Dopamine is an important neurotransmitter that plays a key role in neuropsychiatric illness. Sex differences in dopaminergic signaling have been acknowledged for decades and have been linked to sex-specific heterogeneity in both dopamine-related behaviours as well as in various neuropsychiatric disorders. However, the overall number of studies that have evaluated sex differences in dopamine signaling, both in health and in these disorders, is low. This review will bring together what is known regarding sex differences in innate dopamine receptor expression and function, as well as highlight the known sex-specific roles of dopamine in addiction, depression, anxiety, schizophrenia, and attention deficit hyperactivity disorder. Due to differences in prognosis, diagnosis, and symptomatology between male and female subjects in disorders that involve dopamine signaling, or in responses that utilize pharmacological interventions that target dopamine receptors, understanding the fundamental sex differences in dopamine receptors is of vital importance for the personalization of therapeutic treatment strategies.

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Autism spectrum disorder (ASD) is a complex neurodevelopmental disorder that is associated with functional brain alterations that underlie the expression of behaviour. Males are diagnosed up to four times more than females, and sex differences have been identified in memory, cognitive flexibility, verbal fluency, and social communication. Unfortunately, there exists a lack of information on the sex-dependent mechanisms of ASD, as well as biological markers to distinguish sex-specific symptoms in ASD. This can often result in a standardized diagnosis for individuals across the spectrum, despite significant differences in the various ASD subtypes. Alterations in neuronal connectivity and oscillatory activity, such as is observed in ASD, are highly coupled to behavioural states. Yet, despite the well-identified sexual dimorphisms that exist in ASD, these functional patterns have rarely been analyzed in the context of sex differences or symptomology. This review summarizes alterations in neuronal oscillatory function in ASD, discusses the age, region, symptom and sex-specific differences that are currently observed across the spectrum, and potential targets for regulating neuronal oscillatory activity in ASD. The need to identify sex-specific biomarkers, in order to facilitate specific diagnostic criteria and allow for more targeted therapeutic approaches for ASD will also be discussed.

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Background. Alterations in glycogen synthase kinase-3β (GSK-3β) activity have been implicated in disorders of cognitive impairment including Alzheimer’s disease and schizophrenia. Another characteristic of cognitive impairment is the dysregulation of neural oscillatory activity, macroscopic electrical rhythms in brain critical to systems communication. A direct functional relationship between GSK-3β and neural oscillations has not been elucidated.Methods. In the present study, the impact of increasing GSK-3β activity in prefrontal cortex (PFC) or hippocampus (HIP) on the regulation of neural oscillations in rats was investigated using an adeno-associated viral vector containing a persistently active mutant of GSK-3β (S9A), and changes in learning and memory and tau phosphorylation assessed.Results. Increasing GSK-3β activity in either region had similar effects on oscillatory spectral power, enhancing theta and/or gamma oscillatory power recorded from one or both regions. Increasing PFC GSK-3β activity additionally suppressed high gamma PFC-HIP coherence. These oscillatory changes were accompanied by deficits in recognition memory, spatial learning and/or reversal learning. Increased pathogenic tau phosphorylation was also evident in regions where GSK-3β activity was elevated. Conclusions. These findings indicate that increased GSK-3β activity in PFC or HIP dysregulates neural oscillatory function in, and between, these regions. This suggests that GSK-3β may not only play an early role in cognitive decline in Alzheimer’s disease but may also play a more central role in disorders of cognitive dysfunction through the regulation of neurophysiological network function.

The deposition of dense fibril plaques represents the pathological hallmark for a multitude of human disorders, including many neurodegenerative diseases. Fibril plaques are predominately composed of amyloid fibrils, characterized by their underlying cross beta-sheet architecture. Research into the mechanisms of amyloid formation has mostly focused on characterizing and modeling the growth of individual fibrils and associated oligomers from their monomeric precursors. Much less is known about the mechanisms causing individual fibrils to assemble into ordered fibrillar suprastructures. Elucidating the mechanisms regulating this “secondary” self-assembly into distinct suprastructures is important for understanding how individual protein fibrils form the prominent macroscopic plaques observed in disease. Whether and how amyloid fibrils assemble into either 2D or 3D supramolecular structures also relates to ongoing efforts on using amyloid fibrils as substrates or scaffolds for self-assembling functional biomaterials. Here, we investigated the conditions under which preformed amyloid fibrils of a lysozyme assemble into larger superstructures as a function of charge screening or pH. Fibrils either assembled into three-dimensional gel clusters or two-dimensional fibril sheets. The latter displayed optical birefringence, diagnostic of amyloid plaques. We presume that pH and salt modulate fibril charge repulsion, which allows anisotropic fibril–fibril attraction to emerge and drive the transition from 3D to 2D fibril self-assembly.