Neurotrophins regulate development, maintenance, and function of vertebrate nervous systems. Neurotrophins activate two different classes of receptors, the Trk family of receptor tyrosine kinases and p75NTR, a member of the TNF receptor superfamily. Through these, neurotrophins activate many signaling pathways, including those mediated by ras and members of the cdc-42/ras/rho G protein families, and the MAP kinase, PI-3 kinase, and Jun kinase cascades. During development, limiting amounts of neurotrophins function as survival factors to ensure a match between the number of surviving neurons and the requirement for appropriate target innervation. They also regulate cell fate decisions, axon growth, dendrite pruning, the patterning of innervation and the expression of proteins crucial for normal neuronal function, such as neurotransmitters and ion channels. These proteins also regulate many aspects of neural function. In the mature nervous system, they control synaptic function and synaptic plasticity, while continuing to modulate neuronal survival.

Neurotrophins: roles in neuronal development and function.

The telencephalon is organized into distinct longitudinal domains: the cerebral cortex and the basal ganglia. The basal ganglia primarily consists of a dorsal region (striatum) and a ventral region (pallidum). Within the telencephalon, the anlage of the pallidum expresses the Nkx2.1 homeobox gene. A mouse deficient in Nkx2.1 function does not form pallidal structures, lacks basal forebrain TrkA-positive neurons (probable cholinergic neurons) and has reduced numbers of cortical cells expressing GABA, DLX2 and calbindin that migrate from the pallidum through the striatum and into the cortex. We present evidence that these phenotypes result from a ventral-to-dorsal transformation of the pallidal primordium into a striatal-like anlage.

Loss of Nkx2.1 homeobox gene function results in a ventral to dorsal molecular respecification within the basal telencephalon: evidence for a transformation of the pallidum into the striatum

Immunocytochemistry has been used to examine the location of trkA, the high-affinity receptor for nerve growth factor, in adult rat dorsal root ganglia, trigeminal ganglia and spinal cord. TrkA immunoreactivity was observed in small and medium sized ganglion cells and in the dorsal horn of the spinal cord. In lumbar L4 and L5 ganglia trkA-immunoreactive cells constitute 40% of dorsal root ganglion cells and range in size from 15 to 45 microns in diameter. Double labelling using markers for various dorsal root ganglion subpopulations revealed that virtually all (92%) trkA-immunoreactive cells express calcitonin gene-related peptide (CGRP) immunoreactivity. In contrast only 4 and 13% of trkA-immunoreactive cells are labelled by the monoclonal antibody LA4 or the lectin Griffonia simplicifolia IB4, markers for small non-peptide-containing cells. Eighteen percent of trkA-immunoreactive cells belong to the 'large light' subpopulation, identified by their strong immunostaining by the neurofilament antibody RT97. TrkA immunoreactivity in the dorsal horn is heaviest in laminae I and II outer, has a similar distribution to CGRP, and is depleted by dorsal rhizotomy. Our results show that trkA-expressing cells in dorsal root ganglia correspond almost exactly with the CGRP, peptide-producing population. The receptor is present not only on cell bodies but also on central terminals. Non-peptide-containing small cells, which constitute 30% of dorsal root ganglion cells, are not trkA-immunoreactive and therefore most probably are functionally independent of nerve growth factor.

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Immunocytochemical localization of trkA receptors in chemically identified subgroups of adult rat sensory neurons.

Alzheimer’s disease and the basal forebrain cholinergic system: relations to β-amyloid peptides, cognition, and treatment strategies

GDNF, NGF and BDNF as therapeutic options for neurodegeneration.

The present investigation used an antibody directed against the extracellular domain of the signal transducing nerve growth factor receptor, trkA, to reveal immunoreactive perikarya or fibers within the olfactory bulb and tubercle, cingulate cortex, nucleus accumbens, striatum, endopiriform nucleus, septal/diagonal band complex, nucleus basalis, hippocampal complex, thalamic paraventricular and reuniens nuclei, periventricular hypothalamus, interpeduncular nucleus, mesencephalic nucleus of the fifth nerve, dorsal nucleus of the lateral lemniscus, prepositus hypoglossal nucleus, ventral cochlear nucleus, ventral lateral tegmentum, medial vestibular nucleus, spinal trigeminal nucleus oralis, nucleus of the solitary tract, raphe nuclei, and spinal cord. Colocalization experiments revealed that virtually all striatal trkA-immunoreactive neurons (> 99%) coexpressed choline acetyltransferase (ChAT) but not p75 nerve growth factor receptor (NGFR). Within the septal/diagonal band complex virtually all trkA neurons (> 95%) coexpressed both ChAT and p75 NGFR. More caudally, dual stained sections revealed numerous trkA/ChAT (> 80%) and trkA/p75 NGFR (> 95%) immunoreactive neurons within the nucleus basalis. In the brainstem, raphe serotonergic neurons (45%) coexpressed trkA. Sections stained with a pan-trk antibody that recognizes primarily trkA, as well as trkB and trkC, labeled neurons within all of these regions as well as within the hypothalamic arcuate, supramammilary, and supraoptic nuclei, hippocampus, inferior and superior colliculus, substantia nigra, ventral tegmental area of T'sai, and cerebellular Purkinje cells. Virtually all of these other regions with the exception of the cerebellum also expressed pan-trk immunoreactivity in the monkey. The widespread expression of trkA throughout the central neural axis suggests that this receptor may play a role in signal transduction mechanisms linked to NGF-related substances in cholinergic basal forebrain and noncholinergic systems. These findings suggest that pharmacological use of ligands for trkA could have beneficial effects on the multiple neuronal systems that are affected in such disorders as Alzheimer's disease.

/pdf/trka-immunoreactive-profiles-in-the-central-nervous-system-425v1h717t.pdf

TrkA-Immunoreactive Profiles in the Central Nervous System: Colocalization With Neurons Containing p75 Nerve Growth Factor Receptor, Choline Acetyltransferase, and Serotonin

This study was undertaken to evaluate efficacy and long‐term safety of triheptanoin in patients >1 year old, not on a ketogenic diet, with drug‐resistant seizures associated with glucose transporter 1 deficiency syndrome (Glut1DS).

https://onlinelibrary.wiley.com/doi/pdfdirect/10.1111/epi.17263

A randomized, double‐blind trial of triheptanoin for drug‐resistant epilepsy in glucose transporter 1 deficiency syndrome

eP235: Interim results of the Vigilan observational study: clinical characteristics of creatine transporter deficiency

Aim: The purpose of this research was to collect caregiver-reported data on the burden of creatine transporter deficiency (CTD). Materials & methods: Following institutional review board approval, caregivers of individuals with CTD were recruited through advocacy networks and clinical sites. Interested caregivers were consented, screened and sent a survey link. The survey included questions about CTD diagnosis, management and characteristics. Results: Thirty-seven caregivers provided data for 40 patients with CTD. Results demonstrated delays in developmental milestones and deficits in speech, communication, and fine and gross motor skills. Patients saw on average six specialists before receiving a CTD diagnosis. Conclusion: The burden of CTD is substantial and there is a need for effective management and treatment.

Melanie M. Brandabur

Papers

TrkA-Immunoreactive Profiles in the Central Nervous System: Colocalization With Neurons Containing p75 Nerve Growth Factor Receptor, Choline Acetyltransferase, and Serotonin

A randomized, double‐blind trial of triheptanoin for drug‐resistant epilepsy in glucose transporter 1 deficiency syndrome

eP235: Interim results of the Vigilan observational study: clinical characteristics of creatine transporter deficiency

An international cross-sectional survey to characterize the humanistic burden of creatine transporter deficiency