Cholinergic circuits and signaling in the pathophysiology of schizophrenia

Abstract

Central cholinergic signaling has long been associated with aspects of memory, motivation, and mood, each affected functions in neuropsychiatric disorders such as schizophrenia. In this chapter, we review evidence related to the core hypothesis that dysregulation of central cholinergic signaling contributes to the pathophysiology of schizophrenia. Although central cholinergic circuits are resistant to simplification-particularly when one tries to parse the contributions of various classes of cholinergic receptors to disease related phenomena--the potential role of ACh signaling in Schizophrenia pathophysiology deserves careful consideration for prospective therapeutics. The established role of cholinergic circuits in attentional tuning is considered along with recent work on how the patterning of cholinergic activity may modulate corticostriatal circuits affected in schizophrenia.

Fig. 1

Schematic diagram of cholinergic circuits (in red) and their projections within a subset of key brain regions affected in SZ. Cholinergic inputs to prefrontal cortex and hippocampus arise primarily from the basal forebrain group, including the septal cholinergic neurons, the nbM, the preoptic and diagonal band nuclei. Other contributors to the forebrain ACh group are neurons within the substantia innonimata and ventral pallidum. The second major subgroup of ACh-containing neurons, the pontomesencephalic (PM) cholinergic neurons, provides input to brainstem aminergic nuclei (e.g., VTA, SN, and raphe). Cholinergic interneurons intrinsic to the basal ganglia are thought to modulate the relative impact of glutamatergic, dopaminergic, and GABAergic circuits within the ventral striatum. Potential mechanisms of cholinergic regulation of neuronal excitability in prefrontal cortex and hippocampus are also discussed in the text.

Fig. 2

Schematic diagram of an aspiny cholinergic neuron (ASpN) and its projections to convergent sites of glutamatergic and dopaminergic input on striatal GABAergic medium spiny projection neurons (MSpN). Changes in local [ACh], from pauses in the firing of these TANS, modulate the net output of the striatum by interactions with ACh receptors and binding sites in pre-, post-, and perisynaptic compartments.