**5. Synaptic plasticity and disease**

In disease conditions, aberrant synaptic plasticity or any defect in signaling mechanism may cause substantial deficits in different aspects of central nervous system. The role of synaptic plasticity in disease is becoming more evident across a wide range of CNS disorders. Understanding the molecular basis of normal and diseased plasticity will provide a platform to study the molecular basis of many of the diseases and to target drugs on plasticity related molecules to treat many of the CNS disorders. Cognitive deficits are the early symptoms that appear much before the onset of neuritic dystrophy and pathology. Often, it is likely that the immediate consequence of aberrant signaling could be impairment of synaptic plasticity. This would later develop into synaptic and neuronal loss. Thus plasticity related mechanisms could have the advantage of being targets for early therapeutic intervention in CNS disorders.

Among the CNS disorders such as Alzheimer's disease (AD), schizophrenia, epilepsy and in disorders associated with learning disabilities where there are alterations of synaptic plasticity, Alzheimer's disease has been extensively studied.

#### **5.1 Alzheimer's disease**

Hippocampus, amygdala, neocortex, anterior thalamus, entrohinal, and transentrohinal cortices are some of the areas affected in Alzheimers disease (Sweatt, 2010). Synapse loss

Fig. 7. Scheme of shared post synaptic signaling pathways leading to LTP and LTD

In disease conditions, aberrant synaptic plasticity or any defect in signaling mechanism may cause substantial deficits in different aspects of central nervous system. The role of synaptic plasticity in disease is becoming more evident across a wide range of CNS disorders. Understanding the molecular basis of normal and diseased plasticity will provide a platform to study the molecular basis of many of the diseases and to target drugs on plasticity related molecules to treat many of the CNS disorders. Cognitive deficits are the early symptoms that appear much before the onset of neuritic dystrophy and pathology. Often, it is likely that the immediate consequence of aberrant signaling could be impairment of synaptic plasticity. This would later develop into synaptic and neuronal loss. Thus plasticity related mechanisms could have the advantage of being targets for early therapeutic intervention in CNS disorders.

Among the CNS disorders such as Alzheimer's disease (AD), schizophrenia, epilepsy and in disorders associated with learning disabilities where there are alterations of synaptic

Hippocampus, amygdala, neocortex, anterior thalamus, entrohinal, and transentrohinal cortices are some of the areas affected in Alzheimers disease (Sweatt, 2010). Synapse loss

plasticity, Alzheimer's disease has been extensively studied.

**5. Synaptic plasticity and disease** 

**5.1 Alzheimer's disease** 

that starts even at early stages of AD, results in a condition where minimum number of synapses are not available for cortical networks and impairment of synaptic plasticity occurs. The neuropathological hallmarks of Alzheimer's disease are the presence of intracellular neurofibrillary tangles (NFT) composed of hyperphosphorylated tau protein and extracellular neuritic plaques composed of amyloid β protein (Aβ) (Montoya, 2011). Aβ is produced by the sequential cleavage of amyloid precursor protein (APP) by β-secretase and γ-secretase (Haass & Selkoe, 1993). 40-residue Aβ (Aβ40) and 42-residue Aβ (Aβ42) are the most common isoforms of Aβ (Xia, 2010). Even before plaques could be observed, significant deficits in synaptic transmission have been detected by electrophysiological recordings from the hippocampus of transgenic mice over expressing APP (Hsia et al., 1999; Mucke et al., 2000). Thus aberrations in synaptic function are the early events followed by the formation of plaques and NFT (Funato et al., 1999; Hartl et al., 2008; Selkoe, 2002; Walsh & Selkoe, 2004, as cited in Proctor et al., 2011).

