Functional interdependence of the actin regulators CAP1 and cofilin1 in control of dendritic spine morphology

The vast majority of excitatory synapses are formed on small dendritic protrusions termed dendritic spines. Dendritic spines vary in size and density that are both crucial determinants of excitatory synaptic transmission. Aberrations in spine morphogenesis can compromise brain function and have been associated with neuropsychiatric disorders. Because actin filaments (F-actin) are the major structural component in spines, actin-binding proteins (ABP) that control F-actin dis-/assembly moved into the focus as critical regulators of brain function. Indeed, mouse studies identified the ABP cofilin1 as a key regulator of spine morphology, synaptic transmission and behavior. These studies emphasized the necessity for a tight control of cofilin1 to ensure proper brain function. We report spine enrichment of cyclase-associated protein 1 (CAP1), a conserved multidomain protein with largely unknown physiological functions. Super-resolution microscopy and live cell imaging of CAP1-deficient hippocampal neurons revealed impaired synaptic F-actin organization and dynamics associated with alterations in spine morphology. Mechanistically, we found that CAP1 cooperated with cofilin1 in spines and that its helical folded domain mediated this interaction. Moreover, our data proved functional interdependence of CAP1 and cofilin1 in control of spine morphology. In summary, we identified CAP1 as a novel regulator of the postsynaptic actin cytoskeleton that was essential for synaptic cofilin1 activity.

Information encoded in volumes and areas of dendritic spines is nearly maximal across mammalian brains

Long-term information associated with neuronal memory resides in dendritic spines. However, spines can have a limited size due to metabolic and neuroanatomical constraints, which should effectively limit the amount of encoded information in excitatory synapses. This study investigates how much information can be stored in the sizes of dendritic spines, and whether is it optimal in any sense? It is shown here, using empirical data for several mammalian brains across different regions and physiological conditions, that dendritic spines nearly maximize entropy contained in their volumes and surface areas for a given mean size. This result is essentially independent of the type of a fitting distribution to size data, as both short- and heavy-tailed distributions yield similar nearly 100 % information efficiency in the majority of cases, although heavy-tailed distributions slightly better fit the data. On average, the highest information is contained in spine volume, and the lowest in spine length or spine head diameter. Depending on a species and brain region, a typical spine can encode between 6.1 and 10.8 bits of information in its volume, and 3.1-8.1 bits in its surface area. Our results suggest a universality of entropy maximization in spine volumes and areas, which can be a new principle of memory storing in synapses.

Properties and proximity proteomics of synaptopodin provide insight into the molecular organization of the spine apparatus of dendritic spines

The spine apparatus is a specialization of the neuronal ER in dendritic spines consisting of stacks of interconnected cisterns separated by a dense matrix. Synaptopodin, a specific actin binding protein of the spine apparatus, is essential for its formation, but the underlying mechanisms remain unknown. We show that synaptopodin, when expressed in fibroblasts, forms actin-rich structures with connections to the ER, and that an ER-tethered synaptopodin assembles into liquid condensates. We also identified protein neighbors of synaptopodin in spines by in vivo proximity biotinylation. We validated a small subset of such proteins and showed that they co-assemble with synaptopodin in living cells. One of them is Pdlim7, an actin binding protein not previously identified in spines, and we show its precise colocalization with synaptopodin. We suggest that the matrix of the spine apparatus has the property of a liquid protein condensate generated by a multiplicity of low affinity interactions.

Effects of Aging on the Structure and Expression of NMDA Receptors of Somatostatin Expressing Neurons in the Mouse Hippocampus

Changes in the physiology, neurochemistry and structure of neurons, particularly of their dendritic spines, are thought to be crucial players in age-related cognitive decline. One of the most studied brain structures affected by aging is the hippocampus, known to be involved in different essential cognitive processes. While the aging-associated quantitative changes in dendritic spines of hippocampal pyramidal cells have already been studied, the relationship between aging and the structural dynamics of hippocampal interneurons remains relatively unknown. Spines are not a frequent feature in cortical inhibitory neurons, but these postsynaptic structures are abundant in a subpopulation of somatostatin expressing interneurons, particularly in oriens-lacunosum moleculare (O-LM) cells in the hippocampal CA1. Previous studies from our laboratory have shown that the spines of these interneurons are highly plastic and influenced by NMDA receptor manipulation. Thus, in the present study, we have investigated the impact of aging on this interneuronal subpopulation. The analyses were performed in 3−, 9−, and 16-month-old GIN mice, a strain in which somatostatin positive interneurons express GFP. We studied the changes in the density of dendritic spines, en passant boutons, and the expression of NMDA receptors (GluN1 and GluN2B) using confocal microscopy and image analysis. We observed a significant decrease in dendritic spine density in 9-month-old animals when compared with 3-month-old animals. We also observed a decrease in the expression of the GluN2B subunit in O-LM cells, but not of that of GluN1, during aging. These results will constitute the basis for more advanced studies of the structure and connectivity of interneurons during aging and their contribution to cognitive decline.

