Examining Form and Function of Dendritic Spines

The majority of fast excitatory synaptic transmission in the central nervous system takes place at protrusions along dendrites called spines. Dendritic spines are highly heterogeneous, both morphologically and functionally. Not surprisingly, there has been much speculation and debate on the relationship between spine structure and function. The advent of multi-photon laser-scanning microscopy has greatly improved our ability to investigate the dynamic interplay between spine form and function. Regulated structural changes occur at spines undergoing plasticity, offering a mechanism to account for the well-described correlation between spine size and synapse strength. In turn, spine structure can influence the degree of biochemical and perhaps electrical compartmentalization at individual synapses. Here, we review the relationship between dendritic spine morphology, features of spine compartmentalization and synaptic plasticity. We highlight emerging molecular mechanisms that link structural and functional changes in spines during plasticity, and also consider circumstances that underscore some divergence from a tight structure-function coupling. Because of the intricate influence of spine structure on biochemical and electrical signalling, activity-dependent changes in spine morphology alone may thus contribute to the metaplastic potential of synapses. This possibility asserts a role for structural dynamics in neuronal information storage and aligns well with current computational models

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

SummaryTranslational 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 of FXR1P 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 of GluA2 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

Serotoninergic and noradrenergic systems : their involvement in the mechanism of action of antidepressants

There is an historical debate in which the role and importance of the serotoninergic (5-HT) and noradrenergic (NE) systems as being the key components in the antidepressant response is disputed. Alternatively, this contentious debate has directly led to the hypothesis which posits that a combined pharmacological action on both these systems might result in an enhanced antidepressant efficacy. The development of the dual 5-HT/NE reuptake inhibitor venlafaxine has allowed to put to the test this hypothesis. Hence, clinical insight into this problem was provided by studies that documented a greater efficacy of venlafaxine in major depression when used at high doses. The present research endeavour, undertaken in parallel at the Neurobiological Psychiatry Unit with clinical studies, sought to determine the effects of acute and prolonged treatments with venlafaxine on the rat 5-HT and NE systems such as to suggest a biological substratum for its clinical features. Using in vivo electrophysiological paradigms in the rat dorsal hippocampus, dorsal raphe and locus coeruleus, we have shown that: (1) venlafaxine blocks the reuptake of 5-HT more potently than that of NE; (2) venlafaxine and the SSRI paroxetine are equipotent in blocking the reuptake of 5-HT; (3) the NE reuptake inhibitor desipramine is more potent than venlafaxine in blocking the reuptake of NE. We have documented an important discrepancy between the affinity of venlafaxine for both the 5-HT and NE transporters binding sites and its in vivo reuptake inhibition potencies: the in vivo 5-HT and NE reuptake inhibition potencies of venlafaxine are much greater than could have been predicted from its affinities for the 5-HT and NE transporters. The disclosure of this peculiarity sheds doubt on the exact nature of the mechanism by which venlafaxine blocks both reuptake processes and, ultimately, exerts its antidepressant effect. The complementary use of in vivo electrophysiological and in vitro superfusion paradig

Metaplasticity at CA1 Synapses by Homeostatic Control of Presynaptic Release Dynamics

Summary: Hebbian and homeostatic forms of plasticity operate on different timescales to regulate synaptic strength. The degree of mechanistic overlap between these processes and their mutual influence are still incompletely understood. Here, we report that homeostatic synaptic strengthening induced by prolonged network inactivity compromised the ability of CA1 synapses to exhibit LTP. This effect could not be accounted for by an obvious deficit in the postsynaptic capacity for LTP expression, since neither the fraction of silent synapses nor the ability to induce LTP by two-photon glutamate uncaging were reduced by the homeostatic process. Rather, optical quantal analysis reveals that homeostatically strengthened synapses display a reduced capacity to maintain glutamate release fidelity during repetitive stimulation, ultimately impeding the induction, and thus expression, of LTP. By regulating the short-term dynamics of glutamate release, the homeostatic process thus influences key aspects of dynamic network function and exhibits features of metaplasticity. : Several forms of synaptic plasticity operating over distinct spatiotemporal scales have been described at hippocampal synapses. Whether these distinct plasticity mechanisms interact and influence one another remains incompletely understood. Here, Soares et al. show that homeostatic plasticity induced by network silencing influences short-term release dynamics and Hebbian plasticity rules at hippocampal synapses. Keywords: synapse, LTP, homeostatic plasticity, metaplasticity, iGluSNF

