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Background: The lateral entorhinal cortex (LEC), followed by area CA1 of hippocampus, are interconnected brain areas implicated early in Alzheimer's disease (AD). Processing of LEC input by CA1 pyramidal neurons (PNs) is critical for non‐spatial memory, in which deficits are seen in early AD. How this process is affected by tauopathy is unclear. Furthermore, CA1 PNs are divided into molecularly and functionally distinct superficial (sPN) and deep (dPN) subpopulations. It is additionally unclear if and how LEC input processing by these subpopulations are differentially impacted. Method: LEC of female PS19 and WT mice (8‐10 month old) were injected with an AAV expressing channelrhodopsin ChrR2. After two weeks, acute hippocampal slices were prepared and whole cell patch clamp recordings were performed on dPNs/sPNs of distal CA1 in current clamp and voltage clamp mode using a potassium‐ or cesium‐based intracellular solution, respectively. Synaptic responses were measured in current clamp and voltage clamp mode, with LEC axons optogenetically activated by blue LED light. In current clamp, excitatory postsynaptic potentials (EPSPs) were measured with inhibition blocked. In voltage clamp, excitatory postsynaptic currents (EPSCs) were evaluated by holding membrane potential at ‐70mV, and inhibitory postsynaptic currents (IPSCs) were evaluated by holding at 0mV. Result: All data is n = 3‐8/group. Compared to WT, LEC‐driven EPSCs showed significant reductions in PS19 sPNs (18.7pA vs. 8.4pA, p = 0.0016) but were unchanged in dPNs (12.4pA vs. 13.6pA, p = 0.2841). Measurements of LEC‐driven EPSPs showed analogous findings. There was no change in paired pulse ratio, ruling out presynaptic changes. There was no change in EPSP decay time constant or temporal summation of the EPSP, ruling out changes in postsynaptic excitability. In contrast to excitation, LEC‐driven IPSCs were unchanged in PS19 versus WT mice in both sPNs (45.7pA vs. 51.9pA, p = 0.62) and dPNs (25.46pA vs. 22.3pA, p = 0.22). Conclusion: LEC drive of CA1 PNs exhibits a cell type‐specific vulnerability to tauopathy, with sPNs differentially susceptible to a reduction of excitation, without changes in feedforward inhibition. Our results further support a postsynaptic mechanism that may be due to spine loss, changes in spine morphology, or shifts in glutamate receptor expression. [ABSTRACT FROM AUTHOR]

Background: How tauopathy disrupts direct entorhinal cortex (EC) inputs to CA1 and their plasticity is understudied, despite its critical role in memory. Moreover, dysfunction of lateral EC (LEC) input is less clear, despite its relevance to early Alzheimer's disease pathogenesis. Here we examined how tau impacts long‐term potentiation (LTP) of LEC→CA1 input in a transgenic model of tauopathy. Method: Acute hippocampal slices were prepared from PS19 and WT mice (8‐10 mo. old, M/F) in which LEC had been injected with an AAV expressing channelrhodopsin ChR2. Ex vivo recordings were achieved with blue LED light to excite LEC axons and an extracellular field electrode in stratum lacunosum moleculare (SLM) of distal CA1 to record field responses. Input‐output curves were established using 25‐100% LED power for field postsynaptic excitatory potentials (fEPSPs) with inhibition blocked (GABAA: 2mm SR95531, GABAB: 1mm CGP55845). LTP of fEPSPs was elicited after a 10" baseline using an LED theta burst stimulation (TBS). Paired pulse ratio (PPR) of fEPSPs was elicited with LED stimulation of 2 pulses at 20Hz. Fluorescence immunohistochemistry (IHC) was performed in separate mice using antibodies to N‐type calcium channels. Result: All results are based on n = 4‐8/sex/genotype. The LEC fEPSP was of reduced magnitude in female PS19 versus WT mice, while unchanged across genotype in male mice. TBS induced a late‐onset LTP (147% at 45") of the LEC fEPSP in female WT mice, which was significantly reduced in female PS19 mice (p = 0.0051). There was no LTP reduction in male mice. LTP in female WT mice was associated with a PPR reduction that was reversed by the addition of the N‐type calcium channel blocker w‐conotoxin GVIA, all of which did not occur in PS19 mice (p<0.0001). PPR was appropriately reduced in male mice across genotype. IHC of N‐type calcium channels showed reduced fluorescence in the SLM of female PS19 mice versus WT. Conclusion: In PS19 mice, the impact of tau on LEC→CA1 input is sex‐dependent, with reduced LEC‐driven excitation and LTP only in female mice. A reduction in presynaptic N‐type calcium channels in PS19 mice may serve as a presynaptic mechanism for the reduced plasticity. [ABSTRACT FROM AUTHOR]

