Biology subjects

Scharfman, H.

Publications and source records attributed to Scharfman, H..

6 recordsLinked to original sources

bioRxiv2026

Brain-derived neurotrophic factor (BDNF), estrogen receptors, and mossy cells

Dentate gyrus (DG) function depends on the neurotrophin brain-derived neurotrophic factor (BDNF) which shows robust synthesis in the principal cells, the granule cells (GCs). However, BDNF protein is present in the inner molecular layer (IML), where most afferents to GCs are from hilar mossy cells (MCs). Therefore, we asked whether MCs express BDNF mRNA and protein. Using adult mice, we found that MC BDNF mRNA and protein were expressed in the majority of MC somata and few other hilar neurons. Interestingly, IML BDNF was significantly greater in the ventral compared to dorsal DG. Additionally, dorsal IML BDNF was significantly higher in females on proestrous morning, when serum levels of estrogen peak, relative to metestrous morning, when estrogen is lower. Consistent with this observation, ventral MC somata, which project to the dorsal IML, showed more BDNF mRNA on proestrous morning than metestrous morning. Next, we asked if strong IML BDNF protein expression on proestrous morning was due to estrogen action at estrogen receptors (ERs) because estrogen binding to ERs can increase BDNF synthesis. We found that MCs have high expression of all ERs: ER, ER{beta} and GPER1 in both sexes. When sexes were pooled, the percent of MCs labeled by ER{beta} and GPER1 exceeded the percent of MCs expressing ER. When proestrous females were examined, GPER1-labeled hilar cells were greater than hilar cells labeled by ER. The results demonstrate robust MC somatic expression of BDNF, relatively high ventral IML expression of BDNF, and estrous cycle dependence. The results also highlight robust MC ER expression, especially ER{beta} and GPER1, making the hilus a previously underestimated site of estrogen and BDNF action.

neuroscience↗

bioRxiv2024

Increased excitability of dentate gyrus mossy cells occurs early in life in the Tg2576 model of Alzheimer's disease.

INTRODUCTIONHyperexcitability in Alzheimers disease (AD) emerge early and contribute to disease progression. The dentate gyrus (DG) is implicated in hyperexcitability in AD. We hypothesized that mossy cells (MCs), regulators of DG excitability, contribute to early hyperexcitability in AD. Indeed, MCs generate hyperexcitability in epilepsy. METHODSUsing the Tg2576 model and WT mice ([~]1month-old), we compared MCs electrophysiologically, assessed c-Fos activity marker, A{beta} expression and mice performance in a hippocampal-dependent memory task. RESULTSTg2576 MCs exhibit increased spontaneous excitatory events and decreased inhibitory currents, increasing the charge transfer excitation/inhibition ratio. Tg2576 MC intrinsic excitability was enhanced, and showed higher c-Fos, intracellular A{beta} expression, and axon sprouting. Granule cells only showed changes in synaptic properties, without intrinsic changes. The effects occurred before a memory task is affected. DISCUSSIONEarly electrophysiological and morphological alterations in Tg2576 MCs are consistent with enhanced excitability, suggesting an early role in DG hyperexcitability and AD pathophysiology. HIGHLIGHTS{circ} MCs from 1 month-old Tg2576 mice had increased spontaneous excitatory synaptic input. {circ}Tg2576 MCs had reduced spontaneous inhibitory synaptic input. {circ}Several intrinsic properties were abnormal in Tg2576 MCs. {circ}Tg2576 GCs had enhanced synaptic excitation but no changes in intrinsic properties. {circ}Tg2576 MCs exhibited high c-Fos expression, soluble A{beta} and axonal sprouting.

neuroscience↗

bioRxiv2023

Increasing adult neurogenesis protects mice from epilepsy.

ABSTRACTNeurogenesis occurs in the adult brain in the hippocampal dentate gyrus, an area that contains neurons which are vulnerable to insults and injury, such as severe seizures. Previous studies showed that increasing adult neurogenesis reduced neuronal damage after these seizures. Because the damage typically is followed by chronic life-long seizures (epilepsy), we asked if increasing adult-born neurons would prevent epilepsy. Adult-born neurons were selectively increased by deleting the pro-apoptotic gene Bax from Nestin-expressing progenitors. Tamoxifen was administered at 6 weeks of age to conditionally delete Bax in Nestin-CreERT2Baxfl/fl mice. Six weeks after tamoxifen administration, severe seizures (status epilepticus; SE) were induced by injection of the convulsant pilocarpine. After mice developed epilepsy, seizure frequency was quantified for 3 weeks. Mice with increased adult-born neurons exhibited fewer chronic seizures. Postictal depression was reduced also. These results were primarily in female mice, possibly because they were the more affected by Bax deletion than males, consistent with sex differences in Bax. The female mice with enhanced adult-born neurons also showed less neuronal loss of hilar mossy cells and hilar somatostatin-expressing neurons than wild type females or males, which is notable because these two hilar cell types are implicated in epileptogenesis. The results suggest that selective Bax deletion to increase adult-born neurons can reduce experimental epilepsy, and the effect shows a striking sex difference. The results are surprising in light of past studies showing that suppressing adult-born neurons can also reduce chronic seizures.

neuroscience↗

bioRxiv2023

Choline supplementation in early life improves and low levels of choline can impair outcomes in a mouse model of Alzheimer's disease.

