Synaptic plasticity deficits via aberrant engagement of metaplasticity in the hippocampus of PS19 mice

Dentate gyrus immaturity and region-specific synaptic and autophagy alterations across hippocampal subfields in schizophrenia.

BACKGROUND Hippocampal abnormalities are consistently observed in schizophrenia. We previously identified a histomorphological phenotype in the dentate gyrus (DG) suggestive of developmental arrest, alongside region-specific alterations in autophagy markers. However, how these features relate to synaptic organisation and neuronal maturity markers remains unclear. METHODS Post-mortem hippocampal tissue from older individuals with chronic schizophrenia (n = 10) and matched controls (n = 12) was examined using immunohistochemistry. Expression of synaptophysin and CD56 was assessed across the DG, CA4 (dentate hilus), and CA1, together with autophagy initiation proteins RB1CC1 and ATG16L1. Group differences were analysed using non-parametric tests, and exploratory correlation analyses were conducted across the cohort. RESULTS In control cases, the DG exhibited a distinct subgranular band-like pattern of synaptophysin immunoexpression consistent with organised synaptic architecture that was absent in schizophrenia. Schizophrenia cases showed a divergent synaptophysin pattern across hippocampal subfields, with reduced expression in the DG and CA4 but increased expression in CA1 (p = 0.003-0.007), while CD56 expression was higher across all regions (all p = 0.003). Autophagy markers showed complementary regional differences, with increased ATG16L1 in the DG (p = 0.048) and reduced RB1CC1 and ATG16L1 in CA1 (p = 0.009 and p = 0.003). Consistent with these regional differences, synaptophysin and CD56 expression showed strong inverse associations across hippocampal subfields, alongside region-dependent associations between synaptic, maturity-related, and autophagy-related markers. CONCLUSIONS These findings indicate regionally divergent alterations in synaptic organisation, neuronal maturity markers, and autophagy initiation signalling across hippocampal subfields in schizophrenia, consistent with the involvement of both neurodevelopmental and dynamic cellular processes and suggesting their potential convergence.

iScience Functional and structural characterization of dendritic spine pathology in a mouse model of tauopathy

Adgrd1 deficiency reveals increased hippocampal vulnerability and selective behavioral alterations in mice

Results suggest that Adgrd1 plays a key role in maintaining hippocampal resilience and regulating motivational behaviors through integrated molecular and circuit-level mechanisms.

Pre-plaque glutamatergic hyperexcitability, mitochondrial dysfunction, and dendritic remodeling in the hippocampus of one-month-old 5xFAD mice

Alzheimer’s disease (AD) is characterized by progressive cognitive decline and stereotyped neuropathology, yet the earliest cellular events that precede overt plaque burden and measurable behavioral impairment remain incompletely defined. Here, we tested the hypothesis that synaptic hyperexcitability and subcellular metabolic dysfunction emerge early in the 5xFAD mouse model and contribute to region-specific neuronal vulnerability before substantial amyloid plaque deposition. Using the 5xFAD heterozygous mouse, we first established the onset of transgene expression and the timing of plaque accumulation. Robust transgene expression was detected by postnatal day 15 and statistically significant plaque accumulation in the CA1 stratum radiatum by 4 months of age. Hippocampal slice electrophysiology revealed an early hyperexcitable phenotype at 1 month of age, including both increased AMPA receptor-mediated transmission and N-methyl-D-aspartate receptor signaling associated with the GluN2B subunit. Given the tight coupling between glutamatergic hyperactivity, oxidative stress, calcium dysregulation, and mitochondrial health, we assessed mitochondrial structure and function at this pre-plaque stage. Mitochondrial abnormalities consistent with impaired bioenergetic homeostasis were evident within hippocampal synaptic processes. Morphological analyses demonstrated that these early changes were associated with altered dendritic architecture in the CA1 and dentate gyrus regions, revealing hippocampal subregional susceptibility. Finally, spatial transcriptomics identified regionally enriched molecular signatures consistent with differential vulnerability. The CA1 subregion exhibited pronounced downregulation of mitochondria-related transcripts, and single-cell deconvolution resolved this transcriptomic suppression specifically to CA1 pyramidal neurons (CA1.ProS); CA3 and dentate gyrus did not show equivalent mitochondrial pathway suppression. Together, these findings define a pre-plaque window in 5xFAD mice marked by GluN2B-linked glutamatergic hyperexcitability, early mitochondrial disruption, and selective dendritic and transcriptional vulnerability. Mitochondrial transcriptomic suppression was anatomically restricted to CA1 pyramidal neurons, establishing a cell-type-specific bioenergetic signature at 1 month of age, well before overt amyloid pathology. While the observations herein are descriptive in nature and detailed mechanisms have yet to be established, nevertheless, the integrated timeline suggests that synaptic and metabolic dysfunctions arise before substantial plaque deposition and may represent tractable early targets for intervention in AD.

PKCα-deficient mice show altered synaptic signaling and impaired fear extinction

Protein kinase C alpha (PKCα), encoded by Prkca, has been implicated in neuronal signaling, plasticity, and memory. Human genetic studies identify PRKCA as a candidate locus relevant to memory and posttraumatic stress disorder (PTSD), but the physiological functions of PKCα remain incompletely defined. Here, we examined the anatomical distribution, signaling function, and behavioral phenotypes associated with constitutive global PKCα deficiency in Prkca-/- mice. PKCα was enriched in forebrain regions, including the hippocampus and prefrontal cortex. It was detected in MAP2-positive neurons and was not detected in GFAP-positive astrocytes. In cultured hippocampal neurons, PKC activation induced redistribution of PKCα to dendritic and membrane-associated compartments, including PSD95-positive postsynaptic sites. PKCα deficiency did not alter gross hippocampal morphology or the basal abundance of major neuronal and synaptic marker proteins, but it reduced basal phosphorylation of pan-PKC, CaMKIIα, and the AMPA receptor subunit GluR1 at Ser831. Male Prkca-/- mice showed impaired hippocampus-dependent spatial memory, increased anxiety-like behavior, and a marked deficit in contextual fear extinction. These findings identify PKCα as part of a signaling program associated with synaptic function and support a role for PKCα-dependent processes in adaptive updating of learned fear.

Procognitive restoration of PV neuron plasticity in neurodevelopmental disorders

The hippocampus forms memories of our experiences in populations of coactive pyramidal neurons (PNs)1–3. Fast-spiking parvalbumin-expressing inhibitory neurons (PV INs) in the dentate gyrus–CA3/CA2 circuit of the hippocampus precisely control PN activity through mossy fibre-dependent feedforward inhibition4–11. PV INs coordinate experience-dependent changes in their intrinsic excitability, synaptic connectivity, physiology and plasticity properties9,12–15—referred to here as experience-dependent PV IN plasticity—to regulate PN activity. PV IN impairments in early life, when neural circuitry is highly sensitive to experience, are thought to result in network hyperexcitability, seizures and impaired cognition, which are hallmarks of neurodevelopmental disorders (NDDs)16–18. Here we designed an input-specific translatome screen to identify regulators of experience-dependent PV IN plasticity genes (XPGs) in the CA3/CA2 subregion of adult hippocampus. We demonstrate that a substantial proportion of upregulated candidate XPGs exhibit haploinsufficiency in autism spectrum disorder, epilepsies, bipolar disorder and schizophrenia, which suggests that there is impaired experience-dependent PV IN plasticity in NDDs. In proof-of-concept experiments, targeted upregulation of a candidate XPG, the homeobox gene Meis2 (ref. 19), in CA3/CA2 PV INs in an NDD risk mouse model in adulthood is sufficient to restore experience-dependent PV IN plasticity. Moreover, ensemble and sharp-wave ripple properties and cognition were improved, and seizures were suppressed. Thus, experience-dependent PV IN plasticity is a convergent mechanism for NDD risk genes that can be re-instated in adulthood to reverse developmental deficits in circuitry, network excitability and cognition.