Preventing Effect of L-Type Calcium Channel Blockade on Electrophysiological Alterations in Dentate Gyrus Granule Cells Induced by Entorhinal Amyloid Pathology

Abstract

The entorhinal cortex (EC) is one of the earliest affected brain regions in Alzheimer’s disease (AD). EC-amyloid pathology induces synaptic failure in the dentate gyrus (DG) with resultant behavioral impairment, but there is little known about its impact on neuronal properties in the DG. It is believed that calcium dyshomeostasis plays a pivotal role in the etiology of AD. Here, the effect of the EC amyloid pathogenesis on cellular properties of DG granule cells and also possible neuroprotective role of L-type calcium channel blockers (CCBs), nimodipine and isradipine, were investigated. The amyloid beta (Aβ) 1–42 was injected bilaterally into the EC of male rats and one week later, electrophysiological properties of DG granule cells were assessed. Voltage clamp recording revealed appearance of giant sIPSC in combination with a decrease in sEPSC frequency which was partially reversed by CCBs in granule cells from Aβ treated rats. EC amyloid pathogenesis induced a significant reduction of input resistance (Rin) accompanied by a profound decreased excitability in the DG granule cells. However, daily administration of CCBs, isradipine or nimodipine (i.c.v. for 6 days), almost preserved the normal excitability against Aβ. In conclusion, lower tendency to fire AP along with reduced Rin suggest that DG granule cells might undergo an alteration in the membrane ion channel activities which finally lead to the behavioral deficits observed in animal models and patients with early-stage Alzheimer’s disease.

Single amyloid‐beta injection exacerbates 4‐aminopyridine‐induced seizures and changes synaptic coupling in the hippocampus

“…As previously shown, a single Aβ injection does not induce a significant effect on CA1‐Schaffer collateral synaptic transmission, as classically assessed through the I/O relationship (Salgado‐Puga et al, ), which is similar to the lack of effect of the long‐term presence of Aβ in basal synaptic transmission (Chapman et al, ; Giacchino, Criado, Games, & Henriksen, ; Peña et al, ; Sun & Alkon, ). However, like other reports, we also found indirect evidence of a decrease in synaptic release probability (i.e., increase in PPR; Peña et al, ; Peña et al, ) and a decrease in CA1‐Schaffer collateral coupling (i.e., reduced fEPSP slope/fEPSP area relationship) (Hsieh et al, ; Jo et al, ; Kurudenkandy et al, ; Pourbadie et al, ; Wang et al, ), which may contribute to the induction of hyperexcitability. In fact, here we found that despite the Aβ‐induced reduction in CA1‐Schaffer collateral coupling efficiency, reflected in a more leveled fEPSP slope/fEPSP area linear relationship, the slices obtained from Aβ‐pretreated animals exhibited extended limits of the synaptic coupling (i.e., higher fEPSP slopes inducing higher fEPSP areas; Figure ), which was exacerbated after the bath application of the convulsant 4AP (Peña & Tapia, ; Peña & Tapia, ) and by Aβ itself.…”

“…Interestingly, we also found that Aβ bath application can produce differential effects in slices obtained from control and Aβ‐pretreated animals (reduction and increase, respectively). These differential effects have been constantly reported in the literature (Abramov et al, ; Cuevas et al, ; Cummings et al, ; Hazra et al, ; Hsieh et al, ; Jo et al, ; Pourbadie et al, ; Wang, Yang, et al, ; Wu, Anwyl, & Rowan, ). Some reports indicate that Aβ decreases synaptic transmission (Hsieh et al, ; Jo et al, ; Kurudenkandy et al, ; Pourbadie et al, ; Wang, Yang, et al, ), while others argue that Aβ increases synaptic transmission (Abramov et al, ; Cuevas et al, ; Cummings et al, ; Kurudenkandy et al, ; Wu et al, ), and other reports show both effects of Aβ in identical experimental conditions (Kurudenkandy et al, ; Wang et al, ).…”

T2N as a new tool for robust electrophysiological modeling demonstrated for mature and adult-born dentate granule cells

“…For this we used reconstructed and synthetic mature rat GC morphologies ( Figure 4A ), which we have recently published ( Beining et al, 2017 ). Interestingly, increasing the Kir conductance (see Appendix 2 for details) was sufficient to replicate mature rat GC I-V recordings ( Pourbadie et al, 2015 ) using rat morphologies ( Figure 4B ). Also, after the adjustment of the Kir conductance, active channel properties and densities from mouse GCs ( Table 1 ) reproduced the spiking behavior of rat GCs ( Figure 4C–D ).…”

“…( A ) Illustration of reconstructed (left) and synthetic (right) rat morphologies used for simulations of rat GCs, from ( Beining et al, 2017 ). ( B ) I-V relationship of the model with (dark solid lines) or without (bright dashed lines) adjustment of passive conductance to experimental rat data (indicated by arrows: red ( Staley et al, 1992 ), yellow ( Mateos-Aparicio et al, 2014 ), green ( Pourbadie et al, 2015 ), violet ( Schmidt-Hieber et al, 2004 ). ( C ) F-I relationship of the model compared to data (black line and standard deviation as gray patch) from Pourbadie et al, 2015 .…”

Practical Radiosynthesis and Preclinical Neuroimaging of [11C]isradipine, a Calcium Channel Antagonist

“…A subunit of the LTCC was among the first to be associated with neuropsychiatric diseases, including schizophrenia and bipolar disorder [ 3 , 4 ]. While Ca 2+ -channel antagonists have a long history in the treatment of hypertension and cardiac disease [ 5 ], the promise these pharmaceuticals hold for treatment of neurological and psychiatric disorders has yet to come to fruition [ 6 , 7 , 8 , 9 , 10 , 11 , 12 , 13 , 14 ]. For example, it is believed that LTCC antagonists protect dopamine neurons in the substantia nigra from degeneration associated with Parkinson’s disease by dopamine D 2 receptor desensitization [ 15 ].…”