Page - (000192) - in Biomedical Chemistry: Current Trends and Developments

pathogenesis is usually associated with glutamate release, altered GABAergic transmission also contributes to disrupting the excitatory/inhibitory balance and leads to impaired cognitive function in AD patients (Rissman, 2011). Several studies have shown that GABAergic neurons as well as GABAergic receptors appear to be resistant to neurodegeneration in AD, particularly in the hippocampus, despite the mild reduction reported for GABAA receptor subunits α1, α5 and β3 (Reinikainen, 1988; Marczynski, 1998). It was then proposed that Aβ decreases pyramidal cell firing, while in these neurons GABA receptors remain unaffected, which will decrease the activation of downstream GABAergic neurons resulting in decreased inhibition of excitatory neurons (Kamenetz, 2003). Increased Aβ may also elicit seizures in the cortex and hippocampus of AD, possibly related to enhanced GABA activity in the dentate gyrus and aberrant excitatory/inhibitory balance (Minkeviciene, 2009; Palop, 2010). It was proposed that Aβ decreases pyramidal cell firing, while in these neurons GABA receptors remain unaffected. This will decrease the activation of downstream GABAergic neurons, which will decrease the inhibition to the inhibitory neurons they innervate, with a resultant decreased inhibition of excitatory neurons (Kamenetz, Tomita et al. 2003). In Parkinson’s disease, the degeneration of dopaminergic neurons in the Substancia Nigra (SN) and consequent loss of dopamine (DA) leads to alteration in the neurotransmitters in the basal ganglia circuitry, particularly an imbalance in glutamate and GABA neurotransmission in the nigrostriatal pathway, resulting in an increased excitation in the SN promoting excitotoxicity and cell death (Ampe, Massie et al. 2007; Calabresi, Picconi et al. 2007; Walker, Moore et al. 2012). There are strong evidences showing a strong interaction between GABA, glutamate and dopamine in the basal ganglia. For instance, the DA input to the striatum affects glutamate and GABA transmission and DA modulates glutamate costicostriatal signalling to GABAergic medium spiny neurons (Kalivas and Duffy 1997; Surmeier, Ding et al. 2007). Dysfunctional GABAergic transmission is also present in the altered function of the reward system that underlies the addictive behavior. Exposure to psychoactive substances may affect the GABAergic system either directly, as in the case of alcohol abuse, or indirectly as in chronic