Crosstalk among electrical activity, trophic factors and morphogenetic proteins in the regulation of neurotransmitter phenotype specification

Abstract

Morphogenetic proteins are responsible for patterning the embryonic nervous system by enabling cell proliferation that will populate all the neural structures and by specifying neural progenitors that imprint different identities in differentiating neurons. The adoption of specific neurotransmitter phenotypes is crucial for the progression of neuronal differentiation, enabling neurons to connect with each other and with target tissues. Preliminary neurotransmitter specification originates from morphogen-driven neural progenitor specification through the combinatorial expression of transcription factors according to morphogen concentration gradients, which progressively restrict the identity that born neurons adopt. However, neurotransmitter phenotype is not immutable, instead trophic factors released from target tissues and environmental stimuli change expression of neurotransmitter-synthesizing enzymes and specific vesicular transporters modifying neuronal neurotransmitter identity. Here we review studies identifying the mechanisms of catecholaminergic, GABAergic, glutamatergic, cholinergic and serotonergic early specification and of the plasticity of these neurotransmitter phenotypes during development and in the adult nervous system. The emergence of spontaneous electrical activity in developing neurons recruits morphogenetic proteins in the process of neurotransmitter phenotype plasticity, which ultimately equips the nervous system and the whole organism with adaptability for optimal performance in a changing environment.

Keywords: Calcium signaling; Morphogenetic proteins; Neurotransmitter phenotype specification and plasticity; Sonic hedgehog; Spontaneous electrical activity; Target-derived trophic factors.

Figure 1. Interplay between Shh and Ca²⁺ spike activity regulates neurotransmitter specification in developing spinal neurons

Shh binds to Patched (Ptc) releasing the constitutive inhibition on the coreceptor Smoothened (Smo) which activates phopholipase C (PLC) that increases inositol triphosphate (IP3) and diacylglycerol (DAG) levels thus enhancing Ca²⁺ spike activity through the activation of transient receptor potential channel 1 (TRPC1), voltage-gated Na⁺ and Ca²⁺ channels (Na_v, Ca_v) and Ca²⁺ release from stores. Enhanced Ca²⁺ spike activity intercalates in Shh canonical pathway, inverting Shh action and leading to Gli2 cytosolic localization, Gli2 and Gli3 processing into repressor forms, repression of Gli1 transcription and an overall downregulation of Gli activity. In contrast, Ca²⁺ spikes activate transcription factors cAMP-responsive element binding protein (CREB) and cJun, which promote the expression of the GABAergic over glutamatergic phenotype by regulating expression of the transcription factor selector tlx3. Based on Cheng et al., 2004, Marek et al., 2010, Belgacem and Borodinsky, 2011, .

Figure 2. Intrinsic and extrinsic stimuli change neurotransmitter specification in developing and mature neurons

Preliminary specification of neural progenitors during the embryonic development is instrumental to morphogenesis of different nervous system structures and functional nuclei. However, the identity of developing neurons is not sealed. Instead features like neurotransmitter phenotype are sensitive to the changing internal and external environment; the emerging stimuli and developmental cues crosstalk with morphogenetic proteins to implement plasticity of neurotransmitter phenotype expression necessary for adapting to the ever-changing environment.