Computer-Based Drug Design of Positive Modulators of Store-Operated Calcium Channels to Prevent Synaptic Dysfunction in Alzheimer’s Disease

Store-operated calcium entry (SOCE) constitutes a fine-tuning mechanism responsible for the replenishment of intracellular stores. Hippocampal SOCE is regulated by store-operated channels (SOC) organized in tripartite complex TRPC6/ORAI2/STIM2. It is suggested that in neurons, SOCE maintains intracellular homeostatic Ca2+ concentration at resting conditions and is needed to support the structure of dendritic spines. Recent evidence suggests that positive modulators of SOC are prospective drug candidates to treat Alzheimer’s disease (AD) at early stages. Although STIM2 and ORAI2 are definitely involved in the regulation of nSOC amplitude and a play major role in AD pathogenesis, growing evidence suggest that it is not easy to target these proteins pharmacologically. Existing positive modulators of TRPC6 are unsuitable for drug development due to either bad pharmacokinetics or side effects. Thus, we concentrate the review on perspectives to develop specific nSOC modulators based on available 3D structures of TRPC6, ORAI2, and STIM2. We shortly describe the structural features of existing models and the methods used to prepare them. We provide commonly used steps applied for drug design based on 3D structures of target proteins that might be used to develop novel AD preventing therapy.

Revisiting I-BAR Proteins at Central Synapses

Dendritic spines, the distinctive postsynaptic feature of central nervous system (CNS) excitatory synapses, have been studied extensively as electrical and chemical compartments, as well as scaffolds for receptor cycling and positioning of signaling molecules. The dynamics of the shape, number, and molecular composition of spines, and how they are regulated by neural activity, are critically important in synaptic efficacy, synaptic plasticity, and ultimately learning and memory. Dendritic spines originate as outward protrusions of the cell membrane, but this aspect of spine formation and stabilization has not been a major focus of investigation compared to studies of membrane protrusions in non-neuronal cells. We review here one family of proteins involved in membrane curvature at synapses, the BAR (Bin-Amphiphysin-Rvs) domain proteins. The subfamily of inverse BAR (I-BAR) proteins sense and introduce outward membrane curvature, and serve as bridges between the cell membrane and the cytoskeleton. We focus on three I-BAR domain proteins that are expressed in the central nervous system: Mtss2, MIM, and IRSp53 that promote negative, concave curvature based on their ability to self-associate. Recent studies suggest that each has distinct functions in synapse formation and synaptic plasticity. The action of I-BARs is also shaped by crosstalk with other signaling components, forming signaling platforms that can function in a circuit-dependent manner. We discuss another potentially important feature—the ability of some BAR domain proteins to impact the function of other family members by heterooligomerization. Understanding the spatiotemporal resolution of synaptic I-BAR protein expression and their interactions should provide insights into the interplay between activity-dependent neural plasticity and network rewiring in the CNS.

Impact of Pharmacological and Non-Pharmacological Modulators on Dendritic Spines Structure and Functions in Brain

Dendritic spines are small, thin, hair-like protrusions found on the dendritic processes of neurons. They serve as independent compartments providing large amplitudes of Ca2+ signals to achieve synaptic plasticity, provide sites for newer synapses, facilitate learning and memory. One of the common and severe complication of neurodegenerative disease is cognitive impairment, which is said to be closely associated with spine pathologies viz., decreased in spine density, spine length, spine volume, spine size etc. Many treatments targeting neurological diseases have shown to improve the spine structure and distribution. However, concise data on the various modulators of dendritic spines are imperative and a need of the hour. Hence, in this review we made an attempt to consolidate the effects of various pharmacological (cholinergic, glutamatergic, GABAergic, serotonergic, adrenergic, and dopaminergic agents) and non-pharmacological modulators (dietary interventions, enriched environment, yoga and meditation) on dendritic spines structure and functions. These data suggest that both the pharmacological and non-pharmacological modulators produced significant improvement in dendritic spine structure and functions and in turn reversing the pathologies underlying neurodegeneration. Intriguingly, the non-pharmacological approaches have shown to improve intellectual performances both in preclinical and clinical platforms, but still more technology-based evidence needs to be studied. Thus, we conclude that a combination of pharmacological and non-pharmacological intervention may restore cognitive performance synergistically via improving dendritic spine number and functions in various neurological disorders.