Biology subjects

Bortolotto, Z. A.

Publications and source records attributed to Bortolotto, Z. A..

5 recordsLinked to original sources

bioRxiv2025

Perirhinal cortex structure and function is dysregulated by corticosteroid treatment

Glucocorticoids play a crucial role in the stress response and in the regulation of circadian function, as well as cognitive, cardiovascular, metabolic and immunological processes. While synthetic glucocorticoids (sGC) are widely used in treating inflammatory disorders, their impact on cognitive functions, which include memory deficits and dysregulation of mood, remains less understood. Here, we demonstrate that chronic treatment with the sGC methylprednisolone (MPL) dysregulates the synaptic proteome and impairs cognitive function in the perirhinal cortex, a region critical for recognition memory and visual perception. Further, we show that synaptic structure and plasticity are altered by MPL treatment, highlighting the mechanisms through which sGCs disrupt mnemonic processing. These results may have broad implications for understanding the cognitive side effects of widely used sGC treatments.

neuroscience↗

bioRxiv2022

Amyloid-β1-42 oligomers enhance mGlu5R-dependent synaptic weakening via NMDAR activation and complement C3aR/C5aR signaling

Synaptic dysfunction, weakening, and loss of synapses are well-correlated with the pathology of Alzheimers disease (AD). Oligomeric amyloid beta (oA{beta}) is considered a major synaptotoxic trigger for AD. Recent studies have implicated hyperactivation of the complement cascade as the driving force for loss of synapses caused by oA{beta}. However, the initial synaptic cues that trigger pathological complement activity remain elusive. Here, we examined a form of synaptic long-term depression (LTD) mediated by metabotropic glutamate receptors (mGluR) which is disrupted in rodent models of AD. Exogenous application of oA{beta} (1-42) to mouse hippocampal slices enhanced the magnitude of mGlu subtype 5 receptor (mGlu5R)-dependent LTD. We found that the enhanced synaptic weakening occurred via both NMDARs and complement C3aR/C5aR signaling. Our findings reveal a mechanistic interaction between mGlu5R, NMDARs, and the complement cascade in synaptic weakening induced by oA{beta}, which could represent an early trigger of synaptic loss and degeneration in AD.

neuroscience↗

bioRxiv2022

Circadian regulation of hippocampal function is disrupted with chronic corticosteroid treatment

Neuropsychiatric disorders such as major depression and schizophrenia are highly prevalent and contribute substantially to disease burden worldwide. Despite this, progress understanding the pathophysiology has remained largely elusive, yet these disorders often exhibit a loss of regulation of biological rhythms, such as sleep/wake cycles and hormonal rhythms. Cushings disease, a condition characterized by chronic corticosteroid (cortisol) hypersecretion is associated with psychiatric and neurocognitive disorders and disruption to the circadian release of cortisol can result in depression and neurocognitive impairment. In rats, we report that circadian regulation of the hippocampal transcriptome integrates crucial functional networks that link corticosteroid-inducible gene regulation to synaptic plasticity regulation via an intra-hippocampal circadian transcriptional clock. During the early active period, when corticosteroid availability is high, CA1 region excitatory and inhibitory post-synaptic currents were augmented along with long-term potentiation. In contrast, chronic corticosteroid exposure disturbed hippocampal function. The hippocampal transcriptome, as well as circadian regulation of synaptic plasticity were ablated, resulting in memory loss during hippocampal-dependent behavior. These findings identify how exposure to elevated levels of corticosteroid, that is often seen in neuropsychiatric illness, results in adverse critical hippocampal function. These data provide novel insights into the molecular mechanisms of neurocognitive disorders and provides evidence for corticosteroid-mediated intervention in disabling mental illnesses.

neuroscience↗

bioRxiv2021

Why do hippocampal mossy cells matter? It depends on the frequency and context.

The discrimination of similar episodes and places, and their representation as distinct memories, depend on a process called pattern separation that relies on the circuitry of the hippocampal dentate gyrus (DG). Mossy cells (MCs) are key neurons in the circuitry, but how they influence DG network dynamics, function, and seizure risk has not been fully elucidated. We found the net impact of MCs was inhibitory at physiological frequencies connected with learning and behaviour, and their absence associated with deficits in pattern separation and spatial memory; at higher frequencies, their net impact was excitatory, and their absence protected against seizures. Thus, MCs influence DG outputs in a highly dynamic manner that varies with frequency and context. One-Sentence SummaryHippocampal mossy cells are required for learning and memory; but their absence protects against seizures.

neuroscience↗

bioRxiv2020

PKA drives an increase in AMPA receptor unitary conductance during LTP in the hippocampus

Long-term potentiation (LTP) at hippocampal CA1 synapses can be expressed by an increase either in the number (N) of AMPA (-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid) receptors or in their single channel conductance ({gamma}). Here we have established how these distinct synaptic processes contribute to the expression of LTP in hippocampal slices obtained from young adult rodents. LTP induced by compressed theta burst stimulation (TBS), with a 10 s inter-episode interval, involved purely an increase in N (LTPN). In contrast, either a spaced TBS, with a 10 min inter-episode interval, or a single TBS, delivered when PKA was activated, resulted in LTP that was associated with a transient increase in {gamma} (LTP{gamma}). This {gamma} increase was due to the insertion of calcium-permeable (CP)-AMPA receptors. Activation of CaMKII was necessary and sufficient for LTPN whilst PKA was additionally required for LTP{gamma}. Thus, two mechanistically distinct forms of LTP co-exist at these synapses.

neuroscience↗