Alzheimer’s disease (AD) therapies predominantly focus on β-amyloid (Aβ), but Aβ effects may be maximal before clinical symptoms appear. Downstream of Aβ, dendritic spine loss correlates most strongly with cognitive decline in AD. Rho-associated kinases (ROCK1 and ROCK2) regulate the actin cytoskeleton, and ROCK1 and ROCK2 protein abundances are increased in early AD. Here, we found that the increased abundance of ROCK1 in cultured primary rat hippocampal neurons reduced dendritic spine length through a myosin-based pathway, whereas the increased abundance of ROCK2 induced spine loss through the serine and threonine kinase LIMK1. Aβ42 oligomers can activate ROCKs. Here, using static imaging studies combined with multielectrode array analyses, we found that the ROCK2-LIMK1 pathway mediated Aβ42-induced spine degeneration and neuronal hyperexcitability. Live-cell microscopy revealed that pharmacologic inhibition of LIMK1 rendered dendritic spines resilient to Aβ42 oligomers. Treatment of hAPP mice with a LIMK1 inhibitor rescued Aβ-induced hippocampal spine loss and morphologic aberrations. Our data suggest that therapeutically targeting LIMK1 may provide dendritic spine resilience to Aβ and therefore may benefit cognitively normal patients that are at high risk for developing dementia.

Cognitive resilience is often defined as the ability to remain cognitively normal in the face of insults to the brain. These insults can include disease pathology, such as plaques and tangles associated with Alzheimer’s disease, stroke, traumatic brain injury, or other lesions. Factors such as physical or mental activity and genetics may contribute to cognitive resilience, but the neurobiological underpinnings remain ill-defined. Emerging evidence suggests that dendritic spine structural plasticity is one plausible mechanism. In this review, we highlight the basic structure and function of dendritic spines and discuss how spine density and morphology change in aging and Alzheimer’s disease. We note evidence that spine plasticity mediates resilience to stress, and we tackle dendritic spines in the context of cognitive resilience to Alzheimer’s disease. Finally, we examine how lifestyle and genetic factors may influence dendritic spine plasticity to promote cognitive resilience before discussing evidence for actin regulatory kinases as therapeutic targets for Alzheimer’s disease.

The cause of schizophrenia (SZ) is unknown and no single region of the brain can be pinpointed as an area of primary pathology. Rather, SZ results from dysfunction of multiple neurotransmitter systems and miswiring between brain regions. It is necessary to elucidate how communication between regions is disrupted to advance our understanding of SZ pathology. The nucleus accumbens (NAcc) is a prime region of interest, where inputs from numerous brain areas altered in SZ are integrated. Aberrant signaling in the NAcc is hypothesized to cause symptoms of SZ, but it is unknown if these abnormalities are actually present. Electron microscopy was used to study the morphology of synaptic connections in SZ. The NAcc core and shell of 6 SZ subjects and 8 matched controls were compared in this pilot study. SZ subjects had a 19% increase in the density of asymmetric axospinous synapses (characteristic of excitatory inputs) in the core, but not the shell. Both groups had similar densities of symmetric synapses (characteristic of inhibitory inputs). The postsynaptic densities of asymmetric synapses had 22% smaller areas in the core, but not the shell. These results indicate that the core receives increased excitatory input in SZ, potentially leading to dysfunctional dopamine neurotransmission and cortico-striatal-thalamic stimulus processing. The reduced postsynaptic density size of asymmetric synapses suggests impaired signaling at these synapses. These findings enhance our understanding of the role the NAcc might play in SZ and the interaction of glutamatergic and dopaminergic abnormalities in SZ.Key words: electron microscopy/anatomy/striatum/ synapseThe exact pathophysiology for the origin of schizophrenia (SZ) is unknown, however evidence from decades of research implies that interactions between multiple brain regions and multiple neurotransmitter systems are likely at play. One region that is implicated in SZ pathology is the nucleus accumbens (NAcc). The NAcc integrates signaling from multiple regions of the brain, receiving input from areas including the prefrontal cortex, hippocampus, amygdala, thalamus, and midbrain.1 Importantly, all of these areas have been associated with SZ, making the NAcc a prime region for integrating multiple disrupted areas to provide a comprehensive understanding of SZ pathology.2 Reciprocal connections between the NAcc and substantia nigra/ventral tegmental area (SN/VTA) indicate further importance of this region. Via these connections, the NAcc modulates dopaminergic input to the dorsal striatum, 3 and striatal dopamine (DA) dysfunction is a hallmark characteristic of the disorder.4 Though many studies have implicated the NAcc in SZ, none have been able to describe its circuitry.The purpose of this study was to provide the first ultrastructural analysis in postmortem human NAcc, and examine the neurocircuitry in the NAcc in SZ to establish the role this region may play in the disorder. We used stereological analysis of electron micrographs in postmortem SZ to analyze the organization an...

Schizophrenia is a severe mental illness affecting approximately 1% of the population worldwide. Despite its prevalence, the cause remains unknown, and treatment is not effective in all patients. Dopamine is thought to play a role in schizophrenia pathology, yet the substantia nigra (SN), the origin of dopaminergic pathways, has not been studied extensively in schizophrenia. In this study, electron microscopy was used to examine neurons, oligodendrocytes, and myelinated axons in the SN of normal controls (NCs, n=9) and schizophrenia subjects with varying response to antipsychotic drugs [SZ, n=14; treatment resistant (TR)=6, treatment responsive (RESP)=6, unknown=2]. Postmortem tissue was analyzed for qualitative and quantitative markers of ultrastuctural integrity. A significantly higher percentage of axons in the schizophrenia group had inclusions in the myelin sheath compared to NCs (SZ: 3.9±1.7, NC: 2.6±2.0). When considering treatment response, a significantly higher percentage of axons lacked cytoplasm (TR: 9.7±5.5, NC: 3.5±2.3), contained cellular debris (TR: 7.5±3.2, NC: 2.3±1.3) or had protrusions in the myelin sheath (TR: 0.4±0.5, NC: 0.2±0.3). The G-ratio, a measure of myelin thickness, was significantly different between treatment response groups and was greater in TR (0.72±0.02) as compared to NCs (0.68±0.03), indicating decreased myelination in TR. These findings, which suggest myelin pathology in the SN in schizophrenia, are consistent with findings elsewhere in the brain. In addition, our results suggest cytoskeletal abnormalities, which may or may not be associated with myelin pathology.

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