Abraham Lukpata

CHAPTER ONE 1.0 INTRODUCTION One of the most important and fascinating properties of the mammalian brain is its plasticity; the capacity of the neural activity generated by an experience to modify neural circuit function and thereby modify subsequent thoughts, feelings, and behavior (Michmizos et al., 2011). Synaptic plasticity specifically refers to the activity-dependent modification of the strength or efficacy of synaptic transmission at preexisting synapses, and for over a century has been proposed to play a central role in the capacity of the brain to incorporate transient experiences into persistent memory traces (Michmizos et al., 2011). Synaptic plasticity is also thought to play key roles in the early development of neural circuitry and evidence is accumulating that impairments in synaptic plasticity mechanisms contribute to several prominent neuropsychiatric disorders. Thus, elucidating the detailed molecular mechanisms underlying synaptic plasticity in any number of different brain regions is critical for understanding the neural basis of many aspects of normal and pathological brain function. Given the diversity of the functions ascribed to synaptic plasticity, it is not surprising that many forms and mechanisms of synaptic plasticity have been described (Michmizos et al., 2011). Synaptic transmission can be either enhanced or depressed by activity, and these changes span temporal domains ranging from milliseconds to hours, days, and presumably even longer. Furthermore, virtually all excitatory synapses in the mammalian brain simultaneously express a number of different forms of synaptic plasticity. Here, we attempt to provide a broad overview of the mechanisms of the most prominent forms of plasticity observed at excitatory synapses in the mammalian brain. After briefly reviewing short-lasting forms of synaptic plasticity, we will emphasize current understanding of the cellular mechanisms and possible functions of the class of phenomena commonly termed long-term potentiation (LTP) and long-term depression (LTD). In neuroscience, synaptic plasticity is the ability of synapses to strengthen or weaken over time, in response to increases or decreases in their activity (Michmizos et al., 2011). Since memories are postulated to be represented by vastly interconnected neural circuits in the brain, synaptic plasticity is one of the important neurochemical foundations of learning and memory. Plastic change often results from the alteration of the number of neurotransmitter receptors located on a synapse (Michmizos et al., 2011). There are several underlying mechanisms that cooperate to achieve synaptic plasticity, including changes in the quantity of neurotransmitters released into a synapse and changes in how effectively cells respond to those neurotransmitters (Tazerart et al., 2020). Synaptic plasticity in both excitatory and inhibitory synapses has been found to be dependent upon postsynaptic In 1973, Terje Lømo and Tim Bliss first described the now widely studied phenomenon of long-term potentiation (LTP) in a publication in the Journal of Physiology. The experiment described was conducted on the synapse between the perforant path and dentate gyrus in the hippocampi of anaesthetised rabbits. They were able to show a burst of tetanic (100 Hz) stimulus on perforant path fibres led to a dramatic and long-lasting augmentation in the post-synaptic response of cells onto which these fibres synapse in the dentate gyrus. In the same year, the pair published very similar data recorded from awake rabbits. This discovery was of particular interest due to the proposed role of the hippocampus in certain forms of memory. 1.1 Biochemical mechanisms Two molecular mechanisms for synaptic plasticity involve the NMDA and AMPA glutamate receptors. Opening of NMDA channels (which relates to the level of cellular depolarization) leads to a rise in post-synaptic Ca2+ concentration and this has been linked to long-term potentiation, LTP (as well as to protein kinase activation); strong depolarization of the post-synaptic cell completely displaces the magnesium ions that block NMDA ion channels and allows calcium ions to enter a cell – probably causing LTP, while weaker depolarization only partially displaces the Mg2+ ions, resulting in less Ca2+ entering the post-synaptic neuron and lower intracellular Ca2+ concentrations (which activate protein phosphatases and induce long-term depression, LTD (Chapouthier et al., 2004). These activated protein kinases serve to phosphorylate post-synaptic excitatory receptors (e.g. AMPA