Autophagy is a process preserving the balance between synthesis, degradation and recycling of cellular components and is therefore essential for neuronal survival and function. Several key proteins govern the autophagy pathway including beclin1 and microtubule associated protein 1 light chain 3 (LC3). Here, we show a brain-specific reduction in beclin1 expression in postmortem hippocampus of schizophrenia patients, not detected in peripheral lymphocytes. This is in contrast with activity-dependent neuroprotective protein (ADNP) and ADNP2, which we have previously found to be deregulated in postmortem hippocampal samples from schizophrenia patients, but that now showed a significantly increased expression in lymphocytes from related patients, similar to increases in the anti-apoptotic, beclin1-interacting, Bcl2. The increase in ADNP was associated with the initial stages of the disease, possibly reflecting a compensatory effect. The increase in ADNP2 might be a consequence of neuroleptic treatment, as seen in rats subjected to clozapine treatment. ADNP haploinsufficiency in mice, which results in age-related neuronal death, cognitive and social dysfunction, exhibited reduced hippocampal beclin1 and increased Bcl2 expression (mimicking schizophrenia and normal human aging). At the protein level, ADNP co-immunoprecipitated with LC3B suggesting a direct association with the autophagy process and paving the path to novel targets for drug design.

Autophagy is a vital lysosomal degradation and recycling pathway in the eukaryotic cell, responsible for maintaining an intricate balance between cell survival and cell death, necessary for neuronal survival and function. This dual role played by autophagy raises the question whether this process is a protective or a destructive pathway, the contributor of neuronal cell death or a failed attempt to repair aberrant processes? Deregulated autophagy at different steps of the pathway, whether excessive or downregulated, has been proposed to be associated with neurodegenerative disorders such as Alzheimer’s-, Huntington’s-, and Parkinson’s-disease, known for their intracellular accumulation of protein aggregates. Recent observations of impaired autophagy also appeared in psychiatric disorders such as schizophrenia and bipolar disorder suggesting an additional contribution to the pathophysiology of mental illness. Here we review the current understanding of autophagy’s role in various neuropsychiatric disorders and, hitherto, the prevailing new potential autophagy-related therapeutic strategies for their treatment.

Glycogen synthase kinase (GSK)-3β, a serine/threonine kinase highly abundant in brain is a negative regulator of signal transduction cascades includi

The term neuroinflammation refers to inflammation of the nervous tissue, in general, and in the central nervous system (CNS), in particular. It is a driver of neurotoxicity, it is detrimental, and implies that glial cell activation happens prior to neuronal degeneration and, possibly, even causes it. The inflammation-like glial responses may be initiated in response to a variety of cues such as infection, traumatic brain injury, toxic metabolites, or autoimmunity. The inflammatory response of activated microglia engages the immune system and initiates tissue repair. Through translational research the role played by neuroinflammation has been acknowledged in different disease entities. Intriguingly, these entities include both those directly related to the CNS (commonly designated neuropsychiatric disorders) and those not directly related to the CNS (e.g., cancer and diabetes type 2). Interestingly, all the above-mentioned entities belong to the same group of “complex disorders”. This review aims to summarize cumulated data supporting the hypothesis that neuroinflammation is a common denominator of a wide variety of complex diseases. We will concentrate on cancer, type 2 diabetes (T2DM), and neuropsychiatric disorders (focusing on mood disorders).

Lithium is the prototype mood stabilizer but its mechanism is still unresolved. Two hypotheses dominate—the consequences of lithium’s inhibition of inositol monophosphatase at therapeutically relevant concentrations (the ‘inositol depletion’ hypothesis), and of glycogen-synthase kinase-3. To further elaborate the inositol depletion hypothesis that did not decisively determine whether inositol depletion per se, or phosphoinositols accumulation induces the beneficial effects, we utilized knockout mice of either of two inositol metabolism-related genes—IMPA1 or SMIT1, both mimic several lithium’s behavioral and biochemical effects. We assessed in vivo, under non-agonist-stimulated conditions, ³H-inositol incorporation into brain phosphoinositols and phosphoinositides in wild-type, lithium-treated, IMPA1 and SMIT1 knockout mice. Lithium treatment increased frontal cortex and hippocampal phosphoinositols labeling by several fold, but decreased phosphoinositides labeling in the frontal cortex of the wild-type mice of the IMPA1 colony strain by ~50%. Inositol metabolites were differently affected by IMPA1 and SMIT1 knockout. Inositoltrisphosphate administered intracerebroventricularly affected bipolar-related behaviors and autophagy markers in a lithium-like manner. Namely, IP₃ but not IP₁ reduced the immobility time of wild-type mice in the forced swim test model of antidepressant action by 30%, an effect that was reversed by an antagonist of all three IP₃ receptors; amphetamine-induced hyperlocomotion of wild-type mice (distance traveled) was 35% reduced by IP₃ administration; IP₃ administration increased hippocampal messenger RNA levels of Beclin-1 (required for autophagy execution) and hippocampal and frontal cortex protein levels ratio of Beclin-1/p62 by about threefold (p62 is degraded by autophagy). To conclude, lithium affects the phosphatidylinositol signaling system in two ways: depleting inositol, consequently decreasing phosphoinositides; elevating inositol monophosphate levels followed by phosphoinositols accumulation. Each or both may mediate lithium-induced behavior.

Lithium inhibits IMPase (inositol monophosphatase) activity, as well as inositol transporter function. To determine whether one or more of these mechanisms might underlie lithium's behavioural effects, we studied Impa1 (encoding IMPase) and Smit1 (sodium–myo-inositol transporter 1)-knockout mice. In brains of adult homozygous Impa1-knockout mice, IMPase activity was found to be decreased; however, inositol levels were not found to be altered. Behavioural analysis indicated decreased immobility in the forced-swim test as well as a strongly increased sensitivity to pilocarpine-induced seizures. These are behaviours robustly induced by lithium. In homozygous Smit1-knockout mice, free inositol levels were decreased in the frontal cortex and hippocampus. These animals behave like lithium-treated animals in the model of pilocarpine seizures and in the Porsolt forced-swim test model of depression. In contrast with O'Brien et al. [O'Brien, Harper, Jove, Woodgett, Maretto, Piccolo and Klein (2004) J. Neurosci. 24, 6791–6798], we could not confirm that heterozygous Gsk3b (glycogen synthase kinase 3β)-knockout mice exhibit decreased immobility in the Porsolt forced-swim test or decreased amphetamine-induced hyperactivity in a manner mimicking lithium's behavioural effects. These data support the role of inositol-related processes rather than GSK3β in the mechanism of the therapeutic action of lithium.