Homeostatic plasticity

The capacity of neurons to sustain consistent activity levels in response to variations in synaptic input is known as homeostatic synaptic plasticity. Homeostatic synaptic plasticity occurs when neurons modify their synaptic strength in response to variations in activity levels to preserve network stability. This response serves to keep neuronal circuits in the appropriate range of activity for proper functioning. Homeostatic synaptic plasticity can be shown in presynaptic alterations, postsynaptic receptor expression, changes in intrinsic characteristics, and synaptic scaling.File:Synapse figure.png

Homeostatic presynaptic plasticity refers to the ability of neurons to regulate neurotransmitter release at presynaptic terminals, ensuring a steady range of brain activity. This process involves various mechanisms, such as quantal size adjustment, differential expression of presynaptic proteins, and modification of vesicle recycling. Quantal size adjustment helps maintain steady postsynaptic responses despite changes in synaptic strength. Differential expression of presynaptic proteins, such as calcium channels or synaptic vesicle proteins, can also be altered by neurons to affect neurotransmitter release rate.

Homeostatic postsynaptic plasticity is crucial for maintaining consistent levels of synaptic activity in neurons, which are formed at specific synapses in the brain. Homeostatic processes involve changes in the expression of receptors, changes in receptor sub-unit composition, and changes to intracellular signaling pathways. For example, the NMDA receptor can change its sub-unit composition to improve sensitivity to neurotransmitters. Additionally, changes in the expression and location of neurotransmitter receptors can impact synaptic transmission when specific signaling pathways are activated. Synaptic adhesion molecules can also be influenced by homeostatic processes. Overall, homeostatic postsynaptic plasticity contributes to the stability and proper functioning of neural circuits, allowing the brain to adapt to changing conditions without compromising the overall stability of neuronal activity.{{cite journal | vauthors = Turrigiano GG | title = The dialectic of Hebb and homeostasis | journal = Philosophical Transactions of the Royal Society of London. Series B, Biological Sciences | volume = 372 | issue = 1715 | pages = 20160258 | date = March 2017 | pmid = 28093556 | pmc = 5247594 | doi = 10.1098/rstb.2016.0258 }}

Homeostatic intrinsic plasticity refers to the ability of neurons to change their intrinsic electrical characteristics in response to changes in synaptic or network activity. This process involves alterations in the excitability or firing characteristics of individual neurons, rather than primarily adjusting synaptic strength. Intrinsic plasticity processes associated with homeostasis include ion channel expression alterations, membrane conductance modifications, action potential threshold alterations, and regulation of intrinsic excitability. Neurons can up-regulate the expression of sodium channels to maintain firing rates and increase excitability in case of a drop in synaptic activity. These changes impact the input-output link between neurons and the homeostatic control of neuronal activity.

Synaptic scaling is a homeostatic mechanism that allows neurons to modulate the strength of all synapses to maintain stable activity levels within a specific range. This process is characterized by changes in the quantity or sensitivity of neurotransmitter receptors on the postsynaptic membrane. Neurons can reduce the number of neurotransmitter receptors in response to network activity spikes, reducing synaptic strength, or increase the density in response to network activity drops, increasing sensitivity and boosting synaptic strength. This homeostatic regulation of brain circuits supports other types of synaptic plasticity, such as long-term depression and long-term potentiation.

Functional plasticity is a type of plasticity that allows the brain the ability to adapt to changes in its functions with changes in their environment. At every point in the child's life, their brain is able to balance malleable processes that represent neural plasticity and promote the change with homeostatic process in order to promote stability.{{cite journal | vauthors = Dennis M, Spiegler BJ, Simic N, Sinopoli KJ, Wilkinson A, Yeates KO, Taylor HG, Bigler ED, Fletcher JM | title = Functional plasticity in childhood brain disorders: when, what, how, and whom to assess | journal = Neuropsychology Review | volume = 24 | issue = 4 | pages = 389–408 | date = December 2014 | pmid = 24821533 | pmc = 4231018 | doi = 10.1007/s11065-014-9261-x }} This means that regardless of a child's brain development as a fetus, typical brain development or atypical brain development, can depend on their environment.