receptors), improving cation conduction, and thereby potentiating the synapse. Also, these signals recruit additional receptors into the post-synaptic membrane, stimulating the production of a modified receptor type, thereby facilitating an influx of calcium. This in turn increases post-synaptic excitation by a given pre-synaptic stimulus. This process can be reversed via the activity of protein phosphatases, which act to dephosphorylate these cation channels (Ben Achour et al., 2010). The second mechanism depends on a second messenger cascade regulating gene transcription and changes in the levels of key proteins at pommel synapses such as CaMKII and PKAII. Activation of the second messenger pathway leads to increased levels of CaMKII and PKAII within the dendritic spine. These protein kinases have been linked to growth in dendritic spine volume and LTP processes such as the addition of AMPA receptors to the plasma membrane and phosphorylation of ion channels for enhanced permeability (Ben Achour et al., 2010). Localization or compartmentalization of activated proteins occurs in the presence of their given stimulus which creates local effects in the dendritic spine. Calcium influx from NMDA receptors is necessary for the activation of CaMKII. This activation is localized to spines with focal stimulation and is inactivated before spreading to adjacent spines or the shaft, indicating an important mechanism of LTP in that particular changes in protein activation can be localized or compartmentalized to enhance the responsivity of single dendritic spines. Individual dendritic spines are capable of forming unique responses to presynaptic cells (Ben Achour et al., 2010). This second mechanism can be triggered by protein phosphorylation but takes longer and lasts longer, providing the mechanism for long-lasting memory storage. The duration of the LTP can be regulated by breakdown of these second messengers. Phosphodiesterase, for example, breaks down the secondary messenger cAMP, which has been implicated in increased AMPA receptor synthesis in the post-synaptic neuron (Ben Achour et al., 2010). Long-lasting changes in the efficacy of synaptic connections (long-term potentiation, or LTP) between two neurons can involve the making and breaking of synaptic contacts. Genes such as activin ß-A, which encodes a subunit of activin A, are up-regulated during early stage LTP. The activin molecule modulates the actin dynamics in dendritic spines through the MAP-kinase pathway. By changing the F-actin cytoskeletal structure of dendritic spines, spine necks are lengthened producing increased electrical isolation (Chapouthier et al., 2004). The end result is long-term maintenance of LTP (Chapouthier et al., 2004). The number of ion channels on the post-synaptic membrane affects the strength of the synapse (Friston et al., 2011). Research suggests that the density of receptors on post-synaptic membranes changes, affecting the neuron's excitability in response to stimuli. In a dynamic process that is maintained in equilibrium, N-methyl D-aspartate receptor (NMDA receptor) and AMPA receptors are added to the membrane by exocytosis and removed by endocytosis (Gaiarsa et al., 2002). These processes, and by extension the number of receptors on the membrane, can be altered by synaptic activity (Friston et al., 2011). Experiments have shown that AMPA receptors are delivered to the synapse through vesicular membrane fusion with the postsynaptic membrane via the protein kinase CaMKII, which is activated by the influx of calcium through NMDA receptors. CaMKII also improves AMPA ionic conductance through phosphorylation (Friston et al., 2011). When there is high-frequency NMDA receptor activation, there is an increase in the expression of a protein PSD-95 that increases synaptic capacity for AMPA receptors (Gaiarsa et al., 2002). This is what leads to a long-term increase in AMPA receptors and thus synaptic strength and plasticity. If the strength of a synapse is only reinforced by stimulation or weakened by its lack, a positive feedback loop will develop, causing some cells never to fire and some to fire too much. But two regulatory forms of plasticity, called scaling and metaplasticity, also exist to provide negative feedback (Gerrow et al., 2010). Synaptic scaling is a primary mechanism by which a neuron is able to stabilize firing rates up or down (Gaiarsa et al., 2002). Synaptic scaling serves to maintain the strengths of synapses relative to each other, lowering amplitudes of small excitatory postsynaptic potentials in response to continual