Search

Key points: Tau mislocalization to dendritic spines and associated postsynaptic deficits are mediated through different and non‐overlapping phosphorylation sites.Tau mislocalization to dendritic spines depends upon the phosphorylation of either Ser396 or Ser404 in the C‐terminus.Postsynaptic dysfunction instead depends upon the phosphorylation of at least one of five residues in the proline‐rich region of tau.The blockade of both glycogen synthetase kinase 3β and cyclin‐dependent kinase 5 is required to prevent P301L‐induced tau mislocalization to dendritic spines, supporting redundant pathways that control tau mislocalization to spines. Tau protein consists of an N‐terminal projection domain, a microtubule‐binding domain and a C‐terminal domain. In neurodegenerative diseases, including Alzheimer's disease and frontotemporal dementia, the hyperphosphorylation of tau changes its shape, binding partners and resulting function. An early consequence of tau phosphorylation by proline‐directed kinases is postsynaptic dysfunction associated with the mislocalization of tau to dendritic spines. The specific phosphorylation sites leading to these abnormalities have not been elucidated. Here, using imaging and electrophysiological techniques to study cultured rat hippocampal neurons, we show that postsynaptic dysfunction results from a sequential process involving differential phosphorylation in the N‐terminal and C‐terminal domains. First, tau mislocalizes to dendritic spines, in a manner that depends upon the phosphorylation of either Ser396 or Ser404 in the C‐terminal domain. The blockade of both glycogen synthetase kinase 3β and cyclin‐dependent kinase 5 prevents tau mislocalization to dendritic spines. Second, a reduction of functional AMPA receptors depends upon the phosphorylation of at least one of five residues (Ser202, Thr205, Thr212, Thr217 and Thr231) in the proline‐rich region of the N‐terminal domain. This is the first report of differential phosphorylation in distinct tau domains governing separate, but linked, steps leading to synaptic dysfunction. Key points: Tau mislocalization to dendritic spines and associated postsynaptic deficits are mediated through different and non‐overlapping phosphorylation sites.Tau mislocalization to dendritic spines depends upon the phosphorylation of either Ser396 or Ser404 in the C‐terminus.Postsynaptic dysfunction instead depends upon the phosphorylation of at least one of five residues in the proline‐rich region of tau.The blockade of both glycogen synthetase kinase 3β and cyclin‐dependent kinase 5 is required to prevent P301L‐induced tau mislocalization to dendritic spines, supporting redundant pathways that control tau mislocalization to spines. [ABSTRACT FROM AUTHOR]

Stimulants are among the most widely used substances in the world after cannabis, with a rapid rise in methamphetamine use in the last 15 years. Methamphetamine has a high propensity to cause psychosis ranging from transient psychosis during acute intoxication to persisting psychosis with similarities to schizophrenia. Although the former condition may not abrogate criminal responsibility, the latter is recognized as a basis for an exculpatory mental state in a majority of jurisdictions across the United States. Methamphetamine use can therefore complicate criminal responsibility evaluations. We present the literature on methamphetamine-induced psychosis, underscoring the shortfalls in existing classificatory schemes for methamphetamine-associated psychosis that can complicate forensic mental health evaluators' opinions in criminal responsibility evaluations. We offer practical considerations for forensic mental health professionals performing criminal responsibility evaluations where methamphetamine use is a concern., (© 2025 American Academy of Psychiatry and the Law.)