ReviewMolecular regulation of dendritic spine dynamics and their potential impact on synaptic plasticity and neurological diseases
Introduction
The brains of most vertebrates communicate and store information by changing their nervous system through a fundamental process known as synaptic plasticity (Nicoll and Schmitz, 2005, Voglis and Tavernarakis, 2006, Zucker and Regehr, 2002). This involves several mechanisms, including alteration of existing synapses, or substitution of aged synapses to new ones (Nicoll and Schmitz, 2005, Voglis and Tavernarakis, 2006, Zucker and Regehr, 2002). These alterations, or plasticity, involve numerous tiny, specialized, semi-autonomous, postsynaptic compartments that protrude from main dendritic shaft, known as dendritic spine (Hering and Sheng, 2001). These spines are knob-like structures with various shapes and sizes which ultimately are responsible for excitatory postsynaptic input (Hering and Sheng, 2001). They also have rapid rearrangement capabilities, depending on stimulus, cellular environment and location. The spines undergoes constant turnover throughout life and play a fundamental role in information processing in the mammalian nervous system, especially for excitatory synaptic transmission (Fiala et al., 2002, Hering and Sheng, 2001, Sala and Segal, 2014). They are highly plastic in nature and their morphological variations determine the strength of a synapse (Voglis and Tavernarakis, 2006). That is why dendritic spines are considered as the “hot spot” of synaptic plasticity (Bourne and Harris, 2008, Eccles, 1979, Engert and Bonhoeffer, 1999, Maiti et al., 2015). Since their first demonstration as a genuine structure of the synapse by Santiago Ramón y Cajal, it is now widely accepted that they are specialized and distinct compartments, containing several neurotransmitter receptors, actin filaments, polyribosomes, and several cellular organelles, including the spine apparatus and coated vesicles (Sala and Segal, 2014). The morphology of spines not only determine the strength, stability and synaptic transmission, but they also control the calcium dynamics, receptor content, and the ability to change their shape and size over time (Bloodgood and Sabatini, 2007, Hering and Sheng, 2001, Sabatini and Svoboda, 2000, Sala and Segal, 2014). Most interestingly, the majority of spines are stable in mature neurons, but under certain conditions, such as in sensory input, social interactions, stress, environmental enrichment, learning and other behavioral paradigm, this steady state is impaired and they are remodeled to appropriately sub serve specific functions (Fiala et al., 2002, Hering and Sheng, 2001). Further, rearrangement of the structures and functions of most spines can influence synaptic connectivity and neuronal plasticity, which could control our learning, memory, behavior, and motor coordination (Fiala et al., 2002). In contrast, aberrant spines are highly associated with several psychiatric disorders, including autism spectrum disorders, schizophrenia, mental retardation, attention deficit hypersensitive disorders (ADHD), Fragile X-syndrome, Down syndrome, drug addiction, hypoxic/ischemic stress, and epilepsy (Fiala et al., 2002, Hering and Sheng, 2001, Sala and Segal, 2014). Similarly, in several neurodegenerative diseases, particularly those exhibiting cognitive impairments such as Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), autism and Rett's syndrome, the dendritic spines are altered in numbers and shape before eventual neuronal death is observed (Fiala et al., 2002, Penzes et al., 2011). However, despite extensive research on dendritic spine dynamics, structure–function regulation, and underlying, detailed mechanisms of their frequent remodeling, their role in different brain diseases remain unclear. The paucity of information surroundings theses mechanism is particularly acute for addressing the following questions: (i) which class of spines is lost in different brain diseases, transient or persistent spines; (ii) does spine loss always correlate with symptoms in different neurological diseases; (iii) how do spine sense a stressful cellular environment; (iv) how do spine cope with the stressful conditions; (v) what are the extreme conditions under which spine lose their appearance; and (vi) would rescue of neuronal loss be able to restore spines structure–function. In this review, we highlight the essential background concerning the structure, function, morphogenesis and the plasticity of dendritic spines. We also address recent insights and uncover details of the molecular mechanisms underlying the regulation of spine pathology in different neurological conditions and psychiatric diseases, and explore potential ways to restore dendritic spine integrity under these conditions.