excitation and raising them after prolonged blockage or inhibition (Gerrow et al., 2010). This effect occurs gradually over hours or days, by changing the numbers of NMDA receptors at the synapse (Pérez-Otaño and Ehlers, 2005). Metaplasticity varies the threshold level at which plasticity occurs, allowing integrated responses to synaptic activity spaced over time and preventing saturated states of LTP and LTD. Since LTP and LTD (long-term depression) rely on the influx of Ca2+ through NMDA channels, metaplasticity may be due to changes in NMDA receptors, altered calcium buffering, altered states of kinases or phosphatases and a priming of protein synthesis machinery (Gaiarsa et al., 2002). Synaptic scaling is a primary mechanism by which a neuron to be selective to its varying inputs. The neuronal circuitry affected by LTP/LTD and modified by scaling and metaplasticity leads to reverberatory neural circuit development and regulation in a Hebbian manner which is manifested as memory, whereas the changes in neural circuitry, which begin at the level of the synapse, are an integral part in the ability of an organism to learn (Haas et al., 2011). There is also a specificity element of biochemical interactions to create synaptic plasticity, namely the importance of location. Processes occur at microdomains – such as exocytosis of AMPA receptors is spatially regulated by the t-SNARE STX4 (Ben Achour et al., 2010). Specificity is also an important aspect of CAMKII signaling involving nanodomain calcium (Michmizos et al., 2011). CHAPTER TWO 2.0 What is synaptic plasticity? Plasticity is the ability of the brain to change and adapt to new information. Synaptic plasticity is change that occurs at synapses, the junctions between neurons that allow them to communicate (Gerrow et al., 2010). The idea that synapses could change, and that this change depended on how active or inactive they were, was first proposed in the 1949 by Canadian psychologist Donald Hebb (Haas et al., 2011). Because of synaptic plasticity’s probable contribution to memory storage, it has since become one of the most intensively researched topics in all of neuroscience. Synaptic plasticity refers to the ability of neurons to modify the strength of their connections and is an important neurophysiological process involved in brain networks development and reorganization after damage (Gerrow et al., 2010). Plasticity and network organization are highly intermingled, although they are generally studied as independent phenomena. Different forms of synaptic plasticity, namely, anti-homeostatic (i.e., Hebbian) and homeostatic plasticity (i.e., synaptic scaling), have been described. A fine balance between these two forms of synaptic plasticity could be crucial to maintain an optimal brain network architecture [9]. Types Of Synaptic Plasticity 2.1 Long-Term Potentiation (LTP) 2.1.1 Definition and Mechanisms Long-term potentiation (LTP) is a persistent increase in synaptic strength that occurs after high-frequency stimulation of presynaptic neurons. LTP is often associated with learning and memory processes. Mechanistically, it involves the activation of NMDA receptors, which allow calcium influx into the postsynaptic neuron. This calcium influx triggers a cascade of intracellular events that lead to an increase in AMPA receptor trafficking to the synapse, enhancing its responsiveness to neurotransmitters. 2.1.2 Role of NMDA receptors: in LTP NMDA receptors play a critical role in the induction of LTP due to their unique properties. They require both pre and postsynaptic activity to be simultaneously active for activation, making them coincidence detectors. This requirement ensures that LTP is only induced when there is a strong correlation between pre and postsynaptic firing, which is essential for learning-related processes. 2.1.3 Molecular cascades involved in LTP (e.g., AMPA receptor trafficking) The activation of NMDA receptors leads to intracellular signaling cascades, including the activation of protein kinases, such as calcium-calmodulin-dependent protein kinase II (CaMKII). CaMKII plays a crucial role in the trafficking of AMPA receptors to the postsynaptic membrane, leading to an increase in the number of functional AMPA receptors at the synapse, which strengthens the synaptic connection. 2.2 Long-Term Depression (LTD) 2.2.1 Definition and Mechanisms Long-term depression (LTD): is the opposite of LTP, resulting in a persistent decrease in synaptic strength following low-frequency stimulation or prolonged low-level activity of presynaptic neurons (Gaiarsa et al., 2002). LTD is involved in processes such as forgetting and synaptic pruning during development. Mechanistically, LTD is often triggered by the activation of metabotropic receptors, which can lead to the removal of AMPA receptors from the postsynaptic membrane. 