rKv1.2 overexpression in the central medial thalamic area decreases caffeine-induced arousal.

The voltage-gated potassium channel Kv1.2 belongs to the shaker-related family and has recently been implicated in the control of sleep profile on the basis of clinical and experimental evidence in rodents. To further investigate whether increasing Kv1.2 activity would promote sleep occurrence in rats, we developed an adeno-associated viral vector that induces overexpression of rat Kv1.2 protein. The viral vector was first evaluated in vitro for its ability to overexpress rat Kv1.2 protein and to produce functional currents in infected U2OS cells. Next, the adeno-associated Kv1.2 vector was injected stereotaxically into the central medial thalamic area of rats and overexpression of Kv1.2 was showed by in situ hybridization, ex vivo electrophysiology and immunohistochemistry. Finally, the functional effect of Kv1.2 overexpression on sleep facilitation was investigated using telemetry system under normal conditions and following administration of the arousing agent caffeine, during the light phase. While no differences in sleep profile were observed between the control and the treated animals under normal conditions, a decrease in the pro-arousal effect of caffeine was seen only in the animals injected with the adeno-associated virus-Kv1.2 vector. Overall, our data further support a role of the Kv1.2 channel in the control of sleep profile, particularly under conditions of sleep disturbance.

Spike-timing-dependent plasticity in hippocampal CA3 neurons.

Synaptic plasticity of different inputs converging onto CA3 pyramidal neurons is central to theories of hippocampal function. The mossy fibre (MF) input to these neurons is thought to exhibit plasticity that is in nearly all aspects fundamentally different from plasticity in other brain regions: in particular, when induced by high frequency presynaptic stimulation, plasticity at these synapses is independent of NMDA receptor (NMDAR) activation and presynaptically expressed. Here, we show that different stimulation protocols that depend on the close timing of MF activity and postsynaptic spikes induce bidirectional plasticity in CA3 neurons in 3-week-old rats. Long-term potentiation (LTP) is observed when an excitatory postsynaptic potential (EPSP), evoked by MF stimulation, precedes a single postsynaptic action potential (AP) or a brief AP burst by 10 ms. Instead, timing-dependent long-term depression (LTD) requires the pairing of a single AP to an EPSP with a delay of 30 ms. The pairing of APs to synaptic activity is required for plasticity induction, since the application of unpaired APs or EPSPs did not alter synaptic strength. Furthermore, our results demonstrate that both timing-dependent LTP and LTD critically depend on the activation of NMDARs. Specifically blocking postsynaptic NMDARs prevents plasticity, demonstrating that NMDARs important to spike-timing-dependent plasticity in CA3 neurons are required at postsynaptic sites. In summary, this study shows that the close timing of APs to MF excitatory synaptic input can alter synaptic efficacy in CA3 neurons in a bidirectional manner.

Predictive genetic tests in neurodegenerative disorders: a methodological approach integrating psychological counseling for at-risk individuals and referring clinicians.

The identification of the molecular basis of numerous hereditary neurological disorders allowed the feasibility of predictive genetic tests for at-risk family members. In agreement with international guidelines, we tested a protocol for a predictive test to optimize cooperation among specialists, well-being of participants, and organization of clinical activities. The psychiatrist/psychologist did not meet the at-risk subjects, but cooperated with the team, integrating psychological support for participants and clinicians. We enrolled 60 subjects at risk for Huntington disease, and 32 at risk for spinocerebellar ataxias. Seventy-two subjects (78%) continued the visit program; 55 (60%) received the genetic result, and 38 subjects (41%) completed the program. Participation and outcome were similar in both groups. Mean psychological scores were all below significant levels; however, the need for psychological support was recognized for 5 mutation carriers and a non-carrier. Our data provide a methodological example of a simple and safe procedure for a predictive test, and indicate that the clinical conference represents a good setting to handle psychosocial impact associated with disclosure of genetic results in hereditary late-onset disorders.

[Determinants of depression in 111 Italian patients with systemic sclerosis]. / Determinanti della depressione in 111 pazienti italiani con sclerosi sistemica.

BACKGROUND: A high prevalence of depressive symptoms has been described in systemic sclerosis (SSc), but no clear association with organ involvement or objective indices of disease severity has been depicted. To date, no effort has been made to determine the prevalence of depressive symptoms in Italian patients with SSc or to clarify their cause. METHODS: One-hundred-eleven SSc patients were asked to fill in the Beck Depression Inventory (BDI) questionnaire, the scleroderma Health Assessment Questionnaire (sHAQ) and two additional questions assessing the patient's familiar support and the social consequences of the patient's change in physical appearnace. RESULTS: Thirty-seven subjects (33.4%) presented mild to severe depressive symptoms (BDI >/=17). On univariate analysis the diffuse cutaneous form of the disease (p=0.019), higher pulmonary systolic pressures on echocardiogram (p=0.016), lower FVC percentage of predicted values (p=0.022), higher sHAQ values (p<0.001) or higher VAS values for pain (p=0.007), lung involvement (p=0.02), Raynaud's phenomenon severity (p=0.002), ulcers severity (p=0.006) or disease severity (p<0.001), were associated with the presence of pathologic depressive symptoms. On multivariate analysis only the VAS for disease severity relevant to BDI scores (p=0.016). Social behaviour changes due to SSc-related physical involvement were reported in 14 patients (38%) with depressive symptoms (p=0,006) and were more likely to be observed in younger patients (p=0.001) with a more severe Raynauds's phenomenon (p=0.013). CONCLUSIONS: Mild to severe depressive symptoms are common in SSc patients especially in those with a worse perception of disease severity, these patients should be carefully monitored and a psychological assistance counselled whenever necessary.