Section snippets
Importance of the study of dendritic spine
Postsynaptic activity is intimately linked with the dynamics of dendritic spines. As such dendritic spines are vital for our higher brain functions, including learning and memory. Scientists believe that the dendritic spine is the smallest neuronal compartment capable of performing a complete neurotransmission in a single synapse (Shepherd, 1996). Such spines are considered as the anatomical substrate for synaptic transmission, and are involved in formation of local synapse-specific
Number and distribution of dendritic spines
In the vertebrate brain, particularly in mammalian, most excitatory neurons consist of dendritic spines (Harris and Kater, 1994, Hering and Sheng, 2001). They are found mostly in pyramidal neurons of neocortex, medium spiny neurons in the striatum and the Purkinje cells in the cerebellum (Hering and Sheng, 2001; Table 1).
Interestingly, the majority of these synapses are located in the cerebral cortex (Table 1). Scientists assume that the numbers of neurons in an adult human brain is close to
Ultrastructure of dendritic spines
Understanding the ultra-structure of dendritic spines is a crucial step in determining the synaptic strength or efficiency of a synapse (Nimchinsky et al., 2002). Spine ultrastructure was first elucidated when transmission electron microscope (TEM) was introduced, whereas recent introduction of high-resolution, time-lapse, two-photon laser scanning microscope, stimulated emission depletion (STED) microscope, and super-resolved single-fluorophore microscopes (e.g. STORM, PALM, FPALM, PAINT)
Structural variability of dendritic spines in different brain regions
One of the striking phenomena observed in spine morphology is its structural variability. Using advanced imaging techniques, scientists have described two major groups of spines in the neocortex: transient spines and persistent spines (Holtmaat et al., 2005). The transient spines may vary from day to day in their appearance and disappearance. Their morphology fluctuates with stimuli and cellular environment, and they are predominant in developing cortex and different brain regions during
Signaling molecules involved in dendritic spine dynamics
Over the last few decades, using cDNA transfection methods several hundreds of signaling proteins molecules, hormones, and growth factors has been identified in dendritic spines. On the basis of their functions, they are divided into six main categories: (i) actin binding and cytoskeletal proteins; (ii) small GTP-ase and associated proteins; (iii) cell surface receptors and adhesion molecules; (iv) receptor tyrosine kinases and other kinases; (v) postsynaptic scaffolding proteins and adaptor
Development of dendritic spine
Generally, newly formed dendrites are devoid of dendritic spines. The spine having small head or absence of head have less capability for neurotransmission, which indicates they require maturation after formation. However, as these spines start to develop (spinogenesis), they acquire a long thread-like nascent form, called a filopodium (Fiala et al., 2002). However, these kinds of spines are rarely observed in the mature neurons. During embryonic brain development, even up to first week of
Spine formation and stabilization: Role of calcium and glutamate receptors
The head of a dendritic spine contains PSD, which bears several receptors and signaling molecules, including inotropic (NMDA, AMPA) and metabotropic (mGluR) glutamate receptors. Out of all glutamate receptors, AMPA receptors play an important role in basal synaptic transmission, while NMDA receptors open calcium channels during high synaptic activity (e.g. in long term potentiation; LTP), which can induce spine growth (Lacor, 2007, Lynch, 2004). The hypertrophy or atrophy of spines can be
Plasticity of dendritic spine
One of the most striking phenomena of dendritic spine plasticity is their morphological diversity. For the formation or development of new synaptic circuits, spine dynamics including its motility, turnover, changes of shape, size are crucial (Calabrese et al., 2006). Using advanced imaging techniques, several investigators came to the conclusion that spines are very dynamic in nature and are considered as the morphological basis of synaptic plasticity (Maiti et al., 2015). The degree of
Anomalies of dendritic spines
