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Victims of mild traumatic brain injury (mTBI) do not show clear morphological brain defects, but frequently suffer from long-lasting cognitive deficits, emotional difficulties and behavioral disturbances. In the present study, we investigated the effects of experimental mTBI in mice on cognition, spatial and non-spatial tasks, and depressive-like behavior in mice. Experimental brain injury was induced using a concussive head trauma, which creates the TBI by a weight-drop device. Different groups of mice were tested at 7, 30, 60, and 90 days post-injury for cognitive function (the swim T-maze and the passive avoidance test) and for depression-like behavior (the forced swimming test). These tests have been used infrequently in the past in mTBI research. Significant differences were observed between the injured mice compared to the controls in both the swim T-maze (day 30: p < 0.001) and passive avoidance (day 30: p < 0.05) tests. In addition, a significant difference was detected in the forced swimming test between the injured mice and the controls (day 7: p < 0.05; day 90: p < 0.01), which showed a depressive- like state in the injured animals beginning 7 days post-injury. These results demonstrate that persistent deficits in these tests of cognitive learning abilities and emergence of depressive-like behavior in injured mice are similar to those reported in human post-concussion syndrome.

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Keywords: major depressive disorder (MDD); tryptophan hydroxylase (TPH); serotonin transporter promoter region (5-HTTLPR); serotonin receptor 2A (HTR2A); serotonin receptor 2C (HTR2C); catechol-O-methyl transferase (COMT); dopamine D4 receptor (DRD4); dopamine transporter (DAT1)Major depressive disorder (MDD) is a severe psychiatric disorder with a lifetime prevalence of about 15%. 1 The importance of the genetic component is well accepted, 2 but the mode of inheritance is complex and non-Mendelian. A line of evidence suggests the involvement of serotonin and dopamine neurotransmitters in the pathophysiology of depression. In the present study, 102 unipolar MDD patients and 172 healthy controls were genotyped for polymorphisms in four serotonergic and three dopaminergic candidate genes [tryptophan hydroxylase (TPH), serotonin receptor 2A (HTR2A), serotonin receptor 2C (HTR2C), serotonin transporter promoter region (5-HTTLPR), dopamine receptor D4 (DRD4), dopamine transporter (DAT1) and catechol-O-methyl transferase (COMT)]. There were no statistical differences between MDD patients and healthy controls in the genotypic and allelic distribution of all polymorphisms investigated. Thus, our study does not support a major role for these polymorphisms in contributing to susceptibility to MDD, although it does not preclude minor effects.Pharmacological studies have suggested that MDD is associated with an impairment of brain neurotransmitters. The role of serotonin (5-HT), which is based mainly on the efficacy of selective and nonselective 5-HT reuptake inhibitors in the treatment of MDD, was reviewed by Maes and Meltzer. 3 Dopamine (DA), has also been implicated in the pathophysiology of mood disorders and hypoactivity of the mesolimbic DA pathway may be connected to depressive symptoms. 4 Thus, genes that control the brain 5-HT and DA pathways seem to be good candidates for mediating genetic susceptibility to MDD.Association of polymorphisms in seven genes from the serotonergic and dopaminergic pathways was studied in 102 unipolar patients and 172 healthy control subjects. The patient population was subdivided according to ethnic origin (63 Ashkenazi and 39 nonAshkenazi Jews) and compared to the corresponding group of mentally healthy controls. The distribution of genotypes and alleles in the different populations is shown in Table 1. Comparison of healthy individuals of Ashkenazi and non-Ashkenazi origin revealed that although frequencies of genotypes and alleles showed some differences, they did not reach statistical significance. Nevertheless, in order to avoid possible errors caused by population stratifications we compared the patients with their ethnic counterparts.When unipolar MDD patients were compared to healthy controls of the same ethnic origin (Table 1), the distribution of genotypes and alleles of the seven polymorphisms studied (TPH, HTR2A, HTR2C, 5-HTTLPR, DAT1, DRD4 and COMT) did not show statistically significant differences.Molecular genetic studies in mood disorders performed thus far, have focus...