Most excitatory transmission in the brain is mediated by the AMPA receptor subtype of the ionotropic glutamate receptors. In many neurological diseases, synapse structure and AMPA receptor function are altered, thus making AMPA receptors potential therapeutic targets for clinical intervention. The work summarized in this review suggests a link between AMPA receptor function and debilitating neuropathologies, and discusses the current state of therapies targeting AMPA receptors in four diseases. In amyotrophic lateral sclerosis, AMPA receptors allow cytotoxic levels of calcium into neurons, leading to motor neuron death. Likewise, in some epilepsies, overactivation of AMPA receptors leads to neuron damage. The same is true for ischemia, where oxygen deprivation leads to excitotoxicity. Conversely, Alzheimer's disease is characterized by decreased AMPA activation and synapse loss. Unfortunately, many clinical studies have had limited success by directly targeting AMPA receptors in these diseases. We also discuss how the use of AMPA receptor modulators, commonly known as ampakines, in neurological diseases initially seemed promising in animal studies, but mostly ineffective in clinical trials. We propose that indirectly affecting AMPA receptors, such as by modulating transmembrane AMPA receptor regulatory proteins or, more generally, by regulating glutamatergic transmission, may provide new therapeutic potential for neurological disorders.

BackgroundRecent studies have revealed that excessive activation of microglia and inflammation-mediated neurotoxicity are implicated in the progression of several neurological disorders. In particular, chronic inflammation in vivo and exposure of cultured brain cells to lipopolysaccharide (LPS) in vitro can adversely change microglial morphology and function. This can have both direct and indirect effects on synaptic structures and functions. The integrity of dendritic spines, the postsynaptic component of excitatory synapses, dictates synaptic efficacy. Interestingly, dysgenesis of dendritic spines has been found in many neurological diseases associated with ω-3 polyunsaturated fatty acid (PUFA) deficiency and cognitive decline. In contrast, supplemented ω-3 PUFAs, such as docosahexaenoic acid (DHA), can partly correct spine defects. Hence, we hypothesize that DHA directly affects synaptic integrity and indirectly through neuron-glia interaction. Strong activation of microglia by LPS is accompanied by marked release of nitric oxide and formation of lipid bodies (LBs), both dynamic biomarkers of inflammation. Here we investigated direct effects of DHA on synaptic integrity and its indirect effects via microglia in the hippocampal CA1 region.MethodsMicroglia (N9) and organotypic hippocampal slice cultures were exposed to the proinflammagen LPS (100 ng/ml) for 24 h. Biochemical and morphological markers of inflammation were investigated in microglia and CA1 regions of hippocampal slices. As biomarkers of hyperactive microglia, mitochondrial function, nitric oxide release and LBs (number, size, LB surface-associated proteins) were assessed. Changes in synaptic transmission of CA1 pyramidal cells were determined following LPS and DHA (25-50 μM) treatments by recording spontaneous AMPA-mediated miniature excitatory postsynaptic currents (mEPSCs).ResultsMicroglia responded to LPS stimulation with a significant decrease of mitochondrial function, increased nitric oxide production and an increase in the formation of large LBs. LPS treatment led to a significant reduction of dendritic spine densities and an increase in the AMPA-mediated mEPSC inter-event interval (IEI). DHA normalized the LPS-induced abnormalities in both neurons and microglia, as revealed by the restoration of synaptic structures and functions in hippocampal CA1 pyramidal neurons.ConclusionOur findings indicate that DHA can prevent LPS-induced abnormalities (neuroinflammation) by reducing inflammatory biomarkers, thereby normalizing microglia activity and their effect on synaptic function.Electronic supplementary materialThe online version of this article (doi:10.1186/s12974-015-0244-5) contains supplementary material, which is available to authorized users.

Hyperactivity of microglia and loss of functional circuitry is a common feature of many neurological disorders including those induced or exacerbated by inflammation. Herein, we investigate the response of microglia and changes in hippocampal dendritic postsynaptic spines by dendritic polyglycerol sulfate (dPGS) treatment. Mouse microglia and organotypic hippocampal slices were exposed to dPGS and an inflammogen (lipopolysaccharides). Measurements of intracellular fluorescence and confocal microscopic analyses revealed that dPGS is avidly internalized by microglia but not CA1 pyramidal neurons. Concentration and time-dependent response studies consistently showed no obvious toxicity of dPGS. The adverse effects induced by proinflammogen LPS exposure were reduced and dendritic spine morphology was normalized with the addition of dPGS. This was accompanied by a significant reduction in nitrite and proinflammatory cytokines (TNF-α and IL-6) from hyperactive microglia suggesting normalized circuitry function with dPGS treatment. Collectively, these results suggest that dPGS acts anti-inflammatory, inhibits inflammation-induced degenerative changes in microglia phenotype and rescues dendritic spine morphology.

Autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS) is an early-onset neurodegenerative disease that includes a pronounced and progressive cerebellar dysfunction. ARSACS is caused by an autosomal recessive loss-of-function mutation in the Sacs gene that encodes the protein sacsin. To better understand the cerebellar pathophysiology in ARSACS, we studied synaptic and firing properties of Purkinje cells from a mouse model of ARSACS, Sacs mice. We found that excitatory synaptic drive was reduced onto Sacs Purkinje cells, and that Purkinje cell firing rate, but not regularity, was reduced at postnatal day (P)40, an age when ataxia symptoms were first reported. Firing rate deficits were limited to anterior lobules that later display Purkinje cell death, and were not observed in posterior lobules where Purkinje cells are not lost. Mild firing deficits were observed as early as P20, prior to the manifestation of motor deficits, suggesting that a critical level of cerebellar dysfunction is required for motor coordination to emerge. Finally, we observed a reduction in Purkinje cell innervation onto target neurons in the deep cerebellar nuclei (DCN) in Sacs mice. Together, these findings suggest that multiple alterations in the cerebellar circuit including Purkinje cell input and output contribute to cerebellar-related disease onset in ARSACS.

Accumulating evidence supports the idea that synapses are tripartite, whereby perisynaptic astrocytes modulate both pre- and postsynaptic function. Although some of these features have been uncovered by using electrophysiological methods, less is known about the structural interplay between synapses and glial processes. Here, we investigated how astrocytes govern the plasticity of individual hippocampal dendritic spines. Recently, we uncovered that a subgroup of innervated dendritic spines is able to undergo remodeling by extending spine head protrusions (SHPs) toward neighboring functional presynaptic boutons, resulting in new synapses. Although glutamate serves as a trigger, how this behavior is regulated is unknown. As astrocytes control extracellular glutamate levels through their high-affinity uptake transporters, together with their privileged access to synapses, we investigated a role for astrocytes in SHP formation. Using time-lapse confocal microscopy, we found that the volume overlap between spines and astrocytic processes decreased during the formation of SHPs. Focal application of glutamate also reduced spine-astrocyte overlap and induced SHPs. Importantly, SHP formation was prevented by blocking glial glutamate transporters, suggesting that glial control of extracellular glutamate is important for SHP-mediated plasticity of spines. Hence, the dynamic changes of both spines and astrocytes can rapidly modify synaptic connectivity.