The loss or gain of spines is a common feature of spine dynamics during development or while under stimulation or inhibition (Calabrese et al., 2006, Calabrese et al., 2014). In general, shape, size, and volume of dendritic spines are maintained at an optimal level of synaptic activity, whereas abnormal spine structure and their loss represent a common hallmark of several neurological diseases (Table 6). Scientists report that several of the impairment of cognitive functions observed in
Alzheimer's disease
Alzheimer's disease is the most common age-related neurodegenerative disease and is the leading cause of death in the elderly (Jack et al., 2011). Early memory deficits, followed by gradual decline of cognitive and intellectual functions or dementia, is one of the cardinal features of this disease (Kelley and Petersen, 2007). The principal neuropathological features are the aggregation of amyloid beta protein known as senile plaque which are mainly deposited in extracellular spaces (Glenner and
Preservation of spines by preventing neuronal loss
Due to nature of neuroplasticity events, dendritic spines may reappear in their original locations after a certain time, if given the appropriate cellular environment. They might emerge in new location as filopodia or reappear in previous locations, due to dendritic recovery (Maletic-Savatic et al., 1999, Ziv and Smith, 1996). Although formation of filopodia-like spines in new locations is uncommon in adult brain, and is not due to recovery of dendritic branches, most spines are recovered at
Conclusion
Dendritic spines play a fundamental role in synaptic transmission as well as information processing in mammalian nervous system. They are tiny, specialized, semi-autonomous compartments originated from the main dendritic shaft. The structure and function of dendritic spines are dynamically regulated by local cellular environment and the nature of stimuli they experience. Their shapes, sizes and numbers significantly influence synaptic transmission and these are usually altered in different
Conflict of interest statement
Authors declare no conflict of interest to publish this review article.
Acknowledgements
Financial supports from Field Neurosciences Institute, St. Mary's of Michigan, USA, and Defence Research and Development Organization, Ministry of Defence, Government of India are acknowledged. We are thankful to Prof. Gal Bitan, University California Los Angeles, and Prof. Michael Patrick McDonald, University of Tennessee Health Science center for their help and supports.
References (361)
Abeta(1-42) modulation of Akt phosphorylation via alpha7 nAChR and NMDA receptors
Neurobiol. Aging
(2008)Dendritic morphology of amygdala and hippocampal neurons in more and less predator stress responsive rats and more and less spontaneously anxious handled controls
Behav. Brain Res.
(2012)Thyroid hormones states and brain development interactions
Int. J. Dev. Neurosci.
(2008)- et al.
Dendritic changes of the pyramidal neurons in layer V of sensory-motor cortex of the rat brain during the postresuscitation period
Resuscitation
(1997) - et al.
Occipital cortex ablation in adult rat causes retrograde neuronal death in the lateral geniculate nucleus that resembles apoptosis
Neuroscience
(1998) Molecular evidence for increased expression of genes related to immune and chaperone function in the prefrontal cortex in schizophrenia
Biol. Psychiatry
(2007)- et al.
Inhibition of glucocorticoid receptors ameliorates hypobaric hypoxia induced memory impairment in rat
Behav. Brain. Res.
(2013) - et al.
Fragile X syndrome: loss of local mRNA regulation alters synaptic development and function
Neuron
(2008) mTOR signaling in the hippocampus is necessary for memory formation
Neurobiol. Learn. Mem.
(2007)- et al.
Studies on the 3-dimensional architecture of dendritic spines and varicosities in human cortex by confocal laser scanning microscopy and Lucifer yellow microinjections
J. Neurosci. Methods
(1995)
Prenatal alcohol exposure and the effects of environmental enrichment on hippocampal dendritic spine density
Alcohol
Ca(2+) signaling in dendritic spines
Curr. Opin. Neurobiol.
Modulation of dendritic spines and synaptic function by Rac1: a possible link to Fragile X syndrome pathology
Brain Res.
Structural plasticity of dendritic spines
Curr. Opin. Neurobiol.
Transgenic mice overexpressing the extracellular domain of NCAM are impaired in working memory and cortical plasticity
Neurobiol. Dis.
Degenerative phenomena and reactive modifications of the adult rat inferior olivary neurons following axotomy and disconnection from their targets
Neuroscience
Rapid, concurrent alterations in pre- and postsynaptic structure induced by naturally-secreted amyloid-beta protein
Mol. Cell Neurosci.
