Divergence in Neuronal Calcium Dysregulation in Brain Aging and Animal Models of AD

Neuronal calcium dysregulation first garnered attention during the mid-1980’s as a key factor in brain aging, which led to the formulation of the Ca2+ hypothesis of brain aging and dementia. Indeed, many Ca2+-dependent cellular processes that change with age, including an increase in the afterhyperpolarization, a decrease in long-term potentiation, an increased susceptibility to long-term depression, and a reduction in short-term synaptic plasticity, have been identified. It was later determined that increased intracellular Ca2+ with age was due to increased Ca2+ channel density, elevated release from intracellular Ca2+ stores, and decreased Ca2+ buffering or clearance. Further, changes in intra- and intercellular Ca2+-dependent processes can lead to poor learning and spatial mapping in aged animals. As these are clear deficits in hippocampal function, many early studies assumed Ca2+ dysregulation phenotypes in animal models of aging were similar to the dysregulated cellular mechanisms seen in Alzheimer’s disease (AD) and other types of dementia. However, with the development of transgenic models to recapitulate hallmark AD phenotypes over the past 20 years, it has become apparent that the mishandling of Ca2+ is notably different across models. Importantly, many of these results were obtained while measuring Ca2+ indirectly and at limited ages. Thus, the once generalizable phenotypes associated with Ca2+ dysregulation, including increased intracellular Ca2+ and reduced synaptic communication, appear to diverge in normal brain aging and AD. The following dissertation investigates direct and indirect Ca2+ measures across the widely used 5xFAD familial AD mouse, as well as the less common Aldh2-/- sporadic AD mouse model. Based on previous evidence, it was hypothesized that a decrease in intracellular Ca2+ and associated processes would manifest in both models across age. Key results showed a reduction in resting Ca2+ in the 5xFAD mice, while in the Aldh2-/- model only minor Ca2+-dependent processes showed a genotype effect. These results highlight the non-generalizable nature of the Ca2+ hypothesis of brain aging to AD phenotypes and emphasize the importance of genetic background characterization, as well as underscore the complexity of cellular alterations in the divergence of aging and neurodegeneration

Neurophysiological characterisation of neurons in the rostral nucleus reuniens in health and disease.

Evidence is mounting for a role of the nucleus reuniens (Re) in higher cognitive function. Despite growing interest, very little is known about the intrinsic neurophysiological properties of Re neurons and, to date, no studies have examined if alterations to Re neurons may contribute to cognitive deficits associated with normal aging or dementia. Work presented chapter 3 provides the first detailed description of the intrinsic electrophysiological properties of rostral Re neurons in young adult (~5 months) C57-Bl/6J mice. This includes a number of findings which are highly atypical for thalamic relay neurons including tonic firing in the theta frequency at rest, a paucity of hyperpolarisation-activated cyclic nucleotide–gated (HCN) mediated currents, and a diversity of responses observed in response to depolarising current injections. Additionally this chapter includes a description of a novel form of intrinsic plasticity which alters the functional output of Re neurons. Chapter 4 investigates whether the intrinsic properties of Re neurons are altered in aged (~15 month) C57-Bl/6J mice as compared to a younger control group (~5 months). The intrinsic properties were remarkably similar across age ranges suggesting that alterations to the intrinsic properties of Re neurons do not contribute to age-related cognitive deficits. Chapter 5 investigates whether alterations to the intrinsic properties of Re neurons occur in the J20 model of amyloidopathy. Alterations to the resting membrane potential (RMP), propensity to rebound fire, and a reduction in action potential (AP) width were observed. This suggests that alterations to the intrinsic properties of Re neurons may contribute to cognitive deficits observed in Alzheimer’s disease (AD). Chapter 6 investigates whether alterations to the intrinsic properties of Re neurons occur in a mouse model (CHMP2Bintron5) of frontotemporal dementia (FTD). Only subtle changes were observed suggesting that alterations to the intrinsic properties of Re neurons does not contribute to cognitive deficits observed in FTD linked to chromosome 3 (FTD-3)

