Biology subjects

Criscuolo, C.

Publications and source records attributed to Criscuolo, C..

3 recordsLinked to original sources

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

Stability of dentate gyrus granule cell mossy fiber BDNF protein expression with age and resistance of granule cells to Alzheimers disease neuropathology in a mouse model

The neurotrophin brain-derived neurotrophic factor (BDNF) is important in development and maintenance of neurons and their plasticity. Hippocampal BDNF has been implicated Alzheimers disease (AD) because hippocampal levels in AD patients and AD animal models are consistently downregulated, suggesting that reduced BDNF contributes to AD. However, the location where hippocampal BDNF protein is most highly expressed, the mossy fiber (MF) axons of dentate gyrus (DG) granule cells (GCs), has been understudied, and never in controlled in vivo conditions. We examined MF BDNF protein in the Tg2576 mouse model of AD. Tg2576 and wild type (WT) mice of both sexes were examined at 2-3 months of age, when amyloid-{beta} (A{beta}) is present in neurons but plaques are absent, and 11-20 months of age, after plaque accumulation. As shown previously, WT mice exhibited high levels of MF BDNF protein. Interestingly, there was no significant decline with age in either genotype or sex. Notably, we found a correlation between MF BDNF protein and GC {Delta}FosB, a transcription factor that increases after 1-2 weeks of elevated neuronal activity. Remarkably, there was relatively little evidence of A{beta} in GCs or the GC layer even at old ages. Results indicate MF BDNF is stable in the Tg2576 mouse, and MF BDNF may remain unchanged due to increased GC neuronal activity, since BDNF expression is well known to be activity-dependent. The resistance of GCs to long-term A{beta} accumulation provides an opportunity to understand how to protect other vulnerable neurons from increased A{beta} levels and therefore has translational implications. SIGNIFICANCEDeclining hippocampal brain-derived neurotrophic factor (BDNF) has been implicated in the pathogenesis of Alzheimers disease (AD). However, few studies have examined where hippocampal BDNF protein has its highest concentration, and plays a critical role in memory, the dentate gyrus granule cell (GC) axons (mossy fibers; MFs). Using a well-established mouse model of cerebral amyloid overexpression, the Tg2576 mouse model of AD, we found that MF BDNF did not decline with age, suggesting a notable exception to the idea that reduced hippocampal BDNF contributes to AD pathobiology. We also identified that Tg2576 GC activity correlates with MF BDNF protein based on GC expression of the transcription factor {Delta}FosB. These data are consistent with the activity-dependence of MF BDNF. In addition, we found that Tg2576 GCs were relatively resistant to accumulation of amyloid-b, providing insight into AD resilience, which has strong therapeutic implications.

neuroscience↗