Distinct Synchronous Network Activity During the Second Postnatal Week of Medial Entorhinal Cortex Development

The medial entorhinal cortex (MEC) contains specialized cell types whose firing is tuned to aspects of an animal’s position and orientation in the environment, reflecting a neuronal representation of space. The spatially tuned firing properties of these cells quickly emerge during the third postnatal week of development in rodents. Spontaneous synchronized network activity (SSNA) has been shown to play a crucial role in the development of neuronal circuits prior to week 3. SSNA in MEC is well described in rodents during the first postnatal week, but there are little data about its development immediately prior to eye opening and spatial exploration. Furthermore, existing data lack single-cell resolution and are not integrated across layers. In this study, we addressed the question of whether the characteristics and underlying mechanisms of SSNA during the second postnatal week resemble that of the first week or whether distinct features emerge during this period. Using a combined calcium imaging and electrophysiology approach in vitro, we confirm that in mouse MEC during the second postnatal week, SSNA persists and in fact peaks, and is dependent on ionotropic glutamatergic signaling. However, SSNA differs from that observed during the first postnatal week in two ways: First, EC does not drive network activity in the hippocampus but only in neighboring neocortex (NeoC). Second, GABA does not drive network activity but influences it in a manner that is dependent both on age and receptor type. Therefore, we conclude that while there is a partial mechanistic overlap in SSNA between the first and second postnatal weeks, unique mechanistic features do emerge during the second week, suggestive of different or additional functions of MEC within the hippocampal-entorhinal circuitry with increasing maturation

Hippocampal extracellular matrix alterations contribute to cognitive impairment associated with a chronic depressive-like state in rats

Patients with depression often suffer from cognitive impairments that contribute to disease burden. We used social defeat-induced persistent stress (SDPS) to induce a depressive-like state in rats and then studied long-lasting memory deficits in the absence of acute stressors in these animals. The SDPS rat model showed reduced short-term object location memory and maintenance of long-term potentiation (LTP) in CA1 pyramidal neurons of the dorsal hippocampus. SDPS animals displayed increased expression of synaptic chondroitin sulfate proteoglycans in the dorsal hippocampus. These effects were abrogated by a 3-week treatment with the antidepressant imipramine starting 8 weeks after the last defeat encounter. Next, we observed an increase in the number of perineuronal nets (PNNs) surrounding parvalbumin-expressing interneurons and a decrease in the frequency of inhibitory postsynaptic currents (IPSCs) in the hippocampal CA1 region in SDPS animals. In vivo breakdown of the hippocampus CA1 extracellular matrix by the enzyme chondroitinase ABC administered intracranially restored the number of PNNs, LTP maintenance, hippocampal inhibitory tone, and memory performance on the object place recognition test. Our data reveal a causal link between increased hippocampal extracellular matrix and the cognitive deficits associated with a chronic depressive-like state in rats exposed to SDPS

Morphoelectric and transcriptomic divergence of the layer 1 interneuron repertoire in human versus mouse neocortex

Neocortical layer 1 (L1) is a site of convergence between pyramidal-neuron dendrites and feedback axons where local inhibitory signaling can profoundly shape cortical processing. Evolutionary expansion of human neocortex is marked by distinctive pyramidal neurons with extensive L1 branching, but whether L1 interneurons are similarly diverse is underexplored. Using Patch-seq recordings from human neurosurgical tissue, we identified four transcriptomic subclasses with mouse L1 homologs, along with distinct subtypes and types unmatched in mouse L1. Subclass and subtype comparisons showed stronger transcriptomic differences in human L1 and were correlated with strong morphoelectric variability along dimensions distinct from mouse L1 variability. Accompanied by greater layer thickness and other cytoarchitecture changes, these findings suggest that L1 has diverged in evolution, reflecting the demands of regulating the expanded human neocortical circuit.</p

Signature morphoelectric properties of diverse GABAergic interneurons in the human neocortex

Human cortex transcriptomic studies have revealed a hierarchical organization of γ-aminobutyric acid-producing (GABAergic) neurons from subclasses to a high diversity of more granular types. Rapid GABAergic neuron viral genetic labeling plus Patch-seq (patch-clamp electrophysiology plus single-cell RNA sequencing) sampling in human brain slices was used to reliably target and analyze GABAergic neuron subclasses and individual transcriptomic types. This characterization elucidated transitions between PVALB and SST subclasses, revealed morphological heterogeneity within an abundant transcriptomic type, identified multiple spatially distinct types of the primate-specialized double bouquet cells (DBCs), and shed light on cellular differences between homologous mouse and human neocortical GABAergic neuron types. These results highlight the importance of multimodal phenotypic characterization for refinement of emerging transcriptomic cell type taxonomies and for understanding conserved and specialized cellular properties of human brain cell types.</p