Impact of Oxidative - Nitrosative Stress on Cholinergic Presynaptic Function

Cholinergic neurotransmission plays an essential role in a variety of physiological processes in both the central and peripheral nervous systems. Cholinergic neurons use the classical neurotransmitter acetylcholine (ACh) to communicate with their target cells. In the periphery, ACh is the neurotransmitter used at the skeletal neuromuscular junction, at all preand postganglionic parasympathetic synapses and at preganglionic sympathetic synapses. In the central nervous system, the actions of ACh are widespread with cholinergic neurotransmission involved in attention, learning and memory, cognition, sleep, wakefulness, and modulation of sensory information (Hasselmo, 2006; Sarter & Parihk, 2005; Woolf & Butcher, 2010). Dysfunction of cholinergic neurotransmission in the central nervous system is apparent in a number of neurological disorders, such as Alzheimer’s, Parkinson’s, and Huntington’s diseases, schizophrenia and amyotrophic lateral sclerosis (Bohnen & Albin, 2010; Mesulam, 2004; Oda, 1999). Cholinergic neurons innervate almost all areas of the brain, where this can be mediated by either intrinsic interneurons or by extrinsic projection neurons. Cholinergic interneurons localized in the striatum are involved in motor function, cognition, and behavior (Woolf & Butcher, 2010). The basal forebrain, which is comprised of the nucleus basalis of Meynert, medial septum, diagonal band of Broca, the magnocellular preoptic nucleus, and substantia innominata, contains the cell bodies of cholinergic neurons that project to the hippocampus, amygdala, olfactory bulb, and all areas of the cerebral cortex (Woolf & Butcher, 2010). Collectively, basal forebrain cholinergic neuron activity plays a role in attention, learning, memory, perception, and consciousness (Sarter et al., 2003; Woolf, 1998; Woolf & Butcher, 2010). Cholinergic neurons in the mesopontine region (the pedunculopontine and laterodorsal nuclei) project to the thalamus, hypothalamus, basal forebrain, medial frontal cortex, brainstem and spinal cord (Woolf & Butcher, 2010). Descending cholinergic projections from the mesopontine area decrease muscle tone during rapid eye movement sleep while ascending cholinergic projections are involved in cognitive functions and consciousness (Woolf & Butcher, 2010). Cholinergic projections to the interpeduncular nucleus originate from neurons with cell bodies in the medial habenula; these neurons regulate electroencephalogram patterns and rapid eye movement sleep (Woolf & Butcher, 2010). The cycle of ACh synthesis, storage, release and degradation has been well-characterized at the cellular and molecular levels and is depicted in Figure 1. ACh is synthesized in the