Modifying Rap1-signalling by targeting Pde6δ is neuroprotective in models of Alzheimer’s disease

Background: Neuronal Ca2+ dyshomeostasis and hyperactivity play a central role in Alzheimer's disease pathology arid progression. Amyloid-beta together with non-genetic risk-factors of Alzheimer's disease contributes to increased Ca2+ influx and aberrant neuronal activity, which accelerates neurodegeneration in a feed-forward fashion. As such, identifying new targets and drugs to modulate excessive Ca2+ signalling and neuronal hyperactivity, without overly suppressing them, has promising therapeutic potential. Methods: Here we show, using biochemical, electrophysiological, imaging, and behavioural tools, that pharmacological modulation of Rap1 signalling by inhibiting its interaction with Pde6 delta normalises disease associated Ca2+ aberrations and neuronal activity, conferring neuroprotection in models of Alzheimer's disease. Results: The newly identified inhibitors of the Rap1-Pde6 delta interaction counteract AD phenotypes, by reconfiguring Rapt signalling underlying synaptic efficacy, Ca2+ influx, and neuronal repolarisation, without adverse effects in-cellulo or invivo. Thus, modulation of Rap1 by Pde6 delta accommodates key mechanisms underlying neuronal activity, and therefore represents a promising new drug target for early or late intervention in neurodegenerative disorders. Conclusion: Targeting the Pde6 delta-Rap1 interaction has promising therapeutic potential for disorders characterised by neuronal hyperactivity, such as Alzheimer's disease

Astrocytes: Orchestrating synaptic plasticity?

Synaptic plasticity is the capacity of a preexisting connection between two neurons to change in strength as a function of neural activity. Because synaptic plasticity is the major candidate mechanism for learning and memory, the elucidation of its constituting mechanisms is of crucial importance in many aspects of normal and pathological brain function. In particular, a prominent aspect that remains debated is how the plasticity mechanisms, that encompass a broad spectrum of temporal and spatial scales, come to play together in a concerted fashion. Here we review and discuss evidence that pinpoints to a possible non-neuronal, glial candidate for such orchestration: the regulation of synaptic plasticity by astrocytes

Targeting the cation-chloride co-transporter NKCC1 to re-establish GABAergic inhibition and an appropriate excitatory/inhibitory balance in selective neuronal circuits: a novel approach for the treatment of Alzheimer's disease

GABA, the main inhibitory neurotransmitter in the adult brain, depolarizes and excites immature neurons because of an initially higher intracellular chloride concentration [Cl-]i due to the delayed expression of the chloride exporter KCC2 at birth. Depolarization-induced calcium rise via NMDA receptors and voltage-dependent calcium channels is instrumental in shaping neuronal circuits and in controlling the excitatory (E)/inhibitory (I) balance in selective brain areas. An E/I imbalance accounts for cognitive impairment observed in several neuropsychiatric disorders. The aim of this review is to summarize recent data on the mechanisms by which alterations of GABAergic signaling alter the E/I balance in cortical and hippocampal neurons in Alzheimer's disease (AD) and the role of cation-chloride co-transporters in this process. In particular, we discuss the NGF and AD relationship and how mice engineered to express recombinant neutralizing anti-NGF antibodies (AD11 mice), which develop a neurodegenerative pathology reminiscent of that observed in AD patients, exhibit a depolarizing action of GABA due to KCC2 impairment. Treating AD and other forms of dementia with bumetanide, a selective KCC2 antagonist, contributes to re-establishing a proper E/I balance in selective brain areas, leading to amelioration of AD symptoms and the slowing down of disease progression

Novel Brain Networks Influenced by Ageing: Effects on Gene Expression and Synapses of Diet-Induced Obesity