#### **5.1.1 Disruption of the plasticity of glutamatergic synaptic transmission**

The alterations of synaptic plasticity which happens before synaptic loss may be initiating neurodegeneration. The spatial working memory and LTP were normal in young APP695SWE transgenic mice. There was reduction in LTP and deficits in behavioural performance with aged transgenic mice. The deterioration of LTP in dentate gyrus and CA1 and behavioural deficit appear in a correlated manner (Chapman et al., 1999). Aβ concentrations increased with age. Many lines of investigations show that oligomeric forms of Aβ species interfere with synaptic plasticity, inhibit LTP and impairs maintenance of LTP (Barghorn et al., 2005; Klyubin et al., 2008; Shankar et al., 2008; Walsh et al., 2002; Wang et al., 2002; Stephan et al., 2001). Aβ peptide when applied before and during HFS inhibits LTP induction in the dentate medial perforant path and Schaffer colllateral-CA1 pathway (Chen et al., 2000; Chen et al., 2002). The basal synaptic transmission or short-term synaptic plasticity remained intact. Aβ inhibits maintenance phase of L-LTP and also inhibits protein synthesis in the L-LTP phase when applied after HFS. The effects of Aβ on the induction of LTP and on L-LTP are independent of each other, working through multiple mechanisms (Chen et al., 2002). Different forms of LTP affected by Aβ will be reflected as deficits in different phases of memory and also at a concentration of Aβ, below that is required to produce neurotoxicity (Chen et al., 2002).

#### **5.1.2 Molecular events causing disruption of LTP**

Aβ was shown to increase intracellular Ca2+ concentrations due to potentiation of currents through L-type Ca2+ channels (Ueda et al., 1997) and blockade of fast-inactivating K+ channels that leads to prolonged membrane depolarization and Ca2+ influx (Good et al., 1996). Basal synaptic transmission and NMDAR-dependent forms of LTP are impaired in the aging hippocampus (Foster & Norris, 1997), which correlates with deficits in spatial memory (Barnes & McNaughton, 1985; Diana et al., 1995). Aβ induced Ca2+ transients activate calcineurin and cause desensitization of NMDAR channels, reducing Ca2+ influx through these channels during LTP-inducing stimulus protocol. As a result induction of NMDAR-dependent forms of LTP, E-LTP and also L-LTP are suppressed (Chen et al., 2002). Aβ also inhibited NMDAR mediated EPSCs. Activated calcineurin could impair the mechanisms underlying the components of L-LTP and long-term memory. This could be

Molecular Mechanisms in Synaptic Plasticity 319

receptors can be due to the depletion of PSD-95 from PSD, altering interactions between glutamate receptors and scaffolding proteins. This could possibly be one of the mechanisms leading to the disruption of LTP. AMPA receptors are removed from the synapse by binding to scaffolding protein AKAP-150 and PSD-95 (Bhattacharyya et al., 2009, as cited in Proctor et al., 2011) as seen in LTD. In APP transgenic mouse model loss of AMPARs are seen. The changes in LTP, integrity of spine and reduced NMDAR expression could all be due to the Aβ induced disruption in AMPAR trafficking and expression, as AMPAR regulation is

Elevated Aβ blocks neuronal glutamate uptake at synapse, the outcome of which is an increased glutamate at synaptic cleft (Li et al., 2009). This may lead to the activation of extra or perisynaptic NMDAR promoting LTD. The activation of perisynaptic mGluRs may also be involved in the facilitation of LTD by Aβ. The pathway for Aβ induced LTD induction involves an initial synaptic activation of NMDAR by glutamate followed by synaptic NMDAR desensitization, NMDAR and AMPAR internalization, and activation of perisynaptic NMDARs and mGluRs (Hsieh et al., 2006; Li et al., 2009, as cited in Palop and Mucke, 2010). In patients with Alzheimer's disease, glycogen synthase kinase (GSK3β) deregulation due to its increased expression causes reactivation of NMDAR-LTD, which leads to synaptic loss (Collingridge et al., 2010). Hence Aβ induced LTP deficits seem to

