BackgroundPallister‐Killian syndrome (PKS) is a rare multisystem developmental syndrome usually caused by mosaic tetrasomy of chromosome 12p that is known to be associated with neurological defects.MethodsWe describe two patients with PKS, one of whom has bilateral perisylvian polymicrogyria (PMG), the other with macrocephaly, enlarged lateral ventricles and hypogenesis of the corpus callosum. We have also summarized the current literature describing brain abnormalities in PKS.ResultsWe reviewed available cases with intracranial scans (n = 93) and found a strong association between PKS and structural brain abnormalities (77.41%; 72/93). Notably, ventricular abnormalities (45.83%; 33/72), abnormalities of the corpus callosum (25.00%; 18/72) and cerebral atrophy (29.17%; 21/72) were the most frequently reported, while macrocephaly (12.5%; 9/72) and PMG (4.17%; 3/72) were less frequent. To further understand how 12p genes might be relevant to brain development, we identified 63 genes which are enriched in the nervous system. These genes display distinct temporal as well as region‐specific expression in the brain, suggesting specific roles in neurodevelopment and disease. Finally, we utilized these data to define minimal critical regions on 12p and their constituent genes associated with atrophy, abnormalities of the corpus callosum, and macrocephaly in PKS.ConclusionOur study reinforces the association between brain abnormalities and PKS, and documents a diverse neurogenetic basis for structural brain abnormalities and impaired function in children diagnosed with this rare disorder.

Lithium, a mood stabilizer and common adjunctive treatment for refractory depression, shares overlapping mechanisms of action with ketamine and enhances the duration of ketamine’s antidepressant actions in rodent models at sub-therapeutic doses. Yet, in a recent clinical trial, lithium co-treatment with ketamine failed to improve antidepressant outcomes in subjects previously shown to respond to ketamine alone. The potential for lithium augmentation to improve antidepressant outcomes in ketamine nonresponders, however, has not been explored. The current study examined the behavioral, molecular and metabolic actions of lithium and ketamine co-treatment in a rodent model of antidepressant resistance. Male Wistar rats were administered adrenocorticotropic hormone (ACTH; 100 µg/day, i.p. over 14 days) and subsequently treated with ketamine (10 mg/kg; 2 days; n = 12), lithium (37 mg/kg; 2 days; n = 12), ketamine + lithium (10 mg/kg + 37 mg/kg; 2 days; n = 12), or vehicle saline (0.9%; n = 12). Rats were subjected to open field (6 min) and forced swim tests (6 min). Peripheral blood and brain prefrontal cortical (PFC) tissue was collected one hour following stress exposure. Western blotting was used to determine the effects of treatment on extracellular signal-regulated kinase (ERK); mammalian target of rapamycin (mTOR), phospho kinase B (Akt), and glycogen synthase kinase-3ß (GSK3ß) protein levels in the infralimbic (IL) and prelimbic (PL) subregions of the PFC. Prefrontal oxygen consumption rate (OCR) and extracellular acidification rates (ECAR) were also determined in anterior PFC tissue at rest and following stimulation with brain-derived neurotrophic factor (BDNF) and tumor necrosis factor α (TNFα). Blood plasma levels of mTOR and insulin were determined using enzyme-linked immunosorbent assays (ELISAs). Overall, rats receiving ketamine+lithium displayed a robust antidepressant response to the combined treatment as demonstrated through significant reductions in immobility time (p < 0.05) and latency to immobility (p < 0.01). These animals also had higher expression of plasma mTOR (p < 0.01) and insulin (p < 0.001). Tissue bioenergetics analyses revealed that combined ketamine+lithium treatment did not significantly alter the respiratory response to BDNF or TNFα. Animals receiving both ketamine and lithium had significantly higher phosphorylation (p)-to-total expression ratios of mTOR (p < 0.001) and Akt (p < 0.01), and lower ERK in the IL compared to control animals. In contrast, pmTOR/mTOR levels were reduced in the PL of ketamine+lithium treated animals, while pERK/ERK expression levels were elevated. Taken together, these data demonstrate that lithium augmentation of ketamine in antidepressant nonresponsive animals improves antidepressant-like behavioral responses under stress, together with peripheral insulin efflux and region-specific PFC insulin signaling.

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Hearing loss often results in plastic changes in the central auditory pathways, which may be involved in the generation of tinnitus, a phantom auditory sensation. However, although animal studies have consistently shown increased neural activity in auditory structures after hearing loss, tinnitus does not always develop. It has therefore been suggested that non-auditory structures perform a gating or regulatory role that determines whether the increased activity in auditory structures leads to conscious perception. Recent evidence points to the paraflocculus of the cerebellum as having such a role. Therefore, we investigated the early effects of hearing loss on gene expression in guinea pig paraflocculus. Gene expression was investigated after two weeks recovery from either acoustic or mechanical cochlear trauma. The genes investigated in our study were associated with inhibitory neurotransmission (GABA-A receptor subunit alpha 1; glutamate decarboxylase 1), excitatory neurotransmission (glutamate receptor NMDA subunit 1), and regulation of transmitter release (member of RAB family of small GTPase). Our results show increased mRNA levels of glutamate decarboxylase 1 in ipsilateral paraflocculus with no difference between the different methods of cochlear trauma. Early modulation of gene expression in the paraflocculus suggests that an early effect of hearing loss may affect the influence of this structure on auditory processing.

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