McMahon, L. L. | bioRxiv Science

bioRxiv2019

Alpha1-Adrenergic Receptor Mediated Long-Term Depression at CA3-CA1 Synapses Can be Induced via Accumulation of Endogenous Norepinephrine and is Preserved Following Noradrenergic Denervation

Locus coeruleus (LC) provides the sole source of noradrenergic (NA) innervation to hippocampus, and it undergoes significant degeneration early in Alzheimers disease (AD). Norepinephrine (NE) modulates synaptic transmission and plasticity at hippocampal synapses which likely contributes to hippocampus dependent learning and memory. We previously reported that pharmacological activation of 1 adrenergic receptors (1ARs) induces long-term depression (LTD) at CA3-CA1 synapses. Here we investigated whether accumulation of endogenous NE via pharmacological blockade of NE transporters (NET) and the NE degradative enzyme, monoamine oxidase (MAO), can induce 1AR LTD, as these inhibitors are used clinically. Further, we sought to determine how degeneration of hippocampal NA innervation, as occurs in AD, impacts 1AR function and 1AR LTD. Bath application of NET and MAO inhibitors in slices from control rats reliably induced 1AR LTD when {beta} adrenergic receptors were inhibited. To induce degeneration of LC-NA innervation, rats were treated with the specific NA neurotoxin DSP-4 and recordings performed 1-3 weeks later when NA axon degeneration had stabilized. Even with 85% loss of hippocampal NA innervation, 1AR LTD was successfully induced using either the 1AR agonist phenylephrine or the combined NET and MAO inhibitors, and importantly, the LTD magnitude was not different from saline-treated control. These data suggest that despite significant decreases in NA input to hippocampus, the mechanisms necessary for the induction of 1AR LTD remain functional. Furthermore, we posit that 1AR activation could be a viable therapeutic target for pharmacological intervention in AD and other diseases involving malfunctions of NA neurotransmission.

neuroscience↗

bioRxiv2019

LSO:Ce Inorganic Scintillators are Biocompatible with Neuronal and Circuit Function

Optogenetics is widely used in neuroscience to control neural circuits. However, non-invasive methods for light delivery in brain are needed to avoid physical damage caused by current methods. One potential strategy could employ x-ray activation of radioluminescent particles (RPLs), enabling localized light generation within the brain. RPLs composed of inorganic scintillators can emit light at various wavelengths depending upon composition. Cerium doped lutetium oxyorthosilicate (LSO:Ce), an inorganic scintillator that emits blue light in response to x-ray or UV stimulation, could potentially be used to control neural circuits through activation of channelrhodopsin-2 (ChR2), a light-gated cation channel. Whether inorganic scintillators themselves negatively impact neuronal processes and synaptic function is unknown, and was investigated here using cellular, molecular, and electrophysiological approaches. As proof of principle, we applied UV stimulation to 4 m LSO:Ce particles during whole-cell recording of CA1 pyramidal cells in acutely prepared hippocampal slices from mice that expressed ChR2 in glutamatergic neurons. We observed an increase in frequency and amplitude of spontaneous excitatory postsynaptic currents (EPSCs), indicating UV activation of ChR2 and excitation of neurons. Importantly, we found that LSO:Ce particles have no effect on survival of primary mouse cortical neurons, even after 24 hours of exposure. In extracellular dendritic field potential recordings, we observed no change in strength of basal glutamatergic transmission up to 3 hours of exposure to LSO:Ce microparticles. However, there was a slight decrease in the frequency of spontaneous EPSCs in whole-cell voltage-clamp recordings from CA1 pyramidal cells, with no change in current amplitudes. No changes in the amplitude or frequency of spontaneous inhibitory postsynaptic currents (IPSCs) were observed. Finally, long term potentiation (LTP), a synaptic modification believed to underlie learning and memory and a robust measure of synaptic integrity, was successfully induced, although the magnitude was slightly reduced. Together, these results show LSO:Ce particles are biocompatible even though there are modest effects on baseline synaptic function and long-term synaptic plasticity. Importantly, we show that light emitted from LSO:Ce particles is able to activate ChR2 and modify synaptic function. Therefore, LSO:Ce inorganic scintillators are potentially viable for use as a new light delivery system for optogenetics.

neuroscience↗