The incidence of sudden cardiac death (SCD) in people living with HIV infection (PLWH), especially those with inadequate viral suppression, is high and the reasons for this remain incompletely characterized. The timely opening and closing of type 2 ryanodine receptor (RyR2) is critical for ensuring rhythmic cardiac contraction–relaxation cycles, and the disruption of these processes can elicit Ca2+ waves, ventricular arrhythmias, and SCD. Herein, we show that the HIV protein Tat (HIV-Tat: 0–52 ng/mL) and therapeutic levels of the antiretroviral drugs atazanavir (ATV: 0–25,344 ng/mL), efavirenz (EFV: 0–11,376 ng/mL), and ritonavir (RTV: 0–25,956 ng/mL) bind to and modulate the opening and closing of RyR2. Abacavir (0–14,315 ng/mL), bictegravir (0–22,469 ng/mL), Rilpivirine (0–14,360 ng/mL), and tenofovir disoproxil fumarate (0–18,321 ng/mL) did not alter [3H]ryanodine binding to RyR2. Pretreating RyR2 with low HIV-Tat (14 ng/mL) potentiated the abilities of ATV and RTV to bind to open RyR2 and enhanced their ability to bind to EFV to close RyR2. In silico molecular docking using a Schrodinger Prime protein–protein docking algorithm identified three thermodynamically favored interacting sites for HIV-Tat on RyR2. The most favored site resides between amino acids (AA) 1702–1963; the second favored site resides between AA 467–1465, and the third site resides between AA 201–1816. Collectively, these new data show that HIV-Tat, ATV, EFV, and RTV can bind to and modulate the activity of RyR2 and that HIV-Tat can exacerbate the actions of ATV, EFV, and RTV on RyR2. Whether the modulation of RyR2 by these agents increases the risk of arrhythmias and SCD remains to be explored. [ABSTRACT FROM AUTHOR]

Background: Most hippocampal physiologic studies in Alzheimer disease (AD) have focused on memory circuit dysfunction in dorsal CA1. Ventral CA1 (vCA1) has received little attention, despite evidence supporting its increased susceptibility and its role in mood and affective symptoms, which play a prominent role in AD. We aimed to study the effect of amyloid pathology on circuit dysfunction in vCA1 using 5xFAD mice. We evaluated intrinsic excitability of vCA1 pyramidal neurons (PNs) as well as the impact of two distinct inputs onto their apical dendrite: entorhinal cortex (EC) input onto the distal compartment and CA3 inputs onto the proximal compartment. Method: Acute ventral hippocampal slices were prepared from 12‐14 month old 5xFAD and age‐matched wild type (WT) mice. Whole cell patch clamp recordings were performed on vCA1 PNs. EC and CA3 input responses were elicited with extracellular stimulation of stratum lacunosum moleculare and stratum radiatum. We also addressed presynaptic function (paired pulse ratio), dendritic excitability (decay time constant of synaptic response), and intrinsic excitability (resting membrane potential, input resistance, sag ratio, firing rate). Result: The EC stimulus‐response curve reduced in 5xFAD vs. WT mice (n=6‐10 PNs; p=0.0096) with a peak reduction of ∼33% (1.5mV vs. 1.0mV). In these same cells, the CA3 stimulus‐response curve was also reduced (p<0.0001) but to a much larger extent of ∼67% at the peak (4.3mV vs. 1.4mV). The paired pulse ratio and response decay time constant were not affected with either input. Lastly, there were no statistically significant changes in intrinsic excitability measures. Conclusion: In 5xFAD mice, vCA1 PN circuit dysfunction is dominated by synaptic not intrinsic excitability changes. These changes are not in presynaptic function or postsynaptic ion currents, suggesting glutamate receptor changes or spine loss as alternative mechanisms. Moreover, these alterations are much more evident in CA3 versus EC input responses, perhaps driven by the inherent differences of the proximal and distal dendritic compartment. As such, with amyloidosis, vCA1 PN output shifts from being heavily dependent on CA3 input to being nearly equivalently dependent on EC input. These changes are important for understanding the circuit basis of mood and affect dysfunction in AD. [ABSTRACT FROM AUTHOR]

The perforant path (PP) carries direct inputs from entorhinal cortex to CA1 pyramidal neurons (PNs), with an impact dependent on PN position across transverse (CA1a-CA1c) and radial (superficial/deep) axes. It remains unclear how aging and Alzheimer disease (AD) affect PP input, despite its critical role in memory and early AD. Applying ex vivo recordings and two-photon microscopy in slices from mice up to 30 months old, we interrogated PP responses across PN subpopulations and compared them to Schaffer collateral and intrinsic excitability changes. We found that aging uniquely impacts PP excitatory responses, abolishing transverse and radial differences via a mechanism independent of presynaptic and membrane excitability change. This is amplified in aged 3xTg-AD mice, with further weakening of PP inputs to CA1a superficial PNs associated with distal dendritic spine loss. This demonstrates a unique feature of aging-related circuit dysfunction, with mechanistic implications related to memory impairment and synaptic vulnerability.

Synaptic spine loss is an early pathophysiologic hallmark of Alzheimer disease (AD) that precedes overt loss of dendritic architecture and frank neurodegeneration. While spine loss signifies a decreased engagement of postsynaptic neurons by presynaptic targets, the degree to which loss of spines and their passive components impacts the excitability of postsynaptic neurons and responses to surviving synaptic inputs is unclear. Using passive multicompartmental models of CA1 pyramidal neurons (PNs), implicated in early AD, we find that spine loss alone drives a boosting of remaining inputs to their proximal and distal dendrites, targeted by CA3 and entorhinal cortex (EC), respectively. This boosting effect is higher in distal versus proximal dendrites and can be mediated by spine loss restricted to the distal compartment, enough to impact synaptic input integration and somatodendritic backpropagation. This has particular relevance to very early stages of AD in which pathophysiology extends from EC to CA1.