Biology subjects

Kupferschmidt, D. A.

Publications and source records attributed to Kupferschmidt, D. A..

3 recordsLinked to original sources

bioRxiv2026

Altered thalamo-prefrontal synchrony dynamics during spatial working memory task performance in a SETD1A loss-of-function mouse model of schizophrenia predisposition

Schizophrenia is associated with profound working memory deficits, for which there are no approved treatments. Rare heterozygous null mutations in SETD1A, a gene encoding a key epigenetic regulatory protein, have been definitively linked to increased risk for schizophrenia and neurodevelopmental disorders. To investigate how SETD1A haploinsufficiency impacts the function of circuits supporting working memory, this study examined neural oscillatory synchrony across a network of brain regions critical for spatial working memory (SWM) in mice carrying a loss-of-function allele in the orthologous SETD1A gene. Local field potential recordings were performed in the prefrontal cortex, dorsal and ventral hippocampus, and thalamic nucleus reuniens in male and female wildtype and Setd1a+/- mice performing a delayed non-match to sample task of SWM. Setd1a+/- mice exhibited unaltered prefrontal-hippocampal neural oscillatory synchrony across frequencies and task epochs. In contrast, Setd1a+/- mice displayed reduced beta-frequency synchrony between the prefrontal cortex and nucleus reuniens during SWM maintenance and blunted bidirectional modulation of prefrontal-reuniens beta- and gamma-frequency synchrony across SWM task epochs. Collectively, this work expands our understanding of how genetic risk for schizophrenia alters functional connectivity within distributed circuits supporting SWM. GRAPHICAL ABSTRACT O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=104 SRC="FIGDIR/small/702577v1_ufig1.gif" ALT="Figure 1"> View larger version (22K): org.highwire.dtl.DTLVardef@8107acorg.highwire.dtl.DTLVardef@11ec407org.highwire.dtl.DTLVardef@d7ce18org.highwire.dtl.DTLVardef@1bb31f_HPS_FORMAT_FIGEXP M_FIG C_FIG

neuroscience↗

bioRxiv2025

Hippocampal input-driven plasticity of prefrontal interneurons reveals a circuit basis for impaired spatial working memory.

Long-range projections from ventral hippocampus (vHPC) to medial prefrontal cortex (mPFC) support cognitive functions including spatial working memory (SWM). vHPC input targets multiple prefrontal interneuron classes, yet how hippocampal input recruits these populations in vivo, whether this recruitment is plastic, and how such plasticity influences cognition remain unknown. Here, we combined optical stimulation of mouse vHPC inputs with calcium recordings from discrete mