Regulation of cholinergic phenotype in developing neurons

Area of Science:

• Neuroscience
• Developmental Biology
• Neurochemistry

Background:

• Neurotransmitter phenotype specification is crucial for neural circuit formation.
• Glutamate signaling is implicated in regulating cholinergic phenotypes in the hypothalamus.
• Developing neurons exhibit plasticity influenced by intrinsic and extrinsic factors.

Purpose of the Study:

• To investigate the mechanisms of glutamate-dependent regulation of cholinergic properties in hypothalamic neurons.
• To determine the in vivo and in vitro effects of N-methyl-D-aspartate receptor (NMDAR) blockade on cholinergic phenotype.
• To explore the role of acetylcholine (ACh) receptor signaling in NMDAR-mediated cholinergic up-regulation.

Main Methods:

• Immunocytochemistry, electrophysiology, and calcium imaging were employed.
• Studies were conducted in developing rats in vivo and neuronal cultures (mouse and rat).
• Genetic and pharmacological inactivation of NMDARs and ACh receptors were performed.

Main Results:

• Chronic NMDAR blockade increased choline acetyltransferase expression and ACh receptor agonist responsiveness in hypothalamic neurons.
• NMDAR inactivation induced ACh-dependent synaptic activity and involved signaling pathways like PKA, ERK/MAPK, CREB, and NF-kappaB.
• ACh receptor blockade prevented the cholinergic up-regulation induced by NMDAR blockade.
• Inactivation of ionotropic glutamate receptors induced a cholinergic phenotype in a subset of glutamatergic neurons, with partial switching and corelease of ACh and glutamate.

Conclusions:

• Developing neurons can alter their neurotransmitter phenotypes in response to altered signaling within neural circuits.
• NMDAR signaling plays a significant role in regulating cholinergic development.
• Neuronal plasticity allows for the potential coexpression and switching of neurotransmitter phenotypes, challenging the notion of fixed transmitter identities.