*These authors contributed equally to this work.Neurological and psychiatric syndromes often have multiple disease traits, yet it is unknown how such multi-faceted deficits arise from single mutations. Haploinsufficiency of the voltage-gated sodium channel Na v 1.1 causes Dravet syndrome, an intractable childhood-onset epilepsy with hyperactivity, cognitive deficit, autistic-like behaviours, and premature death. Deletion of Na v 1.1 channels selectively impairs excitability of GABAergic interneurons. We studied mice having selective deletion of Na v 1.1 in parvalbumin-or somatostatin-expressing interneurons. In brain slices, these deletions cause increased threshold for action potential generation, impaired action potential firing in trains, and reduced amplification of postsynaptic potentials in those interneurons. Selective deletion of Na v 1.1 in parvalbumin-or somatostatin-expressing interneurons increases susceptibility to thermally-induced seizures, which are strikingly prolonged when Na v 1.1 is deleted in both interneuron types. Mice with global haploinsufficiency of Na v 1.1 display autistic-like behaviours, hyperactivity and cognitive impairment. Haploinsufficiency of Na v 1.1 in parvalbuminexpressing interneurons causes autistic-like behaviours, but not hyperactivity, whereas haploinsufficiency in somatostatin-expressing interneurons causes hyperactivity without autistic-like behaviours. Heterozygous deletion in both interneuron types is required to impair long-term spatial memory in context-dependent fear conditioning, without affecting short-term spatial learning or memory. Thus, the multi-faceted phenotypes of Dravet syndrome can be genetically dissected, revealing synergy in causing epilepsy, premature death and deficits in long-term spatial memory, but interneuron-specific effects on hyperactivity and autistic-like behaviours. These results show that multiple disease traits can arise from similar functional deficits in specific interneuron types.

Highlights d Single viral vector CRISPR/SaCas9 for efficient in vivo mutagenesis d Cre-and Flp-dependent cell type-specific gene mutagenesis

Highlights d Activation of VTA glutamate neurons can reinforce behavior d Activation of VTA glutamate neurons also leads to dopamine (DA) release d We generated two distinct models to abolish this coincident DA signal d VTA glutamate neuron activity can serve as a reinforcer independent from DA

Collectively, these data demonstrate a functional link between genetically distinct neurons in the LCN and cognitive behaviors.

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Tyrosine hydroxylase (Th) expression has previously been reported in Purkinje cells (PCs) of rodents and humans, but its role in the regulation of behavior is not understood. Catecholamines are well known for facilitating cognitive behaviors and are expressed in many regions of the brain. Here, we investigated a possible role in cognitive behaviors of PC catecholamines, by mapping and testing functional roles of Th positive PCs in mice. Comprehensive mapping analyses revealed a distinct population of Th expressing PCs primarily in the posterior and lateral regions of the cerebellum (comprising about 18% of all PCs). To identify the role of PC catecholamines, we selectively knocked out Th in PCs using a conditional knockout approach, by crossing a Purkinje cell-selective Cre recombinase line, Pcp2-Cre, with a floxed tyrosine hydroxylase mouse line (Th lox/lox) to produce Pcp2-Cre;Th lox/lox mice. This manipulation resulted in approximately 50% reduction of Th protein expression in the cerebellar cortex and lateral cerebellar nucleus, but no reduction of Th in the locus coeruleus, which is known to innervate the cerebellum in mice. Pcp2-Cre;Th lox/lox mice showed impairments in behavioral flexibility, response inhibition, social recognition memory, and associative fear learning relative to littermate controls, but no deficits in gross motor, sensory, instrumental learning, or sensorimotor gating functions. Catecholamines derived from specific populations of PCs appear to support cognitive functions, and their spatial distribution in the cerebellum suggests that they may underlie patterns of activation seen in human studies on the cerebellar role in cognitive function.

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The maintenance of excitatory and inhibitory balance in the brain is essential for its function. Here we find that the developmental axon guidance receptor Roundabout 2 (Robo2) is critical for the maintenance of inhibitory synapses in the adult ventral tegmental area (VTA), a brain region important for the production of the neurotransmitter dopamine. Following selective genetic inactivation of Robo2 in the adult VTA of mice, reduced inhibitory control results in altered neural activity patterns, enhanced phasic dopamine release, behavioral hyperactivity, associative learning deficits, and a paradoxical inversion of psychostimulant responses. These behavioral phenotypes could be phenocopied by selective inactivation of synaptic transmission from local GABAergic neurons of the VTA, demonstrating an important function for Robo2 in regulating the excitatory and inhibitory balance of the adult brain.DOI: http://dx.doi.org/10.7554/eLife.23858.001