2.2.2 Role of metabotropic receptors: in LTD Metabotropic receptors are G-protein-coupled receptors that, upon activation, trigger intracellular signaling pathways that promote the internalization of AMPA receptors from the postsynaptic membrane. This leads to a reduction in the synaptic response to neurotransmitters, causing synaptic depression. 2.2.3 Molecular cascades involved in LTD (e.g., endocannabinoid signaling) One of the well-studied mechanisms for LTD involves the activation of endocannabinoid signaling. When metabotropic receptors are activated, they stimulate the release of endocannabinoids, which act as retrograde messengers. These endocannabinoids then bind to presynaptic cannabinoid receptors, leading to a decrease in neurotransmitter release and, consequently, synaptic depression. 2.3 Short-Term Plasticity and Its Role in Information Processing Short-term plasticity refers to rapid and transient changes in synaptic strength that occur over short periods, such as milliseconds to seconds (Zucker et al., 2002). Unlike LTP and LTD, short-term plasticity is not associated with long-lasting changes in synaptic efficacy. Instead, it modulates the strength of synaptic transmission on a short-term basis, impacting neural information processing, filtering, and temporal integration. Short-term plasticity is essential for various brain functions, including sensory processing, motor control, and attention. 2.4 Importance of Synaptic Plasticity in Neural Functioning: Synaptic plasticity is essential for the neural network's flexibility and adaptability (Stam et al., 2009). It enables neurons to modify their synaptic connections based on ongoing neural activity. CHAPTER THREE 3.0 Cellular and Molecular Mechanisms of Synaptic Plasticity 3.1 Pre-synaptic Mechanisms 3.1.1 Neurotransmitter release regulation: The presynaptic neuron releases neurotransmitters into the synaptic cleft in response to action potentials (Zucker et al., 2002). The efficiency of neurotransmitter release can be regulated by several mechanisms, including presynaptic calcium dynamics, vesicle mobilization, and autoreceptors that modulate neurotransmitter release based on the presynaptic neuron's activity. 3.1.2 Changes in presynaptic membrane properties: Various factors, such as changes in presynaptic membrane composition and structure, can impact neurotransmitter release (Varshney et al., 2011). For example, the presence of presynaptic membrane proteins and lipids can influence the release probability and recycling of synaptic vesicles. 3.2 Post-synaptic Mechanisms 3.2.1 Changes in receptor sensitivity and density: The strength of the postsynaptic response is influenced by the number and sensitivity of neurotransmitter receptors present on the postsynaptic membrane (Stam et al., 2009). Changes in receptor density and their phosphorylation status can lead to alterations in synaptic strength. 3.2.2 AMPA receptor trafficking: AMPA receptors mediate fast excitatory synaptic transmission in the brain. Synaptic plasticity, particularly LTP, involves the trafficking of AMPA receptors to the synapse (Stam et al., 2009). Increased trafficking and incorporation of AMPA receptors into the postsynaptic membrane strengthen the synaptic connection. 3.2.3 Activation of intracellular signaling pathways: Intracellular signaling pathways, such as CaMKII and protein kinase A (PKA), are crucial for modulating synaptic plasticity. These signaling pathways can be activated by calcium influx through NMDA receptors or through metabotropic receptor activation (Stam et al., 2009). 3.3 Synaptic Tagging and Capture 3.3.1 Mechanisms underlying the persistence of plasticity: Synaptic tagging and capture is a process that enables the stabilization of synaptic plasticity (Stam et al., 2009). It involves the local synthesis of plasticity-related proteins at synapses that have undergone plastic changes. These newly synthesized proteins "tag" the synapse, allowing it to "capture" other plasticity-related proteins, leading to the stabilization of the synaptic changes. 3.3.2 Role of protein synthesis in synaptic tagging: The process of synaptic tagging and capture relies on local protein synthesis near the synapse. Protein synthesis is required for the consolidation of long-lasting plastic changes and the establishment of long-term memories CHAPTER FOUR 4.1 Mechanisms Of Plasticity Mechanisms of plasticity can occur through processes that take time, known as slow-onset changes, or through quicker process, known as fast-onset changes (Tazerart et al., 2020). Slow-onset changes are the anatomic changes of the neurons, including axonal growth, dendritic sprouting and neurogenesis--growing completely new structures, while fast onset changes are the activities that occur at the synaptic level. These kinds of fast-onset changes are known as synaptic modulation, which really means the ongoing process of strengthening or weakening of existing synapses. This process can be thought of much like the operation of your car, with the gas pedal representing excitation of synapses and the brake representing inhibition of synaptic responses (Stam et al., 2009). Thus, you really have two ways to make the brain go faster: strengthening synaptic connections through excitation (gas) and inhibition of other synaptic connections (brake). Persistent strengthening of synaptic connections through excitation (putting on the gas) develops long-term potentiation (LTP), or increasing the potential for that response to occur, while persistent weakening of other connections (putting on the brake) produces long-term depression (LTD) of a synaptic response (Gerrow et al., 2010). 4.2 Synaptic Plasticity and Brain Network Organization Addressing the relationship between synaptic plasticity and brain network organization is particularly difficult due to multiple reciprocal influences between brain network structure and function. Indeed, network architecture strongly influences neuronal activity (Tazerart et al., 2020), and patterns of neuronal activity may differently shape synaptic connections. A fundamental characteristic of neuronal networks is the ability to produce rhythmic oscillations in different frequency ranges, providing integration of brain functioning in physiological conditions such as those occurring during sleep and awake (Gerrow et al., 2010). In particular, temporal and spatial variations of frequency are useful to obtain coordinated information processing during sensory, motor and cognitive activities which are subserved by synchronous oscillations of neuronal networks (Gerrow et al., 2010). The excitability state of neurons changes during oscillations so that firing probability is higher during the depolarizing phase, whereas during the hyperpolarizing phase, neurons show less propensity to fire in response to excitatory inputs (Tazerart et al., 2020). Synchronous bursting of neuronal population may induce long-lasting changes in connectivity. In particular, high-frequency bursting induces LTP, whereas low-frequency activity is associated to LTD (Tazerart et al., 2020). Furthermore, the temporal correlation between converging inputs to neurons can bidirectionally modulate synaptic strength according to the so-called spike timing-dependent plasticity (STDP). In particular, the firing of the presynaptic neuron can respectively induce LTP or LTD if occurring shortly before or after the firing of the postsynaptic neuron (Michmizos et al., 2011). STDP provides an additional rule for Hebbian plasticity based on the temporal association of converging activity, bridging brain network organization and neuronal activity. This mechanism is required to form neuronal communities showing high connectivity and strongly coordinated activity during specific processing (Michmizos et al., 2011). Oscillatory activity and STDP interact to shape effective coupling between anatomically connected areas. Intriguingly, the degree of synchrony of neuronal discharges and neuronal firing rate could be independently adjusted (Stevens et al., 1999). Accordingly, neurons cycling in phase with each other tend to show synchronized activity favoring synaptic LTP (Michmizos et al., 2011). Previous synaptic history and state of neuronal excitability further complicate the relationship between neuronal activity and connectivity. It has been demonstrated that repeated synaptic activation may influence subsequent induction of Hebbian plasticity. In particular, considering that low and prolonged calcium entry is associated to LTD whereas high calcium influx likely mediates LTP (Michmizos et al., 2011). it has been proposed that changes in calcium levels into dendritic spines can modify plasticity induction. Similarities existing between synaptic plasticity mechanisms and specific features of brain network organization suggest that different forms of plasticity could be directly involved in generating specific brain networks characteristics. LTP is anti-homeostatic, input-specific, activity-dependent and associative. Due to its properties, LTP could be directly implicated in generating highly connected nodes, allowing the establishment of strong and specific connections by independently acting at each synapse (Michmizos et al., 2011). In particular, the preferential attachment theory of hub formation suggests the existence of an associative, positive feedback mechanisms which strongly follow the Hebbian plasticity rules. 4.3 Synaptic Plasticity Promotes Brain Network Reorganization after Damage Both brain network architecture and synaptic plasticity play an important role in clinical compensation of brain damage. As previously discussed, specific characteristics of brain networks organization provide high resistance to random damage (Michmizos et al., 2011). Notably, anti-homeostatic and homeostatic plasticity could be both involved in promoting an efficient network reorganization after brain damage (Michmizos et al., 2011). Experimental studies pointed out that the efficiency of synaptic plasticity, and particularly of LTP, critically influences clinical recovery. In animal models of brain damage (i.e., focal ischemia), symptoms compensation relies on the ability of surviving neurons to increase their excitability, as shown by a positive correlation between improvement in clinical scores and increased excitatory glutamatergic transmission in perilesional area (Thornton et al., 2003). Synaptic plasticity can be explored non-invasively in humans using transcranial magnetic stimulation (TMS). It has been demonstrated that the amount of LTP-like plasticity inducible with different TMS protocols after brain damage, the so-called LTP reserve, correlated with the degree of clinical recovery (Thornton et al., 2003). These results strongly suggest that LTP, specifically enhancing synaptic efficacy, is a fundamental requisite for network remodeling after brain damage. Synaptic plasticity promotes recovery after neural damage. Healthy condition: a schematic model representing neuronal excitatory connections. Neuron C and D receive synaptic excitatory inputs from neurons A and B respectively. Acute damage: damage to neuron B deprives neuron D of excitatory synaptic input leading to disconnection and symptoms appearance. Recovery of function: clinical recovery is associated to increased excitability of the surviving A neuron that unmasks latent synaptic connections through LTP and restores synaptic activity of neuron D. Importantly, connectivity increases should be tightly regulated to preserve an optimal tradeoff between cost and efficiency (Michmizos et al., 2011). Homeostatic plasticity cooperates with LTP to determine optimal brain network reorganization in both acute and chronic remodeling. In the early phases, synaptic upscaling could induce widespread hyperexcitability favoring network hyperconnectivity, with the aim of partially restoring network efficiency. Moreover, neuronal hyperexcitability favors LTP induction at hub level, further increasing hubs connectivity. Homeostatic plasticity changes may therefore regulate Hebbian plasticity expression. This could be particularly relevant also in the late phases of network reorganization when efficient downscaling is needed to limit excessive connectivity increase, preventing chronic diffuse hyperconnectivity and selectively shaping hub remodeling. Another line of evidence, strongly suggesting a strict relationship between LTP induction and hub remodeling, arises from the paradigm of cognitive reserve. Accordingly, higher levels of education, cognitive abilities, occupation and physical activity have been correlated with reduced functional impact of brain structural damage as demonstrated in healthy aging subjects and in neurological patients (Tazerart et al., 2020). In preclinical studies, environmental enrichment with physical, cognitive, and social stimuli improved the performance in different behavioral tasks exploring memory and learning (Michmizos et al., 2011), and enhanced LTP induction. In humans, cognitive reserve has been linked to increased connectivity of hub regions. In healthy elder subjects, higher cognitive reserve correlated with increased metabolism and functional connectivity of the anterior cingulate cortex (Tazerart et al., 2020). Similarly, higher cognitive reserve has been associated with enhanced functional connectivity in the left frontal cortex and reduced cognitive impairment in MCI and AD patients. It has been proposed that cognitive reserve may promote brain network resilience increasing hubs connectivity, thus enhancing the resistance of hubs to damage (Michmizos et al., 2011). 4.4 Synaptic Plasticity Dysfunction May Drive Brain Network Disruption AD and schizophrenia could represent useful models to explore the relationship between LTP expression and hubs connectivity. In particular, in AD and schizophrenia, impaired plasticity (Michmizos et al., 2011), may be responsible for reduced hubs degree and centrality, and decreased rich club connectiviy (Michmizos et al., 2011), In particular, impaired synaptic plasticity alters the synchrony of both local and distributed neuronal oscillations and could promote brain network dysfunction. AD is a neurodegenerative disease characterized by accumulation of amyloid-β (Aβ) and tau protein (Turrigiano et al., 2004). associated with prominent cognitive decline (Tazerart et al., 2020). In the hippocampus of AD patients synaptic alterations have been evidenced since the early phases of the disease (Michmizos et al., 2011), In particular, it has been proposed that early synaptic plasticity impairment could represent a main cause of memory deficits in AD, even independently of neurodegeneration. Studies in animal models of AD documented lacking hippocampal LTP induction, and pathological LTD enhancement (Turrigiano et al., 2004). Accordingly, it has been observed that elevated levels of soluble Aβ oligomers could reduce LTP and promote LTD expression in the hippocampus (Tazerart et al., 2020). It has been suggested that also impaired homeostatic plasticity could contribute to the clinical manifestations and disease progression in AD. In particular, altered interaction between homeostatic and anti-homeostatic plasticity in AD could ultimately promote synaptic loss. In line with experimental data, in early AD patients TMS studies have confirmed that LTP-like plasticity is abolished, and LTD-like plasticity induction is favored (Turrigiano et al., 2004). Recently, disrupted synaptic plasticity has been proposed as a possible pathophysiological marker of schizophrenia (Tazerart et al., 2020). Accordingly, reduced spine density has been described in the prefrontal and temporal cortices of schizophrenic patients, and altered expression and function of NMDARs and AMPARs have been reported (Turrigiano et al., 2004). NMDARs dysfunction seems to be particularly relevant, as NMDAR antagonists could produce symptoms which strongly resemble schizophrenia manifestations (Michmizos et al., 2011). Impaired LTP and LTD-like plasticity has been consistently reported in patients with schizophrenia. Using a TMS protocol useful to explore cortical connectivity and in particular spike timing-dependent plasticity reduced LTP-like plasticity has been shown between posterior parietal and frontal cortices in schizophrenia compared to control subjects (Michmizos et al., 2011). Previous studies exploring brain network organization in schizophrenia showed alterations of several properties (Turrigiano et al., 2004)]. In particular, reduced hub connectivity and rich club organization have been reported in schizophrenic patients (Stam et al., 2009). Decreased connectivity within the frontal cortex has been considered a pathophysiological hallmark and decreased centrality in cortical and subcortical frontal areas has been reported accordingly (Michmizos et al., 2011). In line with the disconnection hypothesis, impaired hub connectivity and reduced rich club efficiency may alter overall brain connectivity in schizophrenia (Tazerart et al., 2020). CHAPTER FIVE 5.0 SUMMARY Synaptic plasticity mechanisms and specific features of brain network share common principles that contribute to explain how neural plasticity influences brain network organization. Indeed, different forms of synaptic plasticity could be directly involved in generating specific brain networks’ characteristics. A cooperative, associative, input-specific and anti-homeostatic Hebbian plasticity is well suited to form brain networks characterized by modules and hubs, providing segregation and integration of information. LTP could be implicated in generating highly connected nodes that are crucially involved in network remodeling after brain damage and also represent the specific target of pathophysiological processes in different neuropsychiatric conditions. Conversely, homeostatic forms of synaptic plasticity intervene to prevent excessive connectivity in the peripheral nodes, stabilizing network activity and preventing excessive cost-efficiency increase. 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