Cannabis is the most widely used illicit recreational drug. However, very limited information is available as to the developmental functions of the endocannabinoid system mediating marijuana actions in the brain and the molecular signature of in utero cannabis exposure that underpins altered neuronal development.

A causal relationship between prenatal drug exposure and behavioural deficits that endure into the adulthood of affected offspring formulates the concept of ‘prenatal drug addiction’. Accordingly, even brief episodes of maternal drug abuse can impose significant changes at the transcriptome or proteome levels if drug exposure coincides with fundamental events of neuronal specification.

Our work is centred on the concept that maternal cannabis smoking disrupts the temporal and spatial precision of endocannabinoid signalling in the fetal brain thus impacting the acquiring of neuronal identity, and consequently, the establishment of coherent neuronal network functions.

We have successfully studied – utilizing cell biology, live-cell imaging, systems neuroscience, neuropharmacology and molecular genetics – how endocannabinoid signalling affects the proliferation of neural progenitors, long-range cell migration, and the morphogenesis of cortical neurons. We have recently applied this knowledge to gain insights in how endocannabinoid signalling networks interact with other developmentally-regulated signalling cassettes to control neuronal network formation in the developing cerebrum.

Our work is supported by the Scottish Universities Life Science Alliance, the Medical Research Council (MRC), EU Framework 7 program, the European Molecular Biology Organization, Alzheimer’s Association and NIDA.

Selected publications:

Mulder J, Zilberter M, Pasquare S, Alpár A, Schulte G, Ferreira SG, Köfalvi A, Martín-Moreno
AM, Keimpema E, Tanila H, Watanabe M, Mackie K, Hortobágyi T, de Ceballos ML, Harkany
T. Molecular rearrangements of endocannabinoid signalling in Alzheimer’s disease. Brain
(2011) 134:1041-1060.

Keimpema E, Barabas K, Morozov YM, Tortoriello G, Torii M, Cameron G, Yanagawa Y,
Watanabe M, Mackie K, Harkany T. Differential subcellular recruitment of monoacylglycerol
lipase generates spatial specificity of 2-arachidonoyl glycerol signalling during axonal
pathfinding. J Neurosci 2010, 30:13992-14007.

Halleskog C, Mulder J, Dahlström J, Mackie K, Hortobagyi T, Tanila H, Puli LK, Färber K,
Harkany T, Schulte G. WNT signalling in activated microglia is proinflammatory. Glia 2011,
59:119-31.

Usoskin D, Zilberter M, Linnarsson S, Hjerling-Leffler J, Uhlén P, Harkany T, Ernfors P. En
masse in vitro functional profiling of the axonal mechanosensitivity of sensory neurons. Proc
Natl Acad Sci USA 2010, 107:16336-16341.

Gupta A, Mulder J, Gomes I, Rozenfeld R, Bushlin I, Ong E, Lim M, Maillet E, Junek M, Cahill
CM, Harkany T, Devi LA. Increased abundance of opioid receptor heteromers after chronic
morphine administration. Sci Signal 2010, 3:ra54.

Mulder J, Spence L, Tortoriello G, DiNieri JA, Uhlén M, Shui B, Kotrlikoff MI, Yanagawa Y,
Aujard F, Hökfelt T, Hurd YL, Harkany T. Secretagogin is a Ca2+-binding protein identifying
prospective extended amygdala neurons in the developing mammalian telencephalon. Eur J
Neurosci 2010, 31:2166-2177.

Solbu TT, Bjørkmo M, Berghuis P, Harkany T, Chaudhry FA. SAT1, a glutamine transporter,
is preferentially expressed in GABAergic neurons. Front Neuroanat 2010, 3:32, doi:
10.3389/neuro.05.032.2009.

Mulder J, Zilberter M, Spence L, Tortoriello G, Uhlen M, Yanagawa Y, Aujard F, Hökfelt T*,
Harkany T*. Secretagogin is a Ca2+-binding protein specifying telencephalic neurons. Proc
Natl Acad Sci USA 2009, 106:22492-22497.

Rheims S, Holmgren CD, Chazal G, Mulder J, Harkany T, Zilberter T, Zilberter Y. GABA
action in immature neocortical neurons directly depends on the availability of ketone bodies. J Neurochem 2009, 110:1330-1338.

Zilberter M, Holmgren C, Shemer I, Silberberg G, Grillner S, Harkany T*, Zilberter Y*. Input specificity and dependence of spike timing-dependent plasticity on preceding postsynaptic
activity at unitary connections between neocortical layer 2/3 pyramidal cells. Cereb Cortex
2009, 19:2308-2320.

Minkeviciene R, Rheims S, Dobszay MB, Zilberter M, Hartikainen J, Fülöp L, Penke B,
Zilberter Y, Harkany T, Pitkänen A, Tanila H. Amyloid β-induced neuronal hyperexcitability
triggers progressive epilepsy. J Neurosci 2009, 29:3453-3462.

Fettisov SO, Bensing S, Mulder J, Le Maitre E, Hulting A-L, Harkany T, Ekwall O, Sköldberg
F, Husebye E, Perheentupa J, Rorsman F, Kampe O, Hökfelt T. Autoantibodies in autoimmune polyglandular syndrome type I patients react with major brain neurotransmitter systems. J Comp Neurol 2009, 513:1-20; cover image: 513(1): spc1.

Mulder J, Augado T, Keimpema E, Barabas K, Ballaster Rosado CJ, Nguyen L, Monory K, Marsicano G, Di Marzo V, Hurd YL, Guillemot F, Mackie K, Lutz B, Guzman M, Lu H-C, Galve-Roperh I, Harkany T. Endocannabinoid signaling controls pyramidal cell specification and long-range axon patterning. Proc Natl Acad Sci USA 2008, 105:8760-8765.

Berghuis P, Rajnicek AM, Morozov YM, Ross RA, Mulder J, Monory K, Marsicano G, Matteoli
M, Canty A, Yanagawa Y, Rakic P, Lutz B, Mackie K, Harkany T. Hardwiring the brain:
endocannabinoids shape neuronal connectivity, Science 2007, 316:1212-1216.

Harkany T, Mackie K, Doherty P. Wiring and firing neuronal networks: endocannabinoids
take center stage. Curr Opin Neurobiol 2008, 18:338-345.

- neuropharmacology,
- developmental neurobiology,
- neuroanatomy,
- behavioral neurosciences,
- cell biology experimentation.