Biology subjects

Orfila, J. E.

Publications and source records attributed to Orfila, J. E..

5 recordsLinked to original sources

bioRxiv2025

Modeling interaction between focal cerebral ischemia and Alzheimer`s Disease Pathology in an APP/PS1 Mouse Model

Ischemic stroke is one of the leading causes of death and disability in the United States and is a known risk factor for Alzheimers Disease (AD) development. One of the characteristics of AD is the accumulation of {beta}-amyloid peptide due to the proteolysis of Amyloid Precursor Protein (APP) by the protein Presenilin 1 (PS1). The study of interaction between ischemia and AD has been limited due to lack of experimental models. The current study describes a novel model utilizing a brief transient ischemia (15 min MCAO) in an AD mouse model to assess mechanistic interaction. Here we investigate the effects of increased {beta}-amyloid peptide on motor coordination, behavioral and cellular memory, when subjected to brief focal ischemia. APP/PS1 or Wt male mice are initially subjected to either a 15-minute MCAO or Sham surgery. Injury volume using MRI is assessed at 3-days using T2 imaging and demonstrates that injury magnitude was not different between Wild-type and APP/PS1 mice. We observed that 15 min MCAO did not cause significant motor deficits in either WT or APP/PS1 mice, as measured by open field and tapered balance beam. Short-term memory was assessed 7 days after recovery from brief MCAO using the contextual fear conditioning task. APP/PS1 mice exhibited intact memory at 3 months of age and Wt mice also having intact memory 7 days after 15 min MCAO. In contrast, APP/PS1 + 15 min MCAO mice exhibited a significant reduction in freezing behavior suggesting impairment in short term memory. Consistent with our contextual fear conditioning, we observed impaired hippocampal long-term potentiation (LTP) in APP/PS1 + 15 min MCAO compared to their sham counterparts. Remarkably, we observed an additive effect of ischemia and AD, with cellular and behavior memory deficits observed in APP/PS1 mice exposed to brief ischemia that does not cause symptoms in WT mice. This study represents an important new model to be study the mechanistic link between ischemia and accelerated AD progression.

neuroscience↗

bioRxiv2025

Endogenous recovery of hippocampal function following global cerebral ischemia in juvenile female mice is influenced by neuroinflammation and circulating sex hormones.

Cardiac arrest-induced global cerebral ischemia (GCI) in childhood often results in learning and memory deficits. We previously demonstrated in a murine cardiac arrest and cardiopulmonary resuscitation (CA/CPR) mouse model that a cellular mechanism of learning and memory, long-term potentiation (LTP), is acutely impaired in the hippocampus of juvenile males, correlating with deficits in memory tasks. However, little is known regarding plasticity impairments in juvenile females. We performed CA/CPR in juvenile (P21-25) female mice and used slice electrophysiology and hippocampal dependent behavior to assess hippocampal function. LTP was and contextual fear were impaired 7-days after GCI and endogenously recovered by 30-days. LTP remained impaired at 30 days in ovariectomized females, suggesting the surge in gonadal sex hormones during puberty mediates endogenous recovery. Unlike juvenile males, recovery of LTP in juvenile females was not associated with BDNF expression. NanoString transcriptional analysis revealed a potential role of neuroinflammatory processes, and specifically Cd68 pathways, in LTP impairment and hormone-dependent recovery. We were able to restore LTP in ovariectomized females with chronic and acute PPT administration, implicating estrogen receptor alpha in recovery mechanisms. This study supports a mechanism of endogenous LTP recovery after GCI in juvenile female mice which differs mechanistically from juvenile males and does not occur in adults of either sex.

neuroscience↗

bioRxiv2023

TRPM2-CaMKII signaling drives excessive GABAergic synaptic inhibition following ischemia

Following an ischemic insult to the brain, there is an acute loss of GABAergic inhibitory synapses and an increase in excitatory/ inhibitory (E/I) imbalance that drives neuronal hyperexcitability. It is unknown whether this E/I imbalance persists at delayed timepoints and contributes to chronic impairments in memory and long-term potentiation (LTP) in the hippocampus following ischemic brain injury. Here, we reveal a shift to reduced E/I ratio in hippocampal CA1 neurons via a persistent increase in postsynaptic GABAA receptor mediated inhibitory responses and clustering days after a global ischemic insult. This enhancement of postsynaptic inhibitory function and clustering required activation of the Ca2+-permeable TRPM2 ion channel and the Ca2+-dependent kinase, CaMKII. Thus, we propose a mechanism in which acute downregulation of GABAA receptors is followed by a strengthening of inhibitory synapses at delayed periods after ischemia. Targeting this mechanism has therapeutic potential to recover hippocampal plasticity and cognitive function post-ischemia. GRAPHICAL ABSTRACT O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=123 SRC="FIGDIR/small/556550v1_ufig1.gif" ALT="Figure 1"> View larger version (26K): org.highwire.dtl.DTLVardef@16ef5f2org.highwire.dtl.DTLVardef@1d51f19org.highwire.dtl.DTLVardef@ecc726org.highwire.dtl.DTLVardef@106cdd0_HPS_FORMAT_FIGEXP M_FIG C_FIG

neuroscience↗

bioRxiv2023

Short-term CaMKII inhibition with tatCN19o does not erase pre-formed memory and is neuroprotective in non-rodents

The Ca2+/calmodulin-dependent protein kinase II (CaMKII) is a central regulator of learning and memory, which poses a problem for targeting it therapeutically. Indeed, our study supports prior conclusions that long-term interference with CaMKII signaling can erase pre-formed memories. By contrast, short-term pharmacological CaMKII inhibition with tatCN19o interfered with learning in mice only mildly and transiently (for less than 1 h) and did not at all reverse pre-formed memories. This was at [≥]500fold of the dose that protected hippocampal neurons from cell death after a highly clinically relevant pig model of transient global cerebral ischemia: ventricular fibrillation followed by advanced life support and electrical defibrillation to induce return of spontaneous circulation. Of additional importance for therapeutic development, cardiovascular safety studies in mice and pig did not indicate any concerns with acute tatCN19o injection. Taken together, even though prolonged interference with CaMKII signaling can erase memory, acute short-term CaMKII inhibition with tatCN19o did not cause such retrograde amnesia that would pose a contraindication for therapy.

neuroscience↗

bioRxiv2022

CaV3.1 T-type calcium channels regulate spatial memory processing in the dorsal subiculum

The dorsal subiculum (dSub) is one of the key structures responsible for the formation of hippocampal memory traces but the contribution of individual ionic currents to its cognitive function is not well studied. Although we recently reported that low-voltage-activated T-type calcium channels (T-channels) are crucial for the burst firing pattern regulation in the dSub pyramidal neurons, their potential role in learning and memory remains unclear. Here we used in vivo local field potential recordings and miniscope calcium imaging in freely behaving mice coupled with pharmacological and genetic tools to address this gap in knowledge. We show that the CaV3.1 isoform of T-channels is critically involved in controlling neuronal activity in the dSub in vivo. Altering burst firing pattern by inhibiting T-channel activity markedly affects calcium dynamics, synaptic plasticity, neuronal oscillations and phase-amplitude coupling in the dSub, thereby disrupting spatial learning. These results provide a crucial causative link between the CaV3.1 channels, burst firing activity of dSub neurons and memory processing, thus further supporting the notion that changes in neuronal excitability regulate memory trace formation. We posit that subicular CaV3.1 T-channels could be a promising novel drug target for cognitive disorders.

neuroscience↗