Page - (000184) - in Biomedical Chemistry: Current Trends and Developments

glutamatergic function (Snyder, 2005). Moreover, Aβ facilitates LTD in a NMDA-dependent mechanism, indicating that in AD not only receptor levels, but also their function, is impaired and may be linked to reduced glutamatergic transmission associated with cognitive deficits (Kim, 2001). Parkinson’s disease (PD) main pathological hallmarks are the loss of dopaminergic neurons in the substantia nigra pars compacta (SNc) projecting to the corpus striatum, and the presence of cytoplasmic inclusions of protein aggregates, composed mainly of α-synuclein, and other proteins, called Lewi bodies (Betarbet, 2002). Several studies demonstrated that dopaminergic neurodegeneration in SNc is mainly associated with mitochondrial dysfunction and oxidative stress. However, it is widely accepted that glutamate excitotoxicity also plays an important role in PD pathology (Blandini, 2010). The dopaminergic denervation of the striatum associated with SNc neurodegeneration triggers changes in the basal ganglia circuitry which are associated with the motor neurological symptoms of the disease, namely tremors and rigidity (Blandini, 2000). Within the basal ganglia circuitry, glutamate neurotransmission occurs in the projections from cortical areas to the striatum and to the subthalamic nucleus (STN), and from the STN to the substantia nigra, therefore playing an important role in the mechanisms related to PD motor symptoms (Blandini, 2000). Also, glutamate excitotoxic effects may be relevant to the neurodegenerative processes occurring in PD. Dopaminergic neurons from SNc are particularly vulnerable to excitotoxicity triggered by a bioenergetic failure related to an impairment of mitochondrial function (Erecinska, 1990). Also, the presence of dopamine contributes to the sensititvity of SNc neurons to glutamate toxicity, since it may amplify glutamate signaling (Shimizu, 2003). The neurodegeneration of dopaminergic neurons in PD is associated with rearrangements in basal ganglia circuitry. In initial phases of the disease, STN glutamatergic activity may increase the dopaminergic activity of surviving neurons in SNc. However, through disease progression, persistent glutamatergic stimulation of dopaminergic neurons will be neurotoxic, further contributing to neurodegeneration (Shimo, 2009). Schizophrenia is characterized by a dysfunction in cognitive function