Functionally diverse and important GABAergic neurons are located in the brainstem, both within and outside the dopaminergic and serotonergic nuclei. However, the spectrum of the GABAergic neuron subtypes and their molecular characteristics are poorly understood.
Mouse midbrain GABAergic neuron subtypes (red), GABAergic neurons associated with the dopaminergic nuclei (purple), Dopaminergic neurons (green). Reference: Laura Lahti
Our studies have revealed developmental mechanisms and molecular characteristics of GABAergic neuron subtypes in the brainstem. These include the GABAergic neurons associated with the dopaminergic nuclei. Such neurons comprise GABAergic neurons in the VTA, rostromedial tegmental nucles (RMTg, also called the tail of VTA), and posterior part of the SNpr. We have shown that these neurons are born in a specific region of the ventral hindbrain (rhombomere 1), from a pool of progenitors that give rise to glutamatergic neurons as well. Some of these excitatory glutamatergic neuron subtypes also control the dopaminergic system (for example the LDTg glutamatergic neurons). We have revealed the molecular mechanisms that operate in the early precursor cells and control the selection between the GABAergic and glutamatergic lineages. Failure of the ventral hindbrain precursors to select a GABAergic identity results in behavioral abnormalities, including hyperactivity, altered reward response, impulsivity, and learning deficit.
Our ongoing work addresses the cellular diversity, subtype-specific developmental regulatory mechanisms and neurophysiological roles of these brainstem GABAergic and glutamatergic neurons.
Single cell mRNA sequencing reveals the differentiation paths of GABAergic and glutamatergic neurons in the ventral hindbrain. Reference: Morello et al., 2020
For scRNAseq based visualization of gene expression in the embryonic ventral brainstem cells, see www.tegex.fi
Morello, F., Borshagovski, D., Survila, M., Tikker, L., Sadik-Ogli, S., Kirjavainen, A., Estartus, N., Knaapi, L., Lahti, L., Törönen, P., Mazutis, L., Delogu, A., Salminen, M., Achim, K. and Partanen, J. Molecular fingerprint and developmental regulation of the tegmental GABAergic and glutamatergic neurons derived from the anterior hindbrain. Cell Reports 33: 198268. DOI: 10.1016/j.celrep.2020.108268, 2020
Morello, F., Voikar, V., Parkkinen, P., Panhelainen, A., Rosenholm, M., Makkonen, A., Rantamäki, T., Piepponen, P., Aitta-aho, T. and Partanen, J. ADHD-like behaviors caused by inactivation of a transcription factor controlling the balance of inhibitory and excitatory neuron development in the mouse anterior brainstem. Translational Psychiatry 9: in press. DOI: 10.1038/s41398-020-01033-8, 2020
Kala K, Haugas M, Lilleväli K, Guimera J, Wurst W, Salminen M, Partanen J. Gata2 is a tissue-specific post-mitotic selector gene for midbrain GABAergic neurons. Development. 136:253-62, 2009https://www.ncbi.nlm.nih.gov/pubmed/19088086
Peltopuro, P., Kala, K. and Partanen, J. Distinct requirements for Ascl1 in subpopulations of midbrain GABAergic neurons. Dev. Biol., 343: 63-70, 2010 https://www.ncbi.nlm.nih.gov/pubmed/20417196
Achim K, Peltopuro P, Lahti L, Li J, Salminen M, Partanen J. Distinct developmental origins and regulatory mechanisms for GABAergic neurons associated with dopaminergic nuclei in the ventral mesodiencephalic region. Development. 139:2360-70, 2012 https://www.ncbi.nlm.nih.gov/pubmed/22627282
Virolainen, S.-M., Achim, K., Peltopuro, P., Salminen, M., Partanen, J. Transcriptional regulatory mechanisms underlying the GABAergic neuron fate in different diencephalic prosomeres. Development, 139:3795-3805, 2012https://www.ncbi.nlm.nih.gov/pubmed/22991444
Achim, K., Peltopuro, P., Lahti, L., Hui-Hsin, T., Zachariah, A., Åstrand, M., Rowitch, D., Salminen, M. and Partanen, J. The role of Tal2 and Tal1 in the differentiation of midbrain GABAergic neuron precursors. Biology Open, 2:990-997, 2013
Lahti L, Haugas M, Tikker L, Airavaara M, Voutilainen MH, Anttila J, Kumar S, Inkinen C, Salminen M, Partanen J. Differentiation and molecular heterogeneity of inhibitory and excitatory neurons associated with midbrain dopaminergic nuclei. Development. 143(3):516-29, 2016 http://www.ncbi.nlm.nih.gov/pubmed/26718003