Complex behavioral and synaptic effects of dietary branched chain amino acids in a mouse model of amyotrophic lateral sclerosis.

SCOPE: We hypothesized that chronic supplementation with branched chain amino acids (BCAAs) affects neurobehavioral development in vulnerable gene backgrounds. METHODS AND RESULTS: A murine model of amyotrophic lateral sclerosis (ALS), G93A mice bearing the mutated human superoxide dismutase 1 (SOD1) gene, and control mice received from 4 to 16 wk of age dietary supplementation with BCAAs at doses comparable to human usage. Motor coordination, exploratory behaviors, pain threshold, synaptic activity and response to glutamatergic stimulation in primary motor cortex slices were evaluated between the 8th and 16th week. The glial glutamate transporter 1 (GLT-1) and metabotropic glutamate 5 receptor (mGlu5R) were analyzed by immunoblotting in cortex, hippocampus and striatum. BCAAs induced hyperactivity, decreased pain threshold in wild-type mice and exacerbated the motor deficits of G93A mice while counteracting their abnormal pain response. Electrophysiology on G93A brain slices showed impaired synaptic function, reduced toxicity of GLT-1 blocking and increased glutamate toxicity prevented by BCAAs. Immunoblotting indicated down-regulation of GLT-1 and mGlu5R in G93A, both effects counteracted by BCAAs. CONCLUSION: These results, though not fully confirming a role of BCAAs in ALS-like etiology in the genetic model, clearly indicate that BCAAs' complex effects on central nervous system depend on gene background and raise alert over their spread use.

Gestational exposure to the organophosphate chlorpyrifos alters social-emotional behaviour and impairs responsiveness to the serotonin transporter inhibitor fluvoxamine in mice.

BACKGROUND: The organophosphate chlorpyrifos (CPF) is a pesticide largely used worldwide. Studies from animal models indicate that CPF exposure during development at low doses can target different neurotransmitter systems in the absence of overt cholinergic effects. METHODS: Late gestational exposure (gestational days 14-17) to CPF at the dose of 6 mg/kg was evaluated in CD-1 mice at adulthood. Neurobehavioural effects likely involving serotonin (5-hydroxytryptamine, 5HT) transmission were assessed both in males and females, through the light-dark exploration test to assess CPF effects on anxiety profiles and the forced swimming test to evaluate the response to the 5HT transporter (5HTT) inhibitor fluvoxamine (30 mg/kg). In females only, we evaluated the effects of gestational exposure to CPF on maternal aggression, under basal condition or after injection of fluvoxamine. RESULTS: Gestational CPF exposure increased anxiety levels only in female mice, as shown by the augmented thigmotaxis behaviour and the lower latency to enter in the dark compartment. In the forced swimming test, no differences between CPF and control mice were found when assessed under basal condition (saline administration), but both male and female CPF mice missed to show the typical behavioural effects of the 5HTT inhibitor fluvoxamine. During maternal aggression, CPF females showed lower propensity to and intensity of aggressive behaviour, together with mild decreased responsiveness to fluvoxamine administration. CONCLUSIONS: Overall, the present results confirm a specific and sex-dependent vulnerability of affective/emotional domains to developmental CPF exposure. Furthermore, data provide clear indication on the disrupting effects of prenatal CPF on serotoninergic transmission.