Role In Homeostatic Plasticity Research Articles

HOMER1 Polymorphism and Parkinson's Disease-Psychosis: Is there an Association?

Homer1, a postsynaptic protein coded by the HOMER1 gene, presumably has a role in homeostatic plasticity that dampens neuronal responsiveness when the input activity is too high. HOMER1 polymorphism has been studied in major psychiatric disorders such as schizophrenia. The objective of this study is to investigate if polymorphisms of the HOMER1 gene are associated with psychosis in Parkinson's disease (PD-P). One hundred patients with Parkinson's disease (PD) and 100 healthy controls were enrolled consecutively in a PD-P biomarker study at the National Institute of Mental Health and Neurosciences, Bangalore, India. Of the 100 PD patients, 50 had psychosis (PD-P) and 50 did not have psychosis (PD-NP). Two single-nucleotide polymorphisms of HOMER1 (rs4704559 and rs4704560) were analyzed from the DNA isolated from peripheral blood. The allele and genotype frequencies in the PD-P and PD-NP groups were compared. Analysis of HOMER1 rs4704560 revealed a significant difference in both genotype and allele levels between PD-P and PD-NP groups. There was an overrepresentation of T-allele (42% vs. 16%; P < 0.001) and TT genotype (24% vs. 6%; P < 0.001) in the PD-P group compared to PD-NP group. There was no significant difference between PD-P and PD-NP groups when various genotypes and allele frequencies related to HOMER1 rs4704559 were compared. PD-P is probably associated with overrepresentation of T-allele of HOMER1 rs4704560, and larger studies are warranted to confirm our results.

Homeostatic Synaptic Plasticity may be Targeted for the Prevention of Post-Stroke Epilepsy

Stroke is the most common cause of acquired epilepsy, with up to 30 percent of stroke survivors developing epilepsy over time. However, the mechanisms leading to neuronal hyperexcitability and epilepsy in stroke survivors are not fully understood. In a recently published work, we demonstrate that ischemic stroke induces homeostatic plasticity regulation in the surviving neurons in the peri-stroke area. Furthermore, activity enhancement through optogenetic stimulation of excitatory pyramidal neurons in the peri-stroke area or systemic administration of D-cycloserine, a partial N-methyl-D-aspartate (NMDA) receptor agonist, reduces seizure susceptibility in mice. Here, we briefly review current understanding on the role of homeostatic plasticity in post-stroke epileptogenesis and discuss how homeostatic plasticity could be targeted to prevent post-stroke epilepsy. We comment on our activity enhancement findings and close by discussing implications for clinical treatment.

Ca2+ influx and clearance at hyperpolarized membrane potentials modulate spontaneous and stimulated exocytosis in neuroendocrine cells

Neuroendocrine adrenal chromaffin cells release neurohormones catecholamines in response to Ca2+ entry via voltage-gated Ca2+ channels (VGCCs). Adrenal chromaffin cells also express non-voltage-gated channels, which may conduct Ca2+ at negative membrane potentials, whose role in regulation of exocytosis is poorly understood. We explored how modulation of Ca2+ influx at negative membrane potentials affects basal cytosolic Ca2+ concentration ([Ca2+]i) and exocytosis in metabolically intact voltage-clamped bovine adrenal chromaffin cells. We found that in these cells, Ca2+ entry at negative membrane potentials is balanced by Ca2+ extrusion by the Na+/Ca2+ exchanger and that this balance can be altered by membrane hyperpolarization or stimulation with an inflammatory hormone bradykinin. Membrane hyperpolarization or application of bradykinin augmented Ca2+-carrying current at negative membrane potentials, elevated basal [Ca2+]i, and facilitated synchronous exocytosis evoked by the small amounts of Ca2+ injected into the cell via VGCCs (up to 20 pC). Exocytotic responses evoked by the injections of the larger amounts of Ca2+ via VGCCs (> 20 pC) were suppressed by preceding hyperpolarization. In the absence of Ca2+ entry via VGCCs and Ca2+ extrusion via the Na+/Ca2+ exchanger, membrane hyperpolarization induced a significant elevation in [Ca2+]i and asynchronous exocytosis. Our results indicate that physiological interferences, such as membrane hyperpolarization and/or activation of non-voltage-gated Ca2+ channels, modulate basal [Ca2+]i and, consequently, segregation of exocytotic vesicles and their readiness to be released spontaneously and in response to Ca2+ entry via VGCCs. These mechanisms may play role in homeostatic plasticity of neuronal and endocrine cells.

GluA4 subunit of AMPA receptors mediates the early synaptic response to altered network activity in the developing hippocampus.

Development of the neuronal circuitry involves both Hebbian and homeostatic plasticity mechanisms that orchestrate activity-dependent refinement of the synaptic connectivity. AMPA receptor subunit GluA4 is expressed in hippocampal pyramidal neurons during early postnatal period and is critical for neonatal long-term potentiation; however, its role in homeostatic plasticity is unknown. Here we show that GluA4-dependent plasticity mechanisms allow immature synapses to promptly respond to alterations in network activity. In the neonatal CA3, the threshold for homeostatic plasticity is low, and a 15-h activity blockage with tetrodotoxin triggers homeostatic upregulation of glutamatergic transmission. On the other hand, attenuation of the correlated high-frequency bursting in the CA3-CA1 circuitry leads to weakening of AMPA transmission in CA1, thus reflecting a critical role for Hebbian synapse induction in the developing CA3-CA1. Both of these developmentally restricted forms of plasticity were absent in GluA4(-/-) mice. These data suggest that GluA4 enables efficient homeostatic upscaling and responsiveness to temporal activity patterns during the critical period of activity-dependent refinement of the circuitry.

A Role for Stargazin in Experience-Dependent Plasticity

During development, neurons are constantly refining their connections in response to changes in activity. Experience-dependent plasticity is a key form of synaptic plasticity, involving changes in α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) accumulation at synapses. Here, we report a critical role for the AMPAR auxiliary subunit stargazin in this plasticity. We show that stargazin is functional at the retinogeniculate synapse and that in the absence of stargazin, the refinement of the retinogeniculate synapse is specifically disrupted during the experience-dependent phase. Importantly, we found that stargazin expression and phosphorylation increased with visual deprivation and led to reduced AMPAR rectification at the retinogeniculate synapse. To test whether stargazin plays a role in homeostatic plasticity, we turned to cultured neurons and found that stargazin phosphorylation is essential for synaptic scaling. Overall, our data reveal an important role for stargazin in regulating AMPAR abundance and composition at glutamatergic synapses during homeostatic and experience-dependent plasticity.