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Early postnatal events exert powerful effects on development, inducing persistent functional alterations in different brain network, such as the catecholamine prefrontal-accumbal system, and increasing the risk of developing psychiatric disorders later in life. However, a vast body of literature shows that the interaction between genetic factors and early environmental conditions is crucial for expression of psychopathologies in adulthood. We evaluated the long-lasting effects of a repeated cross-fostering (RCF) procedure in 2 inbred strains of mice (C57BL/6J, DBA/2), known to show a different susceptibility to the development and expression of stress-induced psychopathologies. Coping behavior (forced swimming test) and preference for a natural reinforcing stimulus (saccharine preference test) were assessed in adult female mice of both genotypes. Moreover, c-Fos stress-induced activity was assessed in different brain regions involved in stress response. In addition, we evaluated the enduring effects of RCF on catecholamine prefrontal-accumbal response to acute stress (restraint) using, for the first time, a new "dual probes" in vivo microdialysis procedure in mouse. RCF experience affects behavioral and neurochemical responses to acute stress in adulthood in opposite direction in the 2 genotypes, leading DBA mice toward an "anhedonic-like" phenotype and C57 mice toward an increased sensitivity for a natural reinforcing stimulus., (© The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.)

Although patients with Parkinson's disease show impairments in cognitive performance even at the early stage of the disease, the synaptic mechanisms underlying cognitive impairment in this pathology are unknown. Hippocampal long-term potentiation represents the major experimental model for the synaptic changes underlying learning and memory and is controlled by endogenous dopamine. We found that hippocampal long-term potentiation is altered in both a neurotoxic and transgenic model of Parkinson's disease and this plastic alteration is associated with an impaired dopaminergic transmission and a decrease of NR2A/NR2B subunit ratio in synaptic N-methyl-d-aspartic acid receptors. Deficits in hippocampal-dependent learning were also found in hemiparkinsonian and mutant animals. Interestingly, the dopamine precursor l-DOPA was able to restore hippocampal synaptic potentiation via D1/D5 receptors and to ameliorate the cognitive deficit in parkinsonian animals suggesting that dopamine-dependent impairment of hippocampal long-term potentiation may contribute to cognitive deficits in patients with Parkinson's disease.

Although phenylketonuria (PKU) is the most common genetic cause of mental retardation, the cellular mechanisms underlying impaired brain function are still unclear. Using PAHenu2 mice (ENU2), the genetic mouse model of PKU, we previously demonstrated that high phenylalanine levels interfere with brain tryptophan hydroxylase activity by reducing the availability of serotonin (5-hydroxytryptamine, 5-HT), crucial for maturation of neuronal connectivity in the prefrontal cortex (PFC), around the third postnatal week, a critical period for cortical maturation. 5-Hydroxytryptophan (5-HTP), the product of tryptophan hydroxylation, is known to be a better treatment to increase brain 5-HT levels. In this study we investigated the role of 5-HT during the early postnatal period in cognitive disturbances and in cortical dendritic alterations of PKU subjects by restoring temporarily (postnatal days 14-21) physiological brain levels of 5-HT in ENU2 through 5-HTP treatment. In adult ENU2 mice early 5-HTP treatment reverses cognitive deficits in spatial and object recognition tests accompanied by an increase in spine maturation of pyramidal neurons in layer V of the prelimbic/infralimbic area of the PFC, although locomotor deficits are not recovered by treatment. Taken together, our results support the hypothesis that mental retardation in PKU depends on reduced availability of brain 5-HT during critical developmental periods that interferes with cortical maturation and point to 5-HTP supplementation as a highly promising additional tool to heal PKU patients.

Adult early treated hyperphenylalaninaemic patients can show specific deficits of prefrontal cortical functions. The development of additional therapeutic strategies for these patients requires the understanding of the mechanisms involved in phenylalanine-dependent impairment of fronto-cortical functions. We tested the hypothesis of phenylalanine interference with aminergic neurotransmission in the prefrontal cortex by evaluating, in vivo, amine release in adult Pah(enu2) mice, the genetic model of phenylketonuria. Mice of healthy background responded to a psychogenic stressor with the classic time-dependent increase of norepinephrine, dopamine and serotonin release from prefrontal cortical terminals. Neither the dopaminergic nor the serotoninergic responses were observable in the Pah(enu2) mice. Temporary reduction of circulating phenylalanine, by phenylalanine-free diet without amino- acid supplement, promoted recovery of the serotonin response only, demonstrating direct interference with serotonin synthesis in the mature brain. Evaluation of different steps of serotonin synthesis in the prefrontal cortex of hyperphenylalaninaemic mice demonstrated inhibition of cortical tryptophan hydroxylase activity. Finally, systemic administration of 5-hydroxytryptophan, the product of tryptophan hydroxylase activity, allowed frontal cortical serotonin response to stress in hyperphenylalaninaemic mice. Collectively, these results demonstrate that hyperphenylalaninaemia interferes with the ability of the mature prefrontal cortex to respond to psychological challenges, point to serotonin synthesis as the target of phenylalanine interference, and support the use of 5-hydroxytryptophan in lifelong treatment of hyperphenylalaninaemic subjects.

Although the medial prefrontal cortex (mpFC) appears to constrain stress responses, indirect evidences suggest that it might determine the stress response of the mesoaccumbens dopamine (DA) system. To test this hypothesis, we first evaluated the dynamics of norepinephrine (NE) and DA release in the mpFC and of DA release in the nucleus accumbens (NAc) of acutely stressed rats. Then, we tested the effects of selective depletion of NE or DA in the mpFC (by local 6-hydroxydopamine infusion following desipramine or 1-[2[bis(4-fluorophenyl)methoxy]ethyl]-4-(3-phenylpropyl)piperazine(GBR 12909) on stress-induced changes in mesoaccumbens DA release. Rats experiencing restraint stress for 240 min showed an initial, short-lived increase of NE outflow in the mpFC and of DA in the NAc. These responses were followed by a sustained increase of DA in the mpFC and by a decrease to below resting levels of DA in the NAc. Moreover, selective prefrontal NE depletion eliminated the increase of NE in the mpFC and of DA in the NAc, and selective depletion of mesocortical DA eliminated the enhancement of mpFC DA as well as the inhibition of mesoaccumbens DA, without affecting basal catecholamines outflow. These results demonstrate that the opposing influences of mpFC NE and DA determine mesoaccumbens DA response to stress and suggest that alterations of this mechanism may be responsible for some major psychopathological outcomes of stress.