Netrin‐1 receptor‐deficient mice show enhanced mesocortical dopamine transmission and blunted behavioural responses to amphetamine

Abstract

The mesocorticolimbic dopamine (DA) system is implicated in neurodevelopmental psychiatric disorders including schizophrenia but it is unknown how disruptions in brain development modify this system and increase predisposition to cognitive and behavioural abnormalities in adulthood. Netrins are guidance cues involved in the proper organization of neuronal connectivity during development. We have hypothesized that variations in the function of DCC (deleted in colorectal cancer), a netrin-1 receptor highly expressed by DA neurones, may result in altered development and organization of mesocorticolimbic DA circuitry, and influence DA function in the adult. To test this hypothesis, we assessed the effects of reduced DCC on several indicators of DA function. Using in-vivo microdialysis, we showed that adult mice that develop with reduced DCC display increased basal DA levels in the medial prefrontal cortex and exaggerated DA release in response to the indirect DA agonist amphetamine. In contrast, these mice exhibit normal levels of DA in the nucleus accumbens but significantly blunted amphetamine-induced DA release. Concomitantly, using conditioned place preference, locomotor activity and prepulse inhibition paradigms, we found that reduced DCC diminishes the rewarding and behavioural-activating effects of amphetamine and protects against amphetamine-induced deficits in sensorimotor gating. Furthermore, we found that adult DCC-deficient mice exhibit altered dendritic spine density in layer V medial prefrontal cortex pyramidal neurones but not in nucleus accumbens medium spiny neurones. These findings demonstrate that reduced DCC during development results in a behavioural phenotype opposite to that observed in developmental models of schizophrenia and identify DCC as a critical factor in the development of DA function.

Amphetamine in Adolescence Disrupts the Development of Medial Prefrontal Cortex Dopamine Connectivity in a dcc-Dependent Manner

“…We have shown that small alterations to mPFC dopamine connectivity lead to sizeable changes in the pyramidal neuron morphology and excitability and, consequently, to changes in cognitive processing and responses to drugs of abuse (Grant et al, 2007;Manitt et al, 2011Manitt et al, , 2013Pokinko et al, 2014). Similarly, dopamine function in the human prefrontal cortex has been shown to play a critical role in higherorder cognitive processing, including behavioral inhibition and salience attribution, as well as in the regulation of subcortical reward circuitry (Robbins et al, 1994;Rogers et al, 1999;Tomasi et al, 2007;Goldstein and Volkow, 2011).…”

“…DCC expression in dopamine neurons is high during early development and adolescence, in line with the maturational timeline of dopamine pathways. Interestingly, DCC expression is substantially lower during adulthood, suggesting that DCC signaling may play a different, more local, role in the adult brain (Osborne et al, 2005;Grant et al, 2007;Manitt et al, 2010;Reyes et al, 2013;Yetnikoff et al, 2007Yetnikoff et al, , 2010Yetnikoff et al, , 2011Yetnikoff et al, , 2013a. Using rodents, we showed that DCC signaling within the ventral tegmental area (VTA) dopamine neurons determines the extent of their innervation to the mPFC specifically during adolescence and, in turn, organizes the structure and function of mPFC local circuitries (Manitt et al, 2013).…”

“…The total number of dopamine neurons in the VTA and SNc was assessed using the optical fractionator probe of Stereoinvestigator as previously (Grant et al, 2007;Manitt et al, 2013). The counting scheme used a 60 Â 60 mm counting frame (x ¼ 150 mm, y ¼ 150 mm intervals) with a random start point.…”

A Commentary on Axon guidance pathway genes and Parkinson’s disease

“…4 DCC-deficient adult mice showed altered dopamine transmission and locomotor activity accompanied by reduced dendritic spine density in the cerebral cortex. 5 These findings show that DCC is a crucial molecule in the development of dopamine circuitry, and alterations in DCC levels can lead to cognitive and behavioral abnormalities in adulthood. 4,5 In EPHB1-knockout mice, there is a significant cell loss in the substance nigra pars reticulata, but there is no obvious change in the number of dopamine neurons in the substance nigra pars compacta.…”

“…5 These findings show that DCC is a crucial molecule in the development of dopamine circuitry, and alterations in DCC levels can lead to cognitive and behavioral abnormalities in adulthood. 4,5 In EPHB1-knockout mice, there is a significant cell loss in the substance nigra pars reticulata, but there is no obvious change in the number of dopamine neurons in the substance nigra pars compacta. 6 Differential expression of NTNG1 could alter dopaminergic and glutamatergic circuitry.…”