Human-specific genetic modifiers of cortical architecture and function.

Evolution of the cerebral cortex is thought to have been critical for the emergence of our cognitive abilities. Major features of cortical evolution include increased neuron number and connectivity and altered morpho-electric properties of cortical neurons. Significant progress has been made in identifying human-specific genetic modifiers (HSGMs), some of which are involved in shaping these features of cortical architecture.

SRGAP2 and Its Human-Specific Paralog Co-Regulate the Development of Excitatory and Inhibitory Synapses.

The proper function of neural circuits requires spatially and temporally balanced development of excitatory and inhibitory synapses. However, the molecular mechanisms coordinating excitatory and inhibitory synaptogenesis remain unknown. Here we demonstrate that SRGAP2A and its human-specific paralog SRGAP2C co-regulate the development of excitatory and inhibitory synapses in cortical pyramidal neurons in vivo.

unc5c haploinsufficient phenotype: striking similarities with the dcc haploinsufficiency model.

DCC and UNC5 homologs (UNC5H) are guidance cue receptors highly expressed by mesocorticolimbic dopamine neurons. We have shown that dcc heterozygous mice exhibit increased dopamine, but not norepinephrine, innervation and function in medial prefrontal cortex. Concomitantly, dcc heterozygotes show blunted mesolimbic dopamine release and behavioral responses to stimulant drugs.

Dissection and culture of mouse dopaminergic and striatal explants in three-dimensional collagen matrix assays.

Midbrain dopamine (mdDA) neurons project via the medial forebrain bundle towards several areas in the telencephalon, including the striatum(1). Reciprocally, medium spiny neurons in the striatum that give rise to the striatonigral (direct) pathway innervate the substantia nigra(2). The development of these axon tracts is dependent upon the combinatorial actions of a plethora of axon growth and guidance cues including molecules that are released by neurites or by (intermediate) target regions(3,4).

Axon guidance proteins: novel therapeutic targets for ALS?

Amyotrophic lateral sclerosis (ALS) is a progressive, neurodegenerative disease characterized by the selective loss of motor neurons in the brain and spinal cord. Death due to respiratory failure occurs typically 2-5 years after disease onset. The pathogenic mechanism that underlies ALS remains largely unknown, but is known to include both genetic and environmental factors.