The functions and abilities of a certain part of the brain can be moved to another part of the brain when damaged. When a fetus is developing, this type of plasticity occurs rapidly establishing the brain systems.{{cite journal | vauthors = Anderson AL, Thomason ME | title = Functional plasticity before the cradle: a review of neural functional imaging in the human fetus | journal = Neuroscience and Biobehavioral Reviews | volume = 37 | issue = 9 Pt B | pages = 2220–2232 | date = November 2013 | pmid = 23542738 | doi = 10.1016/j.neubiorev.2013.03.013 | series = CNTRICS: Modeling psychosis related cognition in animal systems to enhance translational research + Life-Span Plasticity of Brain and Behavior: A Cognitive Neuroscience Perspective }}

Structural plasticity refers to morphological changes in the structure of the brain through the growth of new synaptic connections.{{cite journal | vauthors = Brown A, Weaver LC | title = The dark side of neuroplasticity | journal = Experimental Neurology | volume = 235 | issue = 1 | pages = 133–141 | date = May 2012 | pmid = 22116043 | doi = 10.1016/j.expneurol.2011.11.004 | pmc = 4851547 }} This process is done through synaptogenesis, neuronal migration, and neurogenesis. These processes are a foundational part of fetal neuron development, but has recently also been found in adult brains. Neurogenesis occurs in the ventricular or subventricular zone of the brain. Neural migration is the process of neurons traveling from these zones towards their final destination in development.{{cite journal | vauthors = Kaneko N, Sawada M, Sawamoto K | title = Mechanisms of neuronal migration in the adult brain | journal = Journal of Neurochemistry | volume = 141 | issue = 6 | pages = 835–847 | date = June 2017 | pmid = 28251650 | doi = 10.1111/jnc.14002 }} Synaptic remodeling in response to learning and memory lead to function consequences in the brain throughout life.{{cite journal | vauthors = Caroni P, Donato F, Muller D | title = Structural plasticity upon learning: regulation and functions | journal = Nature Reviews. Neuroscience | volume = 13 | issue = 7 | pages = 478–490 | date = June 2012 | pmid = 22714019 | doi = 10.1038/nrn3258 | url = https://archive-ouverte.unige.ch/unige:26265 }}

Homeostatic synaptic plasticity is a means of maintaining the synaptic basis for learning, respiration, and locomotion, in contrast to the Hebbian plasticity associated with learning and memory. Although Hebbian forms of plasticity, such as long-term potentiation (LTP) and long-term depression (LTD) occur rapidly, homeostatic plasticity (which relies on protein synthesis) can take hours or days. Homeostatic plasticity is thought to balance Hebbian plasticity by modulating the activity of the synapse or the properties of ion channels.

Synaptic scaling has been labeled as a potential mechanism of homeostatic plasticity.{{cite journal | vauthors = Pozo K, Goda Y | title = Unraveling mechanisms of homeostatic synaptic plasticity | journal = Neuron | volume = 66 | issue = 3 | pages = 337–351 | date = May 2010 | pmid = 20471348 | pmc = 3021747 | doi = 10.1016/j.neuron.2010.04.028 }} Homeostatic plasticity is often used to describe a process that maintains stability of neuronal functions through a coordinated plasticity among subcellular compartments, such as the synapses versus the neurons and the cell bodies versus the axons.{{cite journal | vauthors = Chen N, Chen X, Wang JH | title = Homeostasis established by coordination of subcellular compartment plasticity improves spike encoding | journal = Journal of Cell Science | volume = 121 | issue = Pt 17 | pages = 2961–2971 | date = September 2008 | pmid = 18697837 | doi = 10.1242/jcs.022368 | doi-access = }} Synaptic scaling aids in that regulation of neurons as the role of synaptic scaling is to adjust the strength of neuron's excitatory synapses, helping to keep the neurons in check so homeostatic plasticity can achieve its function properly.{{cite journal |vauthors=Pozo K, Goda Y |date=May 2010 |title=Unraveling mechanisms of homeostatic synaptic plasticity |journal=Neuron |volume=66 |issue=3 |pages=337–351 |doi=10.1016/j.neuron.2010.04.028 |pmc=3021747 |pmid=20471348}} Recently, it was proposed that homeostatic synaptic scaling may play a role in establishing the specificity of an associative memory.{{cite journal | vauthors = Wu CH, Ramos R, Katz DB, Turrigiano GG | title = Homeostatic synaptic scaling establishes the specificity of an associative memory | journal = Current Biology | volume = 31 | issue = 11 | pages = 2274–2285.e5 | date = June 2021 | pmid = 33798429 | pmc = 8187282 | doi = 10.1016/j.cub.2021.03.024 | bibcode = 2021CBio...31E2274W }}

