Glutamatergic regulation prevents hippocampal-dependent age-related cognitive decline through dendritic spine clustering

Abstract

The dementia of Alzheimer's disease (AD) results primarily from degeneration of neurons that furnish glutamatergic corticocortical connections that subserve cognition. Although neuron death is minimal in the absence of AD, age-related cognitive decline does occur in animals as well as humans, and it decreases quality of life for elderly people. Age-related cognitive decline has been linked to synapse loss and/or alterations of synaptic proteins that impair function in regions such as the hippocampus and prefrontal cortex. These synaptic alterations are likely reversible, such that maintenance of synaptic health in the face of aging is a critically important therapeutic goal. Here, we show that riluzole can protect against some of the synaptic alterations in hippocampus that are linked to age-related memory loss in rats. Riluzole increases glutamate uptake through glial transporters and is thought to decrease glutamate spillover to extrasynaptic NMDA receptors while increasing synaptic glutamatergic activity. Treated aged rats were protected against age-related cognitive decline displayed in nontreated aged animals. Memory performance correlated with density of thin spines on apical dendrites in CA1, although not with mushroom spines. Furthermore, riluzole-treated rats had an increase in clustering of thin spines that correlated with memory performance and was specific to the apical, but not the basilar, dendrites of CA1. Clustering of synaptic inputs is thought to allow nonlinear summation of synaptic strength. These findings further elucidate neuroplastic changes in glutamatergic circuits with aging and advance therapeutic development to prevent and treat agerelated cognitive decline.cognitive aging | glutamate | riluzole | neuroplasticity | dendritic spine clustering C ognitive decline often occurs with aging in rodents (1), nonhuman primates (2), and humans (3). Memory loss (4) and executive impairment (5) are of the most functional importance, mediated primarily by the hippocampus and related areas of the medial temporal lobe and the prefrontal cortex (PFC), respectively. The neural circuits vulnerable to aging are composed of glutamatergic pyramidal neurons that furnish corticocortical connections between the association cortices as well as the excitatory hippocampal connections (2, 6). Dendritic spine changes, which appear to be the primary site of structural plasticity in the adult brain (7), occur in the pyramidal neurons of the PFC (5) and in the hippocampus (8, 9) with aging and correlate with behavioral decline. Spines form the postsynaptic component of most excitatory synapses in the cerebral cortex and are capable of rapid formation, expansion, contraction, and elimination (10, 11).Synaptic glutamatergic activity is neuroprotective and critical for long-term potentiation (LTP) and memory formation, whereas extrasynaptic NMDA receptor activity promotes longterm depression and excitotoxicity (12, 13). There is some evidence that astrocytic glutamate transporters decrease with aging (14, 15), and conse...

Stress Effects on Neuronal Structure: Hippocampus, Amygdala, and Prefrontal Cortex

“…In another study involving modulation of excitatory amino-acid actions (Pereira et al, 2014), riluzole was used because it increases glutamate uptake through glial transporters and is thought to decrease glutamate spillover to extrasynaptic NMDA receptors while increasing synaptic glutamatergic activity. Aging rats treated between 10 and 14 months of age were protected against the age-related cognitive decline displayed in non-treated aged animals.…”

“…Furthermore, riluzole-treated rats had an increase in clustering of thin spines that correlated with memory performance and was specific to the apical, but not the basilar, dendrites of CA1. Clustering of synaptic inputs is thought to allow nonlinear summation of synaptic strength (Pereira et al, 2014).…”

Update on Alzheimer's Disease Therapy and Prevention Strategies

“…Clinical data indicate that crenezumab reduces plaques with no vasogenic edema risk, and it is currently being tested in a phase II trial and in a five-year prevention trial. Gantenerumab (Chugai Pharmaceutical Co., Ltd., Roche) ( Table 1) is the first fully human anti-Aβ IgG1 that appears to recognize both the N-terminal tail (Aβ [3][4][5][6][7][8][9][10][11][12] ) and the central region (Aβ [18][19][20][21][22][23][24][25][26][27] ). It has moderate binding affinity to monomers and oligomers and potently binds to and degrades fibrils (39).…”

“…mouse model of disease (3). Accordingly, riluzole (Table 1), an inhibitor of glutamate release and postsynaptic glutamate receptor signaling, is in a phase II trial in mild AD patients.…”

Epigenetic Interactions and the Brain-Body Communication

“…Even in adulthood, gene expression in the brain continually changes with experience [10], and there is loss of resilience of neural architecture with aging [34] that can be redirected by exercise [35] and, to some extent, by pharmacological intervention [36,37]. More generally, there are new approaches to opening windows of plasticity and redirecting the brain towards a more health-promoting state.…”