ZD7288 enhances long-term depression at early postnatal medial perforant path-granule cell synapses

Hyperpolarization-activated, cyclic nucleotide-gated nonselective (HCN) channels modulate both membrane potential and resistance and play a significant role in synaptic plasticity. We compared the influence of HCN channels on long-term depression (LTD) at the medial perforant path-granule cell synapse in early postnatal (P9–15) and adult (P30–60) rats. LTD was elicited in P9–15 slices using low-frequency stimulation (LFS, 900 pulses, 1Hz; 80 ± 4% of baseline). Application of the specific HCN channel blocker ZD7288 (10 μM) before LFS significantly enhanced LTD (62 ± 4%; P < 0.01), showing HCN channels restrain LTD induction. However, when ZD7288 was applied after LFS, LTD was similar to control values and significantly different from the values obtained with ZD7288 application before LFS (81 ± 5%; P < 0.01), indicating that HCN channels do not modulate LTD expression. LTD in slices from adult rats were only marginally lower compared to those in P9–15 slices (85 ± 6%), but bath application of ZD7288 prior to LFS resulted in the same amount of LTD (85 ± 5%). HCN channels in adult tissue hence lose their modulatory effect. In conclusion, we found that HCN channels at the medial perforant path-granule cell synapse compromise LFS-associated induction, but not expression of LTD in early postnatal, but not in adult, rats

Altered physiology and pharmacology in the corticostriatal system in a model of temporal lobe epilepsy

PURPOSE: Temporal lobe epilepsy (TLE) is associated with changes in hippocampal function/morphology. These changes often manifest as a decline in cognitive abilities, which in animal models is reflected in reduced spatial learning and up-regulation or down-regulation of synaptic plasticity. Beyond this, however, changes also occur in other, extralimbic structures, as has been shown on the neurochemical level. Here, our aim was to test whether functional changes occur also in corticostriatal synaptic communication, also because the striatum is instrumental in motor planning and coordination and hence serves important nonlimbic functions. METHODS: We analyzed corticostriatal long-term potentiation (LTP) in brain slices of pilocarpine-treated rats after status epilepticus (SE). To determine whether chronic seizures, or SE itself, impact basal ganglia function, tissue was investigated (1) shortly after SE (3-5 days, acute group), and (2) after chronic epilepsy had been established (chronic group, 4-10 weeks after SE). KEY FINDINGS: Early after SE, only little synaptic plasticity emerged. In the chronic group, however, LTP was enhanced significantly in the SE group versus control preparations. Using pharmacologic blockade of N-methyl-d-aspartate (NMDA) receptors, LTP in chronically epileptic tissue could be dissected into an early, NMDA-dependent and a late, NMDA-independent phase, which reverted to LTD with additional dopamine D₁/D₅ receptor blockade. SIGNIFICANCE: We conclude that chronic limbic epilepsy goes along also with functional alterations in extralimbic structures such as the striatum.status: publishe

GluN2B inhibition rescues impaired potentiation and epileptogenicity at associational-commissural CA3 synapses in a model of anti-NMDAR encephalitis

Kupper M, Porath K, Sellmann T, Bien C, Kohling R, Kirschstein T. GluN2B inhibition rescues impaired potentiation and epileptogenicity at associational-commissural CA3 synapses in a model of anti-NMDAR encephalitis. Neuroscience Letters. 2022;795: 137031.Anti-N-methyl-D-aspartate receptor (anti-NMDAR) encephalitis is an autoimmune epilepsy associated with memory deficits. Research has demonstrated that anti-NMDAR inhibit long-term potentiation, and, at the same time, lead to disinhibition in the form of epileptiform afterpotentials in the potentiated state. While both effects may give rise to the key symptoms of the disease, the molecular basis of being simultaneously inhibitory and disinhibitory is difficult to explain. Here, we explored a possible involvement of the GluN2B subunit. To this aim, we injected cerebrospinal fluid from anti-NMDAR encephalitis patients into the rat hippocampus and prepared brain slices for in vitro field potential recordings. Associational-commissural-fiber-CA3 synapses from anti-NMDAR-treated animals showed increased field potential amplitudes with concomitantly enhanced paired-pulse ratios as compared to control tissue. GluN2B inhibition by Ro25-6981 mimicked these effects in controls but had no effect in anti-NMDAR tissues indicating a presynaptic and occluding effect of anti-NMDAR. We then induced potentiation of associational-commissural-fiber-CA3 synapses, and confirmed that slices from anti-NMDAR-treated animals showed reduced potentiation and pronounced epileptiform afterpotentials. Intriguingly, both effects were absent when Ro25-6981 was added in vitro before inducing potentiation. These results indicate that GluN2B-containing NMDARs, partially expressed presynaptically, show differential sensitivity to anti-NMDAR, and that altered GluN2B function is particularly apparent in the potentiated state rather than under baseline conditions. Since GluN2B inhibition rescued the effects of anti-NMDAR in the potentiated state, this opens the possibility that at least a subgroup of patients could benefit from a GluN2B antagonist. Copyright © 2022 Elsevier B.V. All rights reserved

Increased excitability and compromised long-term potentiation in the neocortical of NPC1−/− mice

Niemann-Pick type C1 (NPC1) disease is a neurodegenerative lysosomal storage disorder caused by mutations in the NPC1 gene which encodes a transmembrane protein of the acidic compartment. Albeit the NPC1(-/-) mouse is available serving as an appropriate animal model of the human disease, the precise function of this protein remains obscure. Here, we investigated the synaptic consequences of this disease and explored long-term potentiation (LTP) in slices taken from the hippocampal CA1 region, the dorsomedial striatum as well as the somatosensory neocortex in NPC1(-/-) mice using extracellular field potential recordings. We did not observe significant changes in synaptic excitability as well as LTP in the hippocampal CA1 region and the dorsomedial striatum of NPC1(-/-) mice when compared to wildtype littermates. However, neocortical excitability was significantly enhanced while LTP was abolished. These results suggest that at least in the somatosensory neocortex NPC1 protein is instrumental in synaptic function.status: accepte