Homeostatic plasticity also uses a separate mechanism to help maintain neuronal excitability in a real-time manner through the coordinated plasticity of threshold and refractory period at voltage-gated sodium channels, keeping them balanced so the barrier remains constant for stable firing actions.{{cite journal | vauthors = Ge R, Chen N, Wang JH | title = Real-time neuronal homeostasis by coordinating VGSC intrinsic properties | journal = Biochemical and Biophysical Research Communications | volume = 387 | issue = 3 | pages = 585–589 | date = September 2009 | pmid = 19616515 | doi = 10.1016/j.bbrc.2009.07.066 }}

Homeostatic plasticity can also be mediated by extracellular signals such as BDNF or TNF-α. These factors are released in an activity-dependent manner and can regulate both excitatory and inhibitory synapses across neurons, contributing to circuit-wide homeostatic adjustments.{{Cite journal |last=Turrigiano |first=G. |date=2012-01-01 |title=Homeostatic Synaptic Plasticity: Local and Global Mechanisms for Stabilizing Neuronal Function |url=http://cshperspectives.cshlp.org/lookup/doi/10.1101/cshperspect.a005736 |journal=Cold Spring Harbor Perspectives in Biology |language=en |volume=4 |issue=1 |pages=a005736–a005736 |doi=10.1101/cshperspect.a005736 |issn=1943-0264|pmc=3249629 }}

Homeostatic plasticity is also very important in the context of central pattern generators. Central pattern generators control rhythmic and repeating pattern.  Moreover, central pattern regulators are crucial for vital functions (i.e. respiration and digestion) and any disruptions can cause immense consequences. Therefore, homeostatic plasticity works to stabilize a given activity pattern. Central pattern generators maintain their rhythmic activity through homeostatic regulation using various intrinsic and network properties. One example of an intrinsic neuronal property is ion channel expression.  For instance, neuron activity is influenced by the expression of ion channel levels. Moreover, changes in membrane voltage are used as feedback signals and those signals can modify the effects of the ion channels.{{Cite journal |last=Temporal |first=Simone |last2=Lett |first2=Kawasi M. |last3=Schulz |first3=David J. |date=2014-08-18 |title=Activity-Dependent Feedback Regulates Correlated Ion Channel mRNA Levels in Single Identified Motor Neurons |url=https://www.sciencedirect.com/science/article/pii/S0960982214007842 |journal=Current Biology |volume=24 |issue=16 |pages=1899–1904 |doi=10.1016/j.cub.2014.06.067 |issn=0960-9822}} Furthermore, the changes allow neurons to adjust and maintain stable activity patterns with various inputs. An example of a network property is synaptic reorganization. Synaptic reorganization refers to the formation and elimination of neuron connections that change synapse function and is key in brain plasticity.{{Cite journal |last=Wolff |first=J. R. |last2=Missler |first2=M. |date=1992 |title=Synaptic reorganization in developing and adult nervous systems |url=https://pubmed.ncbi.nlm.nih.gov/1449216 |journal=Annals of Anatomy |volume=174 |issue=5 |pages=393–403 |doi=10.1016/s0940-9602(11)80257-8 |issn=0940-9602 |pmid=1449216}} Overall homeostatic plasticity is important for central pattern generators, as neuronal properties are modulated in response to environmental changes in order to maintain an appropriate and balanced neural output.{{cite journal | vauthors = Northcutt AJ, Schulz DJ | title = Molecular mechanisms of homeostatic plasticity in central pattern generator networks | journal = Developmental Neurobiology | volume = 80 | issue = 1–2 | pages = 58–69 | date = January 2020 | pmid = 31778295 | doi = 10.1002/dneu.22727 }}