Maternal choline supplementation (MCS) improves cognition in Alzheimers disease (AD) models. However, effects of MCS on neuronal hyperexcitability in AD are unknown. We investigated effects of MCS in a well-established mouse model of AD with hyperexcitability, the Tg2576 mouse. The most common type of hyperexcitability in Tg2576 mice are generalized EEG spikes (interictal spikes; IIS). IIS also are common in other mouse models and occur in AD patients. Im mouse models, hyperexcitability is also reflected by elevated expression of the transcription factor {Delta}FosB in the granule cells (GCs) of the dentate gyrus (DG), which are the principal cell type. Therefore we studied {Delta}FosB expression in GCs. We also studied the the neuronal marker NeuN within hilar neurons of the DG because other studies have reduced NeuN protein expression is a sign of oxidative stress or other pathology. This is potentially important because hilar neurons regulate GC excitability. Tg2576 breeding pairs received a diet with a relatively low, intermediate or high concentration of choline. After weaning, all mice received the intermediate diet. In offspring of mice fed the high choline diet, IIS frequency declined, GC {Delta}FosB expression was reduced, and NeuN expression was restored. Using the novel object location task, spatial memory improved. In contrast, offspring exposed to the relatively low choline diet had several adverse effects, such as increased mortality. They had the weakest hilar NeuN immunoreactivity and greatest GC {Delta}FosB protein expression. However, their IIS frequency was low, which was surprising. The results provide new evidence that a diet high in choline in early life can improve outcomes in a mouse model of AD, and relatively low choline can have mixed effects. This is the first study showing that dietary choline can regulate hyperexcitability, hilar neurons, {Delta}FosB and spatial memory in an animal model of AD.

neuroscience↗

bioRxiv2022

Cannabidiol targets a modulatory system for excitatory-inhibitory synaptic coordination, contributing to its anti-seizure action

Cannabidiol (CBD), a non-euphoric component of cannabis, reduces seizures in multiple forms of pediatric epilepsy, but the mechanism(s) of anti-seizure action remain unclear. In one leading model, CBD acts at glutamatergic axon terminals, blocking pro-excitatory actions of an endogenous membrane phospholipid, lysophosphatidylinositol (LPI), at the G protein-coupled receptor GPR55. However, the impact of LPI-GPR55 signaling at inhibitory synapses and in epileptogenesis remains underexplored. We found that LPI transiently increased hippocampal CA3[->]CA1 excitatory presynaptic release probability and evoked synaptic strength in WT mice, while attenuating inhibitory postsynaptic strength by decreasing GABAAR{gamma}2 and gephyrin puncta. Effects of LPI at both excitatory and inhibitory synapses were eliminated by CBD pretreatment and absent after GPR55 deletion. Acute pentylenetrazole-induced seizures elevated levels of GPR55 and LPI, and chronic lithium pilocarpine-induced epileptogenesis potentiated the pro-excitatory effects of LPI. We propose that CBD exerts potential therapeutic effect both by blocking synaptic effects of LPI and dampening hyperexcitability.

neuroscience↗

bioRxiv2020

Early changes in synaptic and intrinsic properties of dentate gyrus granule cells in a mouse model of Alzheimer's disease neuropathology and atypical effects of the cholinergic antagonist atropine.

It has been reported that hyperexcitability occurs in a subset of patients with Alzheimers disease (AD) and hyperexcitability could contribute to the disease. Several studies have suggested that the hippocampal dentate gyrus (DG) may be an important area where hyperexcitability occurs. Therefore, we tested the hypothesis that the principal DG cell type, granule cells (GCs), would exhibit changes at the single-cell level which would be consistent with hyperexcitability and might help explain it. We used the Tg2576 mouse, where it has been shown that hyperexcitability is robust at 2-3 months of age. GCs from 2-3-month-old Tg2576 mice were compared to age-matched wild type (WT) mice. Effects of muscarinic cholinergic antagonism were tested because previously we found that Tg2576 mice exhibited hyperexcitability in vivo that was reduced by the muscarinic cholinergic antagonist atropine, counter to the dogma that in AD one needs to boost cholinergic function. The results showed that GCs from Tg2576 mice exhibited increased frequency of spontaneous excitatory postsynaptic potentials/currents (sEPSP/Cs) and reduced frequency of spontaneous inhibitory synaptic events (sIPSCs) relative to WT, increasing the excitation:inhibition (E:I) ratio. There was an inward glutamatergic current that we defined here as a novel synaptic current (nsC) in Tg2576 mice because it was very weak in WT mice. Although not usually measured, intrinsic properties were distinct in Tg2576 GCs relative to WT. In summary, GCs of the Tg2576 mouse exhibit early electrophysiological alterations that are consistent with increased synaptic excitation, reduced inhibition, and muscarinic cholinergic dysregulation. The data support previous suggestions that the DG and cholinergic system contribute to hyperexcitability early in life in AD mouse models. HIGHLIGHTSO_LIGranule cells (GCs) in young Tg2576 mice had abnormal synaptic activity. C_LIO_LIYoung Tg2576 GCs had increased excitatory and reduced inhibitory synaptic activity. C_LIO_LIGC intrinsic properties were altered in young Tg2576 mice. C_LIO_LIMuscarinic cholinergic regulation of GCs was altered in young Tg2576 mice. C_LIO_LIAtropine led to a novel spontaneous inward current that was very strong in Tg2576 GCs. C_LI

neuroscience↗