The corticostriatal projection: from synaptic plasticity to dysfunctions of the basal ganglia
Trends Neurosci.
Large neostriatal neurons in the rat: an electron microscopic study of gold-toned Golgi-stained cells
Brain Res. Bull.
Dendritic spine pathologies in hippocampal pyramidal neurons from Rett syndrome brain and after expression of Rett-associated MECP2 mutations
Neurobiol. Dis.
Giant spines and enlarged synapses induced in Purkinje cells by malnutrition
Brain Res.
Effects of protein undernutrition of the dentate gyrus in rats of three age groups
Brain Res.
DHA may prevent age-related dementia
J. Nutr.
Exercise builds brain health: key roles of growth factor cascades and inflammation
Trends Neurosci.
Mapping early brain development in autism
Neuron
Parkinson's disease: mechanisms and models
Neuron
REM sleep deprivation attenuates actin-binding protein cortactin: a link between sleep and hippocampal plasticity
Neurosci. Lett.
Neuroplasticity subserving motor skill learning
Neuron
Abeta oligomers induce neuronal oxidative stress through an N-methyl-d-aspartate receptor-dependent mechanism that is blocked by the Alzheimer drug memantine
J. Biol. Chem.
Spine dynamics and synapse remodeling during LTP and memory processes
Prog. Brain Res.
Endoplasmic reticulum is missing in dendritic spines of Purkinje cells of the ataxic mutant rat
Brain Res.
Progressive cognitive decline in adolescents and adults with epilepsy
Prog. Brain Res.
The beta-propensity of Tau determines aggregation and synaptic loss in inducible mouse models of tauopathy
J. Biol. Chem.
Chronic epilepsy and cognition
Lancet Neurol.
Epigenetic modifications in trinucleotide repeat diseases
Trends Mol. Med.
Dendritic spine pathology: cause or consequence of neurological disorders?
Brain Res. Brain Res. Rev.
Rapid actin-based plasticity in dendritic spines
Neuron
An active and socially integrated lifestyle in late life might protect against dementia
Lancet Neurol.
Experience-dependent structural plasticity in the cortex
Trends Neurosci.
Structural changes in the dendritic spines of pyramidal neurons in layer III of the sensorimotor cortex of the rat cerebral cortex in the late post-ischemic period
Neurosci. Behav. Physiol.
Sex differences in the risk of schizophrenia: evidence from meta-analysis
Arch. Gen. Psychiatry
Biology of Parkinson's disease: pathogenesis and pathophysiology of a multisystem neurodegenerative disorder
Dialogues Clin. Neurosci.
Role of actin in anchoring postsynaptic receptors in cultured hippocampal neurons: differential attachment of NMDA versus AMPA receptors
J. Neurosci.
Anatomical and physiological plasticity of dendritic spines
Annu. Rev. Neurosci.
Inclusion body formation reduces levels of mutant huntingtin and the risk of neuronal death
Nature
Protection of primary neurons and mouse brain from Alzheimer's pathology by molecular tweezers
Brain
The burden of schizophrenia on caregivers: a review
Pharmacoeconomics
Vulnerability of the developing brain to hypoxic-ischemic damage: contribution of the cerebral vasculature to injury and repair?
Front. Physiol.
Developmental and maintenance defects in Rett syndrome neurons identified by a new mouse staging system in vitro
Front. Cell. Neurosci.
Selective neuronal loss in ischemic stroke and cerebrovascular disease
J. Cereb. Blood Flow Metab.
Cited by (96)
Understanding mechanistic aspect of the therapeutic role of herbal agents on neuroplasticity in cerebral ischemic-reperfusion injury
2024, Journal of EthnopharmacologyCo-exposure to low-dose lead, cadmium, and mercury promotes memory deficits in rats: Insights from the dynamics of dendritic spine pruning in brain development
2023, Ecotoxicology and Environmental SafetySpiking neural P systems with myelin and dendritic spines
2023, NeurocomputingHuman stem cell-based models to study synaptic dysfunction and cognition in schizophrenia: A narrative review
2023, Schizophrenia Research