Obesity and ageing are contributing factors to many diseases and deaths across the world. Both are also linked to cognitive decline, synaptic dysfunction and brain volume loss outside of a disease context. Since these factors have shown similar outcomes, it has been hypothesised that an interaction between them may exacerbate mutual pathology. Investigation of the interaction of these two conditions may identify the pathways and mechanisms underlying obesity-related and age-related cognitive dysfunction in the brain. The current work studied a HFD mouse model of obesity across age, from adulthood to the end of mid-life, to discover the impact of the interaction ageing and obesity on synaptic transmission and gene expression. The metabolic and physiological outcomes of the HFD model across age were characterised as well as synaptic transmission and plasticity at 6 and 18 months. A reversal of the HFD to a chow LFD during mid-life to early old age (14-18 months) was used to examine if diet reversal could alter the negative outcomes caused by obesity. The current study found that high-fat diet caused extreme gain in weight, hyperphagia and hyperglycaemia that was maintained across the lifespan, as well as decreased survival and an increased liver cancer rate. No changes in excitatory glutamatergic transmission were found due to an interaction between ageing and obesity. Gene expression analysis found no clear effect of this interaction upon genetic pathways associated with ageing or obesity. However, postsynaptic changes due to the effect of obesity were identified at 18 months of age. A reversal of the HFD removed the HFD-induced weight gain and hyperglycaemia but had no impact upon synaptic transmission. Therefore the current work did not find that the interaction between age and obesity had strong effects upon synaptic transmission and genetic pathways from adulthood to the end of mid-life in the hippocampus

Experience-dependent changes in hippocampal spatial activity and hippocampal circuit function are disrupted in a rat model of Fragile X Syndrome

BACKGROUND: Fragile X syndrome (FXS) is a common single gene cause of intellectual disability and autism spectrum disorder. Cognitive inflexibility is one of the hallmarks of FXS with affected individuals showing extreme difficulty adapting to novel or complex situations. To explore the neural correlates of this cognitive inflexibility, we used a rat model of FXS (Fmr1(−/y)). METHODS: We recorded from the CA1 in Fmr1(−/y) and WT littermates over six 10-min exploration sessions in a novel environment—three sessions per day (ITI 10 min). Our recordings yielded 288 and 246 putative pyramidal cells from 7 WT and 7 Fmr1(−/y) rats, respectively. RESULTS: On the first day of exploration of a novel environment, the firing rate and spatial tuning of CA1 pyramidal neurons was similar between wild-type (WT) and Fmr1(−/y) rats. However, while CA1 pyramidal neurons from WT rats showed experience-dependent changes in firing and spatial tuning between the first and second day of exposure to the environment, these changes were decreased or absent in CA1 neurons of Fmr1(−/y) rats. These findings were consistent with increased excitability of Fmr1(−/y) CA1 neurons in ex vivo hippocampal slices, which correlated with reduced synaptic inputs from the medial entorhinal cortex. Lastly, activity patterns of CA1 pyramidal neurons were dis-coordinated with respect to hippocampal oscillatory activity in Fmr1(−/y) rats. LIMITATIONS: It is still unclear how the observed circuit function abnormalities give rise to behavioural deficits in Fmr1(−/y) rats. Future experiments will focus on this connection as well as the contribution of other neuronal cell types in the hippocampal circuit pathophysiology associated with the loss of FMRP. It would also be interesting to see if hippocampal circuit deficits converge with those seen in other rodent models of intellectual disability. CONCLUSIONS: In conclusion, we found that hippocampal place cells from Fmr1(−/y) rats show similar spatial firing properties as those from WT rats but do not show the same experience-dependent increase in spatial specificity or the experience-dependent changes in network coordination. Our findings offer support to a network-level origin of cognitive deficits in FXS. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s13229-022-00528-z

Astrocytes: orchestrating synaptic plasticity?

Synaptic plasticity is the capacity of a preexisting connection between two neurons to change in strength as a function of neural activity. Because synaptic plasticity is the major candidate mechanism for learning and memory, the elucidation of its constituting mechanisms is of crucial importance in many aspects of normal and pathological brain function. In particular, a prominent aspect that remains debated is how the plasticity mechanisms, that encompass a broad spectrum of temporal and spatial scales, come to play together in a concerted fashion. Here we review and discuss evidence that pinpoints to a possible non-neuronal, glial candidate for such orchestration: the regulation of synaptic plasticity by astrocytes.Comment: 63 pages, 4 figure