Homeostatic plasticity plays a crucial role in neurological disorders such as epilepsy, autism, Alzheimer's disease, and other neurodegenerative diseases. In these disorders, neurons ability to maintain stability in response to changes in activity levels or external stimuli is often altered.{{cite journal | vauthors = Halász P, Timofeev I, Szűcs A | title = Derailment of Sleep Homeostatic Plasticity Affects the Most Plastic Brain Systems and Carries the Risk of Epilepsy | journal = Journal of Integrative Neuroscience | volume = 22 | issue = 5 | pages = 111 | date = August 2023 | pmid = 37735129 | doi = 10.31083/j.jin2205111 | doi-access = free }}

In a healthy brain, neuronal excitability and synaptic strength are homeostatically regulated to maintain balance between excitation and inhibition. Homeostatic plasticity aids the brain by maintaining balance by adjusting neural activity in response to changes in stimulation. In epilepsy, this process can become semi-uncontrolled, leading to excessive neural excitability. This can cause an event where after prolonged network inactivity and/or brain injuries, neurons may become more active to compensate for the irregularity, which can cause the person to be more prone to seizures. Homeostatic plasticity is essential for normal brain function, the overcompensation due to brain dysregulation can contribute to the epileptic activity, highlighting its complex role in both stability and dysfunction.{{cite journal | vauthors = Halász P, Timofeev I, Szűcs A | title = Derailment of Sleep Homeostatic Plasticity Affects the Most Plastic Brain Systems and Carries the Risk of Epilepsy | journal = Journal of Integrative Neuroscience | volume = 22 | issue = 5 | pages = 111 | date = August 2023 | pmid = 37735129 | doi = 10.31083/j.jin2205111 | doi-access = free }} There are ways to attempt to regulate the over-excitability, such as cortical stimulation which increases controlled activity and might decrease excessive excitability, achieving the balance homeostatic plasticity seeks. Some studies also show that electrical stimulation helps those who suffer from drug-resistant epilepsy.{{cite journal | vauthors = Chai Z, Ma C, Jin X | title = Cortical stimulation for treatment of neurological disorders of hyperexcitability: a role of homeostatic plasticity | journal = Neural Regeneration Research | volume = 14 | issue = 1 | pages = 34–38 | date = January 2019 | pmid = 30531066 | pmc = 6262991 | doi = 10.4103/1673-5374.243696 | doi-access = free }} Traditional pharmacological approaches may be ineffective in restoring physiological balance in the neuronal network. However, therapeutic strategies targeting homeostatic plasticity mechanisms may offer a potential solution.