PSD-95 regulates synaptic transmission and plasticity in rat cerebral cortex

PSD-95 is one of the most abundant proteins found in the postsynaptic density of excitatory synapses. However, the precise functional role played by PSD-95 in regulating synaptic transmission and plasticity remains undefined. To address this issue, we have overexpressed PSD-95 in cortical pyramidal neurons in organotypic brain slices using particle-mediated gene transfer and assessed the consequences on synaptic transmission and plasticity. The AMPA receptor/NMDA receptor (AMPAR/NMDAR) ratio of evoked EPSCs recorded at +40 mV was greater in PSD-95-transfected pyramidal neurons than in controls. This difference could not be accounted for by a change in rectification of AMPAR-mediated synaptic currents since the current-voltage curves obtained in controls and in PSD-95-transfected neurons were indistinguishable. However, the amplitude of AMPAR-mediated evoked EPSCs was larger in PSD-95-transfected neurons compared to matched controls. Paired-pulse ratio analysis suggested that overexpression of PSD-95 did not alter presynaptic release probability. Transfection of PSD-95 was further accompanied by an increase in the frequency, but not amplitude, of AMPAR-mediated mEPSCs. Together, these results indicate that transfection of PSD-95 increased AMPAR-mediated synaptic transmission. Furthermore, they suggest that this phenomenon reflects an increased number of synapses expressing AMPARs rather than an increased number or function of these receptors at individual synapses. We tested the consequences of these changes on synaptic plasticity and found that PSD-95 transfection greatly enhanced the probability of observing long-term depression. These results thus identify a physiological role for PSD-95 and demonstrate that this protein can play a decisive role in controlling synaptic strength and activity-dependent synaptic plasticity

Excitable Adult-Generated GABAergic Neurons Acquire Functional Innervation in the Cortex after Stroke

Summary: Ischemic stroke enhances the proliferation of adult-generated precursor cells that ectopically migrate toward the infarct. Studies have correlated precursor cell proliferation and subsequent adult neurogenesis with enhanced stroke recovery, yet it remains unclear whether stroke can generate new neurons capable of functional integration into the injured cortex. Here, using single and bitransgenic reporter mice, we identify spatial and temporal features of a multilineage cellular response to focal ischemia. We reveal that a small population of stroke-induced immature neurons accumulate within the peri-infarct region of the adult sensorimotor cortex, exhibit voltage-dependent conductances, fire action potentials, express GABAergic markers, and receive sparse GABAergic synaptic inputs. Collectively, these findings reveal that GABAergic neurons arising from the lateral ventricle have the capacity to integrate into the stroke-injured cortex, although their limited number and exiguous synaptic integration may limit their ability to participate in stroke recovery. : In this article, Kannangara and colleagues histologically and electrophysiologically characterized the precursor cell response evoked in the adult cortex after focal ischemia. The authors identify a population of doublecortin-expressing GABAergic immature neurons localized to the injured cortical regions with the capacity to fire action potentials and receive GABAergic input, indicative of functionally integration into the cortical network. Keywords: stroke, neurogenesis, GABA, cortex, ischemia, injury, photothrombosis, stem cells, brain repair, subventricular zon

Clinical reasoning difficulties: a taxonomy for clinical teachers

Clinical reasoning is the cornerstone of medical practice. To date, there is no established framework regarding clinical reasoning difficulties, how to identify them, and how to remediate them