In the dentate gyrus, at medial perforant path synapses on the dentate granule cells, pairedpulse facilitation (PPF) and LTP are impaired in mouse transgenic model of AD (Palop et al., 2007; Harris et al., 2010). Tau reduction eliminates abnormalities in synaptic transmission and plasticity in hippocampal subfields of hAPPJ20 mice (Palop et al., 2007; Harris et al., 2010; Roberson et al., 2011). Phosphorylation of tau by GSK3 modulates the pathway by which Aβ exerts its pathogenic downstream effects on LTP. This is similar to the Aβ mediated neurodegeneration (Tackenberg & Brandt, 2009). The absence of tau prevents the

Other diseases conditions where impairments in synaptic plasticity were observed are schizophrenia, Fragile X Syndrome (Lauterborn et al., 2007; Connor et al., 2011, as cited in Kumar, 2011), Parkinson's disease (Bagetta et al., 2010, as cited in Kumar, 2011), Down syndrome (Costa and Grybko, 2005; Siarey et al., 2005, as cited in Kumar, 2011), Rett syndrome (Moretti et al., 2006; Weng et al., 2011, as cited in Kumar, 2011), Huntington's disease (Usdin et al., 1999; Murphy et al., 2000; Lynch et al., 2007, as cited in Kumar, 2011), Niemann–Pick disease type C (Zhou et al., 2011, as cited in Kumar, 2011), Rubinstein–Taybi syndrome (Alarcon et al., 2004, as cited in Kumar, 2011), brain inflammation (Min et al., 2009; Lynch, 2010, as cited in Kumar, 2011), glioma (Wang et al., 2010, as cited in Kumar, 2011) and diabetes (Biessels et al., 1996; Kamal et al., 1999, 2000, 2005; Valastro et al., 2002;

Schizophrenia is caused by abnormal synaptic regulation. Six genes identified for schizophrenia (Harrison & Weinberger, 2005) encode for proteins involved in synaptic plasticity and its modulation (Stephan, 2006). Neurophysiological studies have reported *in* 

important for NMDAR-dependent LTP (Proctor et al., 2011).

synaptic dysfunction induced by Aβ (Shipton et al., 2011).

Artola et al., 2005; Artola, 2008, as cited in Kumar, 2011).

**5.2 Synaptic plasticity and other diseases** 

depend on activation of LTD pathways.

related to early signs of memory deficits of AD. Under the influence of Aβ oligomers, activation of ERK, MAPK, CaMKII and Akt/PKB were reduced during LTP (Selkoe, 2008; Zeng et al., 2010). In Alzheimer's disease mouse models, erratic regulation of *Arc* expression leads to synaptic dysfunction (Shepherd & Bear, 2011).

NMDAR dependent neocortical plasticity deficits were observed in AD patients (Battaglia et al., 2007). Nanomolar concentrations of Aβ reduced the NMDAR-mediated EPSCs in hippocampal slices (Li et al., 2009; Cerpa et al., 2010, as cited in Hu et al., 2011). In APP transgenic mice, there is lower level of cell surface NMDA receptors. Hence, Aβ peptide may be promoting the endocytosis of NMDA receptors. NMDA receptor endocytosis also requires α-7-nicotinic receptors (nAChRs), PP2B and the STEP tyrosine phosphatase. Autopsy tissues of AD patients show a reduction in the NMDAR subunit levels. PP2B is activated, when Aβ oligomers bind and activate α-7-nicotinic receptors. Tyrosine phosphatase STEP is activated by PP2B-mediated dephosphorylation. Dephosphorylation of Y1472 of GluN2B by the activated STEP removes NMDAR from surface. In both AD transgenic mouse models and in the brains of AD subjects increased levels of STEP were detected (Chin et al., 2005; Kurup et al., 2010, as cited in Proctor et al., 2011). Aβ induced changes in LTP could be due to disruption of plasticity mechanism as a result of NMDAR changes. Postsynaptic protein tyrosine kinase EphB2, a regulator of NMDAR trafficking, is cleaved on binding to Aβ and this promotes the removal of synaptic NMDARs (Cissé et al., 2011). Stimulation of inducible nitric oxide synthase (iNOS), superoxide production and activation of microglia, all by Aβ, may also inhibit NMDAR dependent LTP (Wang et al., 2004). The density of dendritic spines decrease and the active synapses are reduced when exposed to physiological concentration of Aβ. Electrophysiological experiments show that decrease in spine density can be correlated to the loss of excitatory synapses (Selkoe, 2008). Aβ requires the activity of NMDA receptors to bring about morphological changes of the dendrite (Shankar et al., 2007).

