Which molecules regulate synaptic brain asymmetries?

Cerebral specialization between the left and right hemisphere is a fundamental concept in neuroscience. Left–right brain asymmetries of macroscopic structures or functions in human brain are well characterized (Toga & Thompson, 2003). For example, the left hemisphere is dominant for language and logical processing, whereas the right hemisphere prevails in spatial cognition. The brain is also lateralized for several behavioural functions in non-human animals (Walker, 1980). For example, the activation of the left hemisphere is dominant in songbirds and primates in response to visual or auditory stimuli, whereas the right hemisphere leads in space and emotion processing in rodents and chick, respectively. Recently, an intriguing lateralization of emotional processing has been observed in the mouse suggesting that only the right, but not the left, anterior cingulate cortex encodes fear learning (Kim et al. 2012). In contrast to the knowledge of brain lateralization at the macroscopic level, virtually nothing was known about brain Figure 1. Hippocampal asymmetry in wild-type (WT, A) or β2m knockout (KO, B) mice Left and right CA3 pyramidal neurons and their axons are labelled red and blue, respectively. A postsynaptic CA1 pyramidal neuron is shown in the centre (black). Filled and open circles show 'ε2-dominant' and 'ε2-non-dominant' synapses, respectively. Apical, apical dendrites; Basal, basal dendrites. Reproduced from Kawahara et al. (2013). C, glass vase by glass master Lino Tagliapietra. Taken from left–right asymmetries at microscopic levels involving molecules, synapses and neurons. A breakthrough occurred 10 years ago when the groups of Ito and Shigemoto reported an unexpected molecular difference at excitatory synapses of the left and right mouse hippocampus. They found that the synaptic distribution of one of the four N-methyl-D-aspartate (NMDA) receptor GluN2 subunits, namely the GluRε2 (GluN2B), is asymmetrical between the left and right (L–R) and between the apical and basal dendrites of CA1 pyramidal neurons (Kawakami et al. 2003; Fig. 1A). Presynaptic axons from the left CA3 pyramidal neurons form ε2-dominant synapses on the apical dendrites of post-synaptic pyramidal neurons in both left and right hippocampus. Conversely, presynaptic axons from the right CA3 pyramidal neurons form ε2-dominant synapses on the basal dendrites of postsynaptic pyramidal neurons in both left and right hippocampus. Subsequently, they demonstrated that such functional asymmetry has structural correlates: GluRε2-dominant synapses are often found on small thin dendritic spines whereas GluRε2 non-dominant synapses are present on large mushroom-type spines (Shinohara et al. 2008). Furthermore, this molecular asymmetry is target specific, namely …