Autism spectrum disorder is a neurodevelopment disorder that is characterized by repetitive patterns of behavior, along with difficulties in social interaction and communication. Dysregulation of homeostatic plasticity and neural imbalance can contribute to the cognitive and behavioral symptoms associated with autism. Sensory inputs and intrinsic brain activity can cause long-term changes in synaptic efficiency and eventually lead to a increase or decrease in the ratio between excitatory and inhibitory neurotransmissions is found in Autism.{{cite journal |vauthors=Ismail FY, Fatemi A, Johnston MV |date=January 2017 |title=Cerebral plasticity: Windows of opportunity in the developing brain |journal=European Journal of Paediatric Neurology |language=English |volume=21 |issue=1 |pages=23–48 |doi=10.1016/j.ejpn.2016.07.007 |pmid=27567276}} Alterations in the expression of synaptic proteins that regulate excitatory or inhibitory leads to dysfunction as the ratio changes. An example linked to autism is Neuroligins 1-4. Neuroligin 1 is mainly present in exictatory synapses, neuroligin 2 is more present in inhibitory synapses, and neuroligin 3 is present in both. Neuroligin 4 is present in glycinergic synapses which are major contributors to the regulation of neuronal excitability as they control fluxes of sensory information. Mutations in neuroligins 3 & 4 have been shakily linked to autism, but neuroligins 1-3 have been found to cause primary inhibitory dysfunction in autism.{{Cite journal |last=Nelson |first=Sacha B. |last2=Valakh |first2=Vera |date=2015-08-19 |title=Excitatory/Inhibitory Balance and Circuit Homeostasis in Autism Spectrum Disorders |url=https://www.cell.com/neuron/fulltext/S0896-6273(15)00675-3 |journal=Neuron |language=English |volume=87 |issue=4 |pages=684–698 |doi=10.1016/j.neuron.2015.07.033 |issn=0896-6273 |pmid=26291155|pmc=4567857 }} Pruning of developing synapses in the central nervous system regulates brain size and shape into the third decade of life. It is a necessary process to keep the brain from being too small or large. Underpruning has been associated autism and results in enlarged brain size due to overgrowth of dendrites from the lack of pruning and modification of neuron number. Motor impairment in autism has been linked specifically to an abundance of white matter in the primary motor cortex. Due to 22q11.2 gene deletion syndrome, found to be connected to autism spectrum disorder, both thicker and thinner cortical regions along with regions of increased cerebral cortex folding can be found in the brain.{{Cite journal |last=Dennis |first=Maureen |last2=Spiegler |first2=Brenda J. |last3=Juranek |first3=Jenifer J. |last4=Bigler |first4=Erin D. |last5=Snead |first5=O. Carter |last6=Fletcher |first6=Jack M. |date=2013-12-01 |title=Age, plasticity, and homeostasis in childhood brain disorders |url=https://www.sciencedirect.com/science/article/abs/pii/S0149763413002194 |journal=Neuroscience & Biobehavioral Reviews |volume=37 |issue=10, Part 2 |pages=2760–2773 |doi=10.1016/j.neubiorev.2013.09.010 |issn=0149-7634|pmc=3859812 }} Environmental factors that effect normal homeostasis are heightened in autism, stopping neurons from maintaining optimum levels of activity.{{cite journal | vauthors = Toro R, Konyukh M, Delorme R, Leblond C, Chaste P, Fauchereau F, Coleman M, Leboyer M, Gillberg C, Bourgeron T | title = Key role for gene dosage and synaptic homeostasis in autism spectrum disorders | language = English | journal = Trends in Genetics | volume = 26 | issue = 8 | pages = 363–372 | date = August 2010 | pmid = 20609491 | doi = 10.1016/j.tig.2010.05.007 | url = https://hal-pasteur.archives-ouvertes.fr/pasteur-01967134/file/TIGS-D-09-00224NEW-1.pdf }}

In Alzheimer's disease, synaptic function and neuronal integrity are impaired. In a healthy brain, these mechanisms are tightly maintained by homeostatic plasticity. In the brain, there are constant changes in synaptic input. Therefore, neurons use homeostatic plasticity to keep their activity stable and prevents neurons from becoming too excited or too quiet. According to researchers, if a neuron does not receive enough activity, the synapses become stronger by adding receptors that help transmit signals. On the other hand, researchers argue that if the neuron receives too much activity the neuron will remove the receptors and weaken the synaptic connection. Researchers describe the regulation of receptors as synaptic scaling. In addition, neurons are able to adjust their intrinsic excitability and the changes help maintain the stability of neuron firing rates. Therefore, homeostatic plasticity potentially plays a significant role in neural stability. Deficits in homeostatic plasticity contribute to cognitive decline and memory impairment which are characteristic symptoms of Alzheimer's disease.

