Changes In Synaptic Protein Expression Research Articles

Early-life adversity increases anxiety-like behavior and modifies synaptic protein expression in a region-specific manner.

Early-life adversity (ELA) can induce persistent neurological changes and increase the risk for developing affective or substance use disorders. Disruptions to the reward circuitry of the brain and pathways serving motivation and emotion have been implicated in the link between ELA and altered adult behavior. The molecular mechanisms that mediate the long-term effects of ELA, however, are not fully understood. We examined whether ELA in the form of neonatal maternal separation (MatSep) modifies behavior and synaptic protein expression in adults. We hypothesized that MatSep would affect dopaminergic and glutamatergic signaling and enhance sensitivity to methamphetamine (Meth) reward or increase anxiety. Male Wistar rats were subjected to MatSep for 180 min/d on postnatal days (PND) 2-14 and allowed to grow to adulthood (PND 60) with no further manipulation. The hippocampus (Hipp), medial prefrontal cortex (mPFC), nucleus accumbens (NAc), and caudate putamen (CPu) were isolated from one subgroup of animals and subjected to Western blot and protein quantitation for tyrosine hydroxylase (TH), α-synuclein (ALPHA), NMDA receptor (NMDAR), dopamine receptor-1 (D1) and -2 (D2), dopamine transporter (DAT), and postsynaptic density 95 (PSD95). Separate group of animals were tested for anxiety-like behavior and conditioned place preference (CPP) to Meth at 0.0, 0.1, and 1.0 mg/kg doses. MatSep rats displayed an increase in basal levels of anxiety-like behavior compared to control animals. MatSep rats also demonstrated CPP to Meth, but their responses did not differ significantly from controls at any drug dose. Increased NMDAR, D2, and ALPHA expression was observed in the NAc and CPu following MatSep; D2 and ALPHA levels were also elevated in the mPFC, along with DAT. MatSep rats had reduced D1 expression in the mPFC and Hipp, with the Hipp also showing a reduction in D2. Only the CPu showed elevated TH and decreased DAT expression levels. No significant changes were found in PSD95 expression in MatSep rats. In conclusion, ELA is associated with long-lasting and region-specific changes in synaptic protein expression that diminish dopamine neurotransmission and increase anxiety-like behavior in adults. These findings illustrate potential mechanisms through which ELA may increase vulnerability to stress-related illness.

Environmental Enrichment Upregulates Striatal Synaptic Vesicle-Associated Proteins and Improves Motor Function

Environmental enrichment (EE) is a therapeutic paradigm that consists of complex combinations of physical, cognitive, and social stimuli. The mechanisms underlying EE-mediated synaptic plasticity have yet to be fully elucidated. In this study, we investigated the effects of EE on synaptic vesicle-associated proteins and whether the expression of these proteins is related to behavioral outcomes. A total of 44 CD-1® (ICR) mice aged 6 weeks were randomly assigned to either standard cages or EE (N = 22 each). Rotarod and ladder walking tests were then performed to evaluate motor function. To identify the molecular mechanisms underlying the effects of EE, we assessed differentially expressed proteins (DEPs) in the striatum by proteomic analysis. Quantitative real-time polymerase chain reaction (qRT-PCR), western blot, and immunohistochemistry were conducted to validate the expressions of these proteins. In the behavioral assessment, EE significantly enhanced performance on the rotarod and ladder walking tests. A total of 116 DEPs (54 upregulated and 62 downregulated proteins) were identified in mice exposed to EE. Gene ontology (GO) analysis demonstrated that the upregulated proteins in EE mice were primarily related to biological processes of synaptic vesicle transport and exocytosis. The GO terms for these biological processes commonly included Synaptic vesicle glycoprotein 2B (SV2B), Rabphilin-3A, and Piccolo. The qRT-PCR and western blot analyses revealed that EE increased the expression of SV2B, Rabphilin-3A and Piccolo in the striatum compared to the control group. Immunohistochemistry showed that the density of Piccolo in the vicinity of the subventricular zone was significantly increased in the EE mice compared with control mice. In conclusion, EE upregulates proteins associated with synaptic vesicle transport and exocytosis such as SV2B, Rabphilin-3A and Piccolo in the striatum. These upregulated proteins may be responsible for locomotor performance improvement, as shown in rotarod and ladder walking tests. Elucidation of these changes in synaptic protein expression provides new insights into the mechanism and potential role of EE.

Nuclear and membrane estrogen receptor antagonists induce similar mTORC2 activation-reversible changes in synaptic protein expression and actin polymerization in the mouse hippocampus.

Estrogens play pivotal roles in hippocampal synaptic plasticity through nuclear receptors (nERs; including ERα and ERβ) and the membrane receptor (mER; also called GPR30), but the underlying mechanism and the contributions of nERs and mER remain unclear. Mammalian target of rapamycin complex 2 (mTORC2) is involved in actin cytoskeleton polymerization and long-term memory, but whether mTORC2 is involved in the regulation of hippocampal synaptic plasticity by ERs is unclear. We treated animals with nER antagonists (MPP/PHTPP) or the mER antagonist (G15) alone or in combination with A-443654, an activator of mTORC2. Then, we examined the changes in hippocampal SRC-1 expression, mTORC2 signaling (rictor and phospho-AKTSer473), actin polymerization (phospho-cofilin and profilin-1), synaptic protein expression (GluR1, PSD95, spinophilin, and synaptophysin), CA1 spine density, and synapse density. All of the examined parameters except synaptophysin expression were significantly decreased by MPP/PHTPP and G15 treatment. MPP/PHTPP and G15 induced a similar decrease in most parameters except p-cofilin, GluR1, and spinophilin expression. The ER antagonist-induced decreases in these parameters were significantly reversed by mTORC2 activation, except for the change in SRC-1, rictor, and synaptophysin expression. nERs and mER contribute similarly to the changes in proteins and structures associated with synaptic plasticity, and mTORC2 may be a novel target of hippocampal-dependent dementia such as Alzheimer's disease as proposed by previous studies.

Cognitive impairments associated with alterations in synaptic proteins induced by the genetic loss of adenosine A2A receptors in mice

The study of psychiatric disorders usually focuses on emotional symptoms assessment. However, cognitive deficiencies frequently constitute the core symptoms, are often poorly controlled and handicap individual's quality of life. Adenosine receptors, through the control of both dopamine and glutamate systems, have been implicated in the pathophysiology of several psychiatric disorders such as schizophrenia and attention deficit/hyperactivity disorder. Indeed, clinical data indicate that poorly responsive schizophrenia patients treated with adenosine adjuvants show improved treatment outcomes. The A2A adenosine receptor subtype (A2AR) is highly expressed in brain areas controlling cognition and motivational responses including the striatum, hippocampus and cerebral cortex. Accordingly, we study the role of A2AR in the regulation of cognitive processes based on a complete cognitive behavioural analysis coupled with the assessment of neurogenesis and sub-synaptic protein expression in adult and middle-aged A2AR constitutional knockout mice and wild-type littermates. Our results show overall cognitive impairments in A2AR knockout mice associated with a decrease in new-born hippocampal neuron proliferation and concomitant changes in synaptic protein expression, in both the prefrontal cortex and the hippocampus. These results suggest a deficient adenosine signalling in cognitive processes, thus providing new opportunities for the therapeutic management of cognitive deficits associated with psychiatric disorders.

FXR1P Limits Long-Term Memory, Long-Lasting Synaptic Potentiation, and De Novo GluA2 Translation

Translational control of mRNAs allows for rapid and selective changes in synaptic protein expression that are required for long-lasting plasticity and memory formation in the brain. Fragile X Related Protein 1 (FXR1P) is an RNA-binding protein that controls mRNA translation in nonneuronal cells and colocalizes with translational machinery in neurons. However, its neuronal mRNA targets and role in the brain are unknown. Here, we demonstrate that removal ofFXR1P from the forebrain of postnatal mice selectively enhances long-term storage of spatial memories, hippocampal late-phase long-term potentiation (L-LTP), and de novo GluA2 synthesis. Furthermore, FXR1P binds specifically to the 5' UTR of GluA2 mRNA to repress translation and limit the amount ofGluA2 that is incorporated at potentiated synapses. This study uncovers a mechanism for regulating long-lasting synaptic plasticity and spatial memory formation and reveals an unexpected divergent role of FXR1P among Fragile X proteins in brain plasticity.

P2‐432: Combined nutrient enrichment induces changes in synaptic protein expression in vitro

P2‐432: Combined nutrient enrichment induces changes in synaptic protein expression <i>in vitro</i>

Experience‐dependent regulation of functional maps and synaptic protein expression in the cat visual cortex

Although the basis of our knowledge of experience-dependent plasticity comes from studies on carnivores and primates, studies examining the physiological and molecular mechanisms that underlie development and plasticity have increasingly employed mice. We have used several common rearing paradigms, such as dark-rearing and monocular deprivation (MD), to examine the timing of the physiological and molecular changes to altered experience in the cat primary visual cortex. Dark-rearing from birth or for 1 week starting at 4 weeks of age produced a similar reduction in the amplitude of responses measured through intrinsic signal imaging and a reduction in orientation selectivity. One week of visual experience following dark-rearing until 4 weeks of age yielded normal responses in both amplitude and orientation selectivity. The depression of deprived-eye responses was similar in magnitude after 2 and 7 days of MD. In contrast, non-deprived-eye responses almost doubled in magnitude after 7 days compared with 2 days of MD. These changes in the functional properties of primary visual cortex neurons were mirrored by specific changes in synaptic protein expression. Changes in proteins such as the NR2A and NR2B subunits of the N-methyl-D-aspartate receptor, postsynaptic density protein 95, alpha-CA(2+) /calmodulin-dependent protein kinase II (αCaMKII), and GABA(A) α1a indicated that the levels of sensory activity regulated mechanisms associated with both excitatory (NR2A and NR2B) and inhibitory (GABA(A) α1a) transmission so as to maintain response homeostasis. Additionally, we found that MD regulated the AMPA receptor glutamate (GluR1) subunit as well as signalling molecules (αCaMKII and synaptic Ras GTPase activating protein, SynGAP) downstream of N-methyl-D-aspartate receptors. Proteins in a common signalling pathway appeared to have similar developmental expression profiles that were broadly similar between cats and rodents.

Multi-nutrient supplementation induces changes in synaptic protein expression in PC12 cells, relevant to Alzheimer's disease

Multi-nutrient supplementation induces changes in synaptic protein expression in PC12 cells, relevant to Alzheimer's disease

P4‐258: Multi‐nutrient supplementation induces changes in synaptic protein expression

P4‐258: Multi‐nutrient supplementation induces changes in synaptic protein expression

Multi-nutrient supplementation induces changes in synaptic protein expression in PC12 cells, relevant to Alzheimer's disease

Multi-nutrient supplementation induces changes in synaptic protein expression in PC12 cells, relevant to Alzheimer's disease

Chronic fluoxetine treatment increases expression of synaptic proteins in the hippocampus of the ovariectomized rat: Role of BDNF signalling

Antidepressant drugs have been suggested to regulate synaptic transmission and structure. We hypothesised that antidepressant-induced changes in synapses and their associated proteins might become more apparent if they were measured under conditions of reduced synapse density. Therefore, in the present study, we examined whether chronic treatment with the antidepressant, fluoxetine alters expression of synaptic proteins in the hippocampus of rodents that underwent ovariectomy, a procedure which reportedly decreases synapse density in the CA1 region of the rat hippocampus. Using Western blotting, we measured changes in hippocampal expression of proteins associated with synapse structure, strength and activity namely, postsynaptic density protein 95 (PSD-95), the alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPA-R) subunit GluR1 and phosphosynapsin (Ser9), respectively. We found that fluoxetine treatment increased expression of phosphosynapsin, PSD-95 and synaptic GluR1 (but not total GluR1) in the hippocampus of ovariectomized but not sham rats. Since BDNF and signalling at its receptor, TrkB, can mediate behavioural responses to antidepressants and induce neuronal plasticity, we investigated the contribution of TrkB signalling to fluoxetine-induced changes in synaptic protein expression by using a transgenic mouse model overexpressing a truncated form of the TrkB receptor (TrkB.T1). Fluoxetine produced a small but significant increase in hippocampal PSD-95 in ovariectomized wildtype mice but not in ovariectomized TrkB.T1 mice or sham mice. In contrast to rats, fluoxetine did not alter expression of synaptic GluR1 and did not reverse ovariectomy-induced decreases in hippocampal phosphosynapsin in either genotype. Taken together, these results suggest that chronic fluoxetine treatment can increase synaptic protein expression in the hippocampus and at least some of these effects require TrkB signalling. Moreover, these effects were only observed in ovariectomized animals, thus suggesting that fluoxetine-induced increases in synaptic protein levels might only occur or become detectable when hippocampal synaptic connectivity is perturbed.