Endocannabinoids and cortical plasticity: CB1R as a possible regulator of the excitation/inhibition balance in health and disease.

The endocannabinoid system has been linked to neurological disorders in which the excitation inhibition (E/I) balance in the neocortex is dysregulated, such as schizophrenia. The main endocannabinoid receptor type 1 of the central nervous system-CB1R-is expressed on different cell types, that when activated, modulate the cortical E/I balance. Here we review how CB1R signalling contributes to phases of heightened plasticity of the neocortex. We review the major role of the CB1R in cortical plasticity throughout life, including the early life sensory critical periods, the later maturation phase of the association cortex in adolescence, and the adult phase of sensory deprivation-induced cortical plasticity. Endocannabinoid-mediated long-term potentiation and depression of synapse strength fine-tune the E/I balance in visual, somatosensory and association areas. We emphasize how a distinct set of key endocannabinoid-regulated elements such as GABA and glutamate release, basket parvalbumin interneurons, somatostatin interneurons and astrocytes, are essential for normal cortical plasticity and dysregulated in schizophrenia. Even though a lot of data has been gathered, mechanistic knowledge about the exact CB1R-based modulation of excitation and/or inhibition is still lacking depending on cortical area and maturation phase in life. We emphasize the importance of creating such detailed knowledge for a better comprehension of what underlies the dysregulation of the neocortex in schizophrenic patients in adulthood. We propose that taking age, brain area and cell type into consideration when modulating the cortical E/I imbalance via cannabinoid-based pharmacology may pave the way for better patient care.

Reconsidering the Border between the Visual and Posterior Parietal Cortex of Mice.

The posterior parietal cortex (PPC) contributes to multisensory and sensory-motor integration, as well as spatial navigation. Based on primate studies, the PPC is composed of several subdivisions with differing connection patterns, including areas that exhibit retinotopy. In mice the composition of the PPC is still under debate. We propose a revised anatomical delineation in which we classify the higher order visual areas rostrolateral area (RL), anteromedial area (AM), and Medio-Medial-Anterior cortex (MMA) as subregions of the mouse PPC. Retrograde and anterograde tracing revealed connectivity, characteristic for primate PPC, with sensory, retrosplenial, orbitofrontal, cingulate and motor cortex, as well as with several thalamic nuclei and the superior colliculus in the mouse. Regarding cortical input, RL receives major input from the somatosensory barrel field, while AM receives more input from the trunk, whereas MMA receives strong inputs from retrosplenial, cingulate, and orbitofrontal cortices. These input differences suggest that each posterior PPC subregion may have a distinct function. Summarized, we put forward a refined cortical map, including a mouse PPC that contains at least 6 subregions, RL, AM, MMA and PtP, MPta, LPta/A. These anatomical results set the stage for a more detailed understanding about the role that the PPC and its subdivisions play in multisensory integration-based behavior in mice.

Analysis of Immediate Early Gene Expression Levels to Interrogate Changes in Cortical Neuronal Activity Patterns upon Vision Loss.

Mapping immediate early gene (IEG) expression levels to characterize changes in neuronal activity patterns has become a golden standard in neuroscience research. Due to straightforward detection methods such as in situ hybridization and immunohistochemistry, changes in IEG expression can be easily visualized across brain regions and in response to physiological and pathological stimulation. Based on in-house experience and existing literature, zif268 represents itself as the IEG of choice to investigate the neuronal activity dynamics induced by sensory deprivation. In the monocular enucleation mouse model of partial vision loss, zif268 in situ hybridization can be implemented to study cross-modal plasticity by charting the initial decline and subsequent rise in neuronal activity in visual cortical territory deprived of direct retinal visual input. Here, we describe a protocol for high-throughput radioactive zif268 in situ hybridization as a readout for cortical neuronal activity dynamics in response to partial vision loss in mice.