File:Neurons (Purkinje cells).jpgSeveral neurological disorders are affected by homeostatic plasticity. Dysregulation of homeostatic plasticity can cause an excitatory or inhibitory network activity. Parkinson's disease, Huntington's disease, and ALS are all examples of disorders where dysregulation of neuronal networks contributes to the pathophysiology of the disorders.{{cite journal | vauthors = Yamazaki Y, Zhao N, Caulfield TR, Liu CC, Bu G | title = Apolipoprotein E and Alzheimer disease: pathobiology and targeting strategies | journal = Nature Reviews. Neurology | volume = 15 | issue = 9 | pages = 501–518 | date = September 2019 | pmid = 31367008 | pmc = 7055192 | doi = 10.1038/s41582-019-0228-7 }} For instance, synaptic impairments occur early in ALS, so the early chances may serve as a method to counteract neuron dysfunction. Although the nervous system does attempt to adapt using synaptic plasticity, the attempts to maintain neural function are most times temporary and may eventually become harmful. For example, researchers believe that the spinal cord attempts to adapt by increasing the size of synaptic contacts, such as glutamatergic synapses to preserve motor function before the disease becomes detrimental.{{Cite journal |last=Gulino |first=Rosario |date=2023-02-27 |title=Synaptic Dysfunction and Plasticity in Amyotrophic Lateral Sclerosis |journal=International Journal of Molecular Sciences |language=en |volume=24 |issue=5 |pages=4613 |doi=10.3390/ijms24054613 |doi-access=free |issn=1422-0067 |pmc=10003601 |pmid=36902042}} However, the increased excitatory synaptic activity becomes too excessive and leads to excitotoxicity. Thus, the neurodegenerative disease progresses further.

Schizophrenia is characterized by disruptions in thought processes, perceptions, and emotions. Alterations in synaptic strength and connectivity potentially due to dysregulation in homeostatic mechanisms may lead to the symptoms observed in schizophrenic patients. These dysregulation contribute to the cognitive deficits and delusions observed in schizophrenia.{{cite journal | vauthors = Wondolowski J, Dickman D | title = Emerging links between homeostatic synaptic plasticity and neurological disease | journal = Frontiers in Cellular Neuroscience | volume = 7 | pages = 223 | date = November 2013 | pmid = 24312013 | pmc = 3836049 | doi = 10.3389/fncel.2013.00223 | doi-access = free }} In fact, a study was conducted to prove that disturbance in the homeostasis of Purkinje cells is an example of how developmental plasticity homeostasis is crucial in preventing mental illnesses like Schizophrenia. Purkinje cells are neurons located in the cerebellum and are involved in cognitive functions.{{cite book | vauthors = Paul MS, Limaiem F | chapter = Histology, Purkinje Cells |date=2025 | title = StatPearls | chapter-url = https://www.ncbi.nlm.nih.gov/books/NBK545154/#:~:text=Purkinje%20cells%20are%20a%20unique%20type%20of%20neuron-specific%20to%20the%20cerebellar%20cortex.&text=%5B6%5D%20In%20the%203-layered%20cerebellar%20cortex,%20the,cells,%20make%20up%20the%20outer%20molecular%20layer. |access-date=2025-02-22 |place=Treasure Island (FL) |publisher=StatPearls Publishing |pmid=31424738}} Moreover, research has shown that Purkinje cells keep the brain’s activity stable after traumatic experiences, and unregulated responses to trauma disrupt normal brain activity, which leads to mental illnesses.{{cite journal | vauthors = Lee J, Kim SH, Jang DC, Jang M, Bak MS, Shim HG, Lee YS, Kim SJ | title = Intrinsic plasticity of Purkinje cell serves homeostatic regulation of fear memory | journal = Molecular Psychiatry | volume = 29 | issue = 2 | pages = 247–256 | date = February 2024 | pmid = 38017229 | doi = 10.1038/s41380-023-02320-8 }}

Gina G. Turrigiano is an American neuroscientist known for her work on homeostatic plasticity mechanisms in the brain. Her research focused on synaptic strength and intrinsic excitability of neurons. Turrigiano discovered and characterized several types of homeostatic plasticity, most notably Synaptic scaling and intrinsic homeostatic plasticity. She considers homeostatic plasticity as how brains "tune themselves up" to remain dynamic and stable. More recently, she and her colleagues have been working to uncover the role of homeostatic plasticity in the development of the neocortex, in tandem with LTP/LTD, through experience-dependent refinement and learning.

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Category:Neuroplasticity