Contact Information

Group leader:

Matti Airaksinen
MD, PhD
Professor of Anatomy

Phone: +358 2941 25250
Fax: +358 2941 25302
Email: matti-dot-airaksinen-at-helsinki-dot-fi

Street address:
Haartmaninkatu 8
(Biomedicum Helsinki)
00290 Helsinki

Mailing address:
P.O. Box 63
00014 University of Helsinki
Finland

GDNF Family Receptors, KCC2, and Novel LRR Proteins in Nervous System Development and Pathophysiology

The Airaksinen group is investigating 1) the biology of the glial cell line-derived neurotrophic factor (GDNF) family in cutaneous and gastric innervation (Kupari); 2) the physiological role and regulation of the neuronal K/C- cotransporter KCC2, a key molecule in inhibitory neurotransmission (Blaesse et al. 2009), in particular, novel isoforms and mechanisms that drive KCC2 gene expression and how lack of KCC2 affects brain function (Markkanen, Uvarov); and 3) the physiological function of a novel family of neuronal leucine-rich repeat (LRR) -containing transmembrane proteins (LRRTMs) using genetically modified mice (Laakso).

Using KCC2-deficient mouse lines created in the lab, previous studies have examined the specific role of hyperpolarizing inhibition in mouse behaviour and electrophysiology and have shown a novel structural role for KCC2 in spine development. Our work has identified a novel isoform of KCC2 that has a unique N-terminus, including a putative SPAK kinase-binding site (Uvarov et al. 2007). Analysis of expression and available mouse lines indicates that the new KCC2a isoform may support vital neuronal functions in the brain stem and spinal cord, whereas the major KCC2b isoform is responsible for the developmental shift of GABAergic responses. Recently we showed that the two KCC2 isoforms are coexpressed in neonatal brain and can form heterodimers (Uvarov et al. 2009) and that the postnatal induction of the KCC2b isoform is partly mediated via BDNF and Egr4 transcription factor (Ludwig et al. 2011).

The LRRTM family members are expressed by overlapping subpopulations of CNS neurons.
Previous studies have identified LRRTM1 as an imprinted gene and the first putative genetic influence on human handedness making it is a candidate gene for involvement in neuro­developmental disorders. A cellular basis for this association was recently provided by a collaboration that identified LRRTM proteins as synaptic organizers (Linhoff et al. 2009). Consistent with this idea, LRRTMs localize to excitatory synapses and can induce presynaptic differentiation of contacting axons in vitro, and LRRTM1-deficient mice show altered distribution of excitatory synaptic markers in vivo. Moreover, LRRTM-deficient mice show distinct behavioral phenotypes that are under investigation. For example, LRRTM1-deficient mice show an unusual claustrophobia-like avoidance of enclosure in several tests (Voikar et al. 2012, submitted).