An increase in Aβ concentration can decrease AMPA receptor-mediated EPSCs or field EPSPs. Aβ binds to GluA2 containing AMPA receptors and causes the endocytosis of AMPARs in a clathrin-dependent, calcineurin and densin mediated pathway (Liu et al., 2010, as cited in Hu et al., 2011). High concentrations of Aβ also induce phosphorylation of GluA2-Ser880 by PKC and subsequent internalization of the receptor. Caspase-3 cleavage of calcineurin facilitates postsynaptic GluA1 dephosphorylation and internalization in the cultured hippocampal neurons from transgenic mouse. This observation was supplemented by hippocampal-dependent contextual fear conditioning (CFC) deficit shown by transgenic AD mouse model and an alteration in basic glutamatergic synaptic transmission and enhanced LTD. The reduced AMPAR-mediated currents are associated with the lower number of AMPAR at the synapse (D'Amelio et al., 2011). The trafficking and anchoring of AMPA and NMDA receptors are disturbed by hyperphosphorylated tau also (Hoover et al., 2010, as cited in Hu et al., 2011).

Aβ is found to be attached to hippocampal neurons and its presence could be seen on dendritic surfaces (Gong et al., 2003). Synapse elimination associated with decrease in size of the synapse can be linked with degradation of the PSD proteinaceous network (Gong & Lippa, 2010). The number and compartmentalization of NMDA and AMPA receptors in PSD are determined by PSD-95, and other scaffolding proteins. PSD-95 and SAP102 are found to be altered in the susceptible regions of AD brain (Gylys et al., 2004; Leuba et al., 2008a, 2008b, as cited in Proctor et al., 2011). The lower levels of NMDA and AMPA

related to early signs of memory deficits of AD. Under the influence of Aβ oligomers, activation of ERK, MAPK, CaMKII and Akt/PKB were reduced during LTP (Selkoe, 2008; Zeng et al., 2010). In Alzheimer's disease mouse models, erratic regulation of *Arc* expression

NMDAR dependent neocortical plasticity deficits were observed in AD patients (Battaglia et al., 2007). Nanomolar concentrations of Aβ reduced the NMDAR-mediated EPSCs in hippocampal slices (Li et al., 2009; Cerpa et al., 2010, as cited in Hu et al., 2011). In APP transgenic mice, there is lower level of cell surface NMDA receptors. Hence, Aβ peptide may be promoting the endocytosis of NMDA receptors. NMDA receptor endocytosis also requires α-7-nicotinic receptors (nAChRs), PP2B and the STEP tyrosine phosphatase. Autopsy tissues of AD patients show a reduction in the NMDAR subunit levels. PP2B is activated, when Aβ oligomers bind and activate α-7-nicotinic receptors. Tyrosine phosphatase STEP is activated by PP2B-mediated dephosphorylation. Dephosphorylation of Y1472 of GluN2B by the activated STEP removes NMDAR from surface. In both AD transgenic mouse models and in the brains of AD subjects increased levels of STEP were detected (Chin et al., 2005; Kurup et al., 2010, as cited in Proctor et al., 2011). Aβ induced changes in LTP could be due to disruption of plasticity mechanism as a result of NMDAR changes. Postsynaptic protein tyrosine kinase EphB2, a regulator of NMDAR trafficking, is cleaved on binding to Aβ and this promotes the removal of synaptic NMDARs (Cissé et al., 2011). Stimulation of inducible nitric oxide synthase (iNOS), superoxide production and activation of microglia, all by Aβ, may also inhibit NMDAR dependent LTP (Wang et al., 2004). The density of dendritic spines decrease and the active synapses are reduced when exposed to physiological concentration of Aβ. Electrophysiological experiments show that decrease in spine density can be correlated to the loss of excitatory synapses (Selkoe, 2008). Aβ requires the activity of NMDA receptors to bring

An increase in Aβ concentration can decrease AMPA receptor-mediated EPSCs or field EPSPs. Aβ binds to GluA2 containing AMPA receptors and causes the endocytosis of AMPARs in a clathrin-dependent, calcineurin and densin mediated pathway (Liu et al., 2010, as cited in Hu et al., 2011). High concentrations of Aβ also induce phosphorylation of GluA2-Ser880 by PKC and subsequent internalization of the receptor. Caspase-3 cleavage of calcineurin facilitates postsynaptic GluA1 dephosphorylation and internalization in the cultured hippocampal neurons from transgenic mouse. This observation was supplemented by hippocampal-dependent contextual fear conditioning (CFC) deficit shown by transgenic AD mouse model and an alteration in basic glutamatergic synaptic transmission and enhanced LTD. The reduced AMPAR-mediated currents are associated with the lower number of AMPAR at the synapse (D'Amelio et al., 2011). The trafficking and anchoring of AMPA and NMDA receptors are disturbed by hyperphosphorylated tau also (Hoover et al.,

Aβ is found to be attached to hippocampal neurons and its presence could be seen on dendritic surfaces (Gong et al., 2003). Synapse elimination associated with decrease in size of the synapse can be linked with degradation of the PSD proteinaceous network (Gong & Lippa, 2010). The number and compartmentalization of NMDA and AMPA receptors in PSD are determined by PSD-95, and other scaffolding proteins. PSD-95 and SAP102 are found to be altered in the susceptible regions of AD brain (Gylys et al., 2004; Leuba et al., 2008a, 2008b, as cited in Proctor et al., 2011). The lower levels of NMDA and AMPA

leads to synaptic dysfunction (Shepherd & Bear, 2011).

about morphological changes of the dendrite (Shankar et al., 2007).

2010, as cited in Hu et al., 2011).

receptors can be due to the depletion of PSD-95 from PSD, altering interactions between glutamate receptors and scaffolding proteins. This could possibly be one of the mechanisms leading to the disruption of LTP. AMPA receptors are removed from the synapse by binding to scaffolding protein AKAP-150 and PSD-95 (Bhattacharyya et al., 2009, as cited in Proctor et al., 2011) as seen in LTD. In APP transgenic mouse model loss of AMPARs are seen. The changes in LTP, integrity of spine and reduced NMDAR expression could all be due to the Aβ induced disruption in AMPAR trafficking and expression, as AMPAR regulation is important for NMDAR-dependent LTP (Proctor et al., 2011).

Elevated Aβ blocks neuronal glutamate uptake at synapse, the outcome of which is an increased glutamate at synaptic cleft (Li et al., 2009). This may lead to the activation of extra or perisynaptic NMDAR promoting LTD. The activation of perisynaptic mGluRs may also be involved in the facilitation of LTD by Aβ. The pathway for Aβ induced LTD induction involves an initial synaptic activation of NMDAR by glutamate followed by synaptic NMDAR desensitization, NMDAR and AMPAR internalization, and activation of perisynaptic NMDARs and mGluRs (Hsieh et al., 2006; Li et al., 2009, as cited in Palop and Mucke, 2010). In patients with Alzheimer's disease, glycogen synthase kinase (GSK3β) deregulation due to its increased expression causes reactivation of NMDAR-LTD, which leads to synaptic loss (Collingridge et al., 2010). Hence Aβ induced LTP deficits seem to depend on activation of LTD pathways.

In the dentate gyrus, at medial perforant path synapses on the dentate granule cells, pairedpulse facilitation (PPF) and LTP are impaired in mouse transgenic model of AD (Palop et al., 2007; Harris et al., 2010). Tau reduction eliminates abnormalities in synaptic transmission and plasticity in hippocampal subfields of hAPPJ20 mice (Palop et al., 2007; Harris et al., 2010; Roberson et al., 2011). Phosphorylation of tau by GSK3 modulates the pathway by which Aβ exerts its pathogenic downstream effects on LTP. This is similar to the Aβ mediated neurodegeneration (Tackenberg & Brandt, 2009). The absence of tau prevents the synaptic dysfunction induced by Aβ (Shipton et al., 2011).

#### **5.2 Synaptic plasticity and other diseases**

Other diseases conditions where impairments in synaptic plasticity were observed are schizophrenia, Fragile X Syndrome (Lauterborn et al., 2007; Connor et al., 2011, as cited in Kumar, 2011), Parkinson's disease (Bagetta et al., 2010, as cited in Kumar, 2011), Down syndrome (Costa and Grybko, 2005; Siarey et al., 2005, as cited in Kumar, 2011), Rett syndrome (Moretti et al., 2006; Weng et al., 2011, as cited in Kumar, 2011), Huntington's disease (Usdin et al., 1999; Murphy et al., 2000; Lynch et al., 2007, as cited in Kumar, 2011), Niemann–Pick disease type C (Zhou et al., 2011, as cited in Kumar, 2011), Rubinstein–Taybi syndrome (Alarcon et al., 2004, as cited in Kumar, 2011), brain inflammation (Min et al., 2009; Lynch, 2010, as cited in Kumar, 2011), glioma (Wang et al., 2010, as cited in Kumar, 2011) and diabetes (Biessels et al., 1996; Kamal et al., 1999, 2000, 2005; Valastro et al., 2002; Artola et al., 2005; Artola, 2008, as cited in Kumar, 2011).

Schizophrenia is caused by abnormal synaptic regulation. Six genes identified for schizophrenia (Harrison & Weinberger, 2005) encode for proteins involved in synaptic plasticity and its modulation (Stephan, 2006). Neurophysiological studies have reported *in* 

Molecular Mechanisms in Synaptic Plasticity 321

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*vivo* disturbances of cortical plasticity and excitability in schizophrenia patients. Paired associative stimulation (PAS) induced LTP-like plasticity was disrupted and these plasticity deficits were indicated to be caused by NMDAR abnormalities in schizophrenia patients (Frantseva et al., 2008). Dysfunction of glutamatergic transmission is associated with the pathophysiological state in schizophrenia and this will lead to disturbed plasticity and neurotoxicity (Hasan et al., 2011; Konradi and Heckers, 2003; Paz, 2008).

Hippocampal LTP in CA1 area was greatly reduced in epilepsy. This reduction was associated with altered dendritic morphology and reduced hippocampal non-spatial memory seen in epileptic mouse model (Sgobio et al., 2010). The composition of ionotropic glutamate receptors in the PSD was found to be altered in brain areas where seizure activity is more pronounced (Wyneken et al., 2003). Application of low frequency stimulation to depoteniate the hyperexcitable synapses were found to be effective in epileptic patients (Tergau et al., 1999).

In drug addiction and fear conditioning related to post traumatic stress disorder, normal LTP and learning are responsible for the undesired condition (Mahan and Ressler, 2011). The impairment of hippocampus-dependent memory retrieval under acute stress condition is mediated by hippocampal LTD (Collingridge et al., 2010). In Fragile X syndrome (FXS), FMRP, is mutated and acts as a negative regulator of *Arc* translation. The dysregulated expression of *Arc* may alter plasticity (Shepherd & Bear, 2011).

A plethora of information thus provide concrete evidence that impairment of synaptic plasticity in diseases can contribute to decline in learning and memory.
