Network Synaptic Plasticity Research Articles

Common Cholinergic, Noradrenergic, and Serotonergic Drugs Do Not Block VNS-Mediated Plasticity.

Vagus nerve stimulation (VNS) delivered during motor rehabilitation enhances recovery from a wide array of neurological injuries and was recently approved by the U.S. FDA for chronic stroke. The benefits of VNS result from precisely timed engagement of neuromodulatory networks during rehabilitative training, which promotes synaptic plasticity in networks activated by rehabilitation. Previous studies demonstrate that lesions that deplete these neuromodulatory networks block VNS-mediated plasticity and accompanying enhancement of recovery. There is a great deal of interest in determining whether commonly prescribed pharmacological interventions that influence these neuromodulatory networks would similarly impair VNS effects. Here, we sought to directly test the effects of three common pharmaceuticals at clinically relevant doses that target neuromodulatory pathways on VNS-mediated plasticity in rats. To do so, rats were trained on a behavioral task in which jaw movement during chewing was paired with VNS and received daily injections of either oxybutynin, a cholinergic antagonist, prazosin, an adrenergic antagonist, duloxetine, a serotonin-norepinephrine reuptake inhibitor, or saline. After the final behavioral session, intracortical microstimulation (ICMS) was used to evaluate reorganization of motor cortex representations, with area of cortex eliciting jaw movement as the primary outcome. In animals that received control saline injections, VNS paired with training significantly increased the movement representation of the jaw compared to naïve animals, consistent with previous studies. Similarly, none of the drugs tested blocked this VNS-dependent reorganization of motor cortex. The present results provide direct evidence that these common pharmaceuticals, when used at clinically relevant doses, are unlikely to adversely impact the efficacy of VNS therapy.

New light on cortical neuropeptides and synaptic network plasticity

Neuropeptides, members of a large and evolutionarily ancient family of proteinaceous cell-cell signaling molecules, are widely recognized as extremely potent regulators of brain function and behavior. At the cellular level, neuropeptides are known to act mainly via modulation of ion channel and synapse function, but functional impacts emerging at the level of complex cortical synaptic networks have resisted mechanistic analysis. New findings from single-cell RNA-seq transcriptomics now illuminate intricate patterns of cortical neuropeptide signaling gene expression and new tools now offer powerful molecular access to cortical neuropeptide signaling. Here we highlight some of these new findings and tools, focusing especially on prospects for experimental and theoretical exploration of peptidergic and synaptic networks interactions underlying cortical function and plasticity.

Enhancement of Learning and Memory by Elevating Brain Magnesium

Learning and memory are fundamental brain functions affected by dietary and environmental factors. Here, we show that increasing brain magnesium using a newly developed magnesium compound (magnesium-L-threonate, MgT) leads to the enhancement of learning abilities, working memory, and short- and long-term memory in rats. The pattern completion ability was also improved in aged rats. MgT-treated rats had higher density of synaptophysin-/synaptobrevin-positive puncta in DG and CA1 subregions of hippocampus that were correlated with memory improvement. Functionally, magnesium increased the number of functional presynaptic release sites, while it reduced their release probability. The resultant synaptic reconfiguration enabled selective enhancement of synaptic transmission for burst inputs. Coupled with concurrent upregulation of NR2B-containing NMDA receptors and its downstream signaling, synaptic plasticity induced by correlated inputs was enhanced. Our findings suggest that an increase in brain magnesium enhances both short-term synaptic facilitation and long-term potentiation and improves learning and memory functions.

Abnormal neurogensis in the hippocampus of a mouse model of fragile X syndromes

Fragile X syndrome is the most common inherited form of mental retardation. It is a neurodevelopmental disorder that is similar in clinical presentation to autism spectrum disorder. However, unlike autism, Fragile X syndrome is caused by the silencing of a single gene, and in recent years, a mouse model of Fragile X syndrome has been generated by deletion of the Fmr1 gene. Surprisingly, a clear neurobiological basis for the learning impairment observed in both these knockout mice and patients has been difficult to elucidate. We hypothesized that neurogenesis, a process that continues into adulthood in the hippocampus, may be abnormal in this syndrome. Support for such a hypothesis comes from the findings that these new neurons may disproportionately contribute to synaptic plasticity in networks engaged during learning and memory. We have shown that the survival of new cells in the hippocampus of young Fmr1 knockout mice is significantly decreased in the ventral hippocampus, a sub-region which may be more involved with emotional, rather than, spatial memory. Further experiments are being conducted to assess the differentiation of these new cells into neurons and glia. We are also characterizing the normal expression of the Fmr1 gene product, FMRP, across the phases of neurogenesis in control mice. In conclusion, we have discovered a clear impairment in a process that may be critical to emotionally-significant learning and memory in a mouse model of Fragile X syndrome.

Sequential implication of the mental retardation proteins ARHGEF6 and PAK3 in spine morphogenesis

The biological mechanisms underlying the mental retardation associated with mutation of the ARHGEF6 gene, a Rac1/Cdc42 exchange factor, are still unknown, although defects in the plasticity of synaptic networks have been postulated. We have cloned the rat ARHGEF6 gene and investigated, using a transfection approach, its involvement in spine morphogenesis and its relationship to p21-activated kinase 3 (PAK3). We found that expression of tagged ARHGEF6 in hippocampal slice cultures shows a punctate staining in dendritic spines that colocalizes with PSD95. Over-expression of ARHGEF6, of PAK3 or constitutively active PAK3 did not alter spine morphology. By contrast, knockdown of ARHGEF6 using a siRNA approach resulted in abnormalities in spine morphology similar to those reported with knockdown of PAK3. This phenotype could be rescued through co-expression of a constitutively active PAK3 protein, but not with wild-type PAK3. Together, these results indicate that ARHGEF6 is localized in dendritic spines where it contributes to regulate spine morphogenesis probably by acting through a downstream activation of PAK3. Similar mechanisms are thus likely to underlie the mental retardation induced by mutations of ARHGEF6 and PAK3.

The Mental Retardation Protein PAK3 Contributes to Synapse Formation and Plasticity in Hippocampus

Mutations of the gene coding for PAK3 (p21-activated kinase 3) are associated with X-linked, nonsyndromic forms of mental retardation (MRX) in which the only distinctive clinical feature is the cognitive deficit. The mechanisms through which PAK3 mutation produces the mental handicap remain unclear, although an involvement in the mechanisms that regulate the formation or plasticity of synaptic networks has been proposed. Here we show, using a transient transfection approach, that antisense and small interfering RNA-mediated suppression of PAK3 or expression of a dominant-negative PAK3 carrying the human MRX30 mutation in rat hippocampal organotypic slice cultures results in the formation of abnormally elongated dendritic spines and filopodia-like protrusions and a decrease in mature spine synapses. Ultrastructural analysis of the changes induced by expression of PAK3 carrying the MRX30 mutation reveals that many elongated spines fail to express postsynaptic densities or contact presynaptic terminals. These defects are associated with a reduced spontaneous activity, altered expression of AMPA-type glutamate receptors, and defective long-term potentiation. Together, these data identify PAK3 as a key regulator of synapse formation and plasticity in the hippocampus and support interpretations that these defects might contribute to the cognitive deficits underlying this form of mental retardation.