intensity of these discharges was lower in PGC-1PV-/- slices, as evident from the reduced power in the gamma range and reduced firing rates in both PV interneurons and pyramidal cells during these discharges. Reflecting this reduced intensity in the pre-ictal discharges, the PGC-1PV-/- brain slices experienced many more discharges before transitioning into a seizure-like event. Consequently, there was a large increase in the latency to the first seizure-like event in brain slices lacking PGC-1 in PV interneurons. We conclude that knocking down PGC-1 limits the range of PV interneuron firing, and this slows the pathophysiological escalation during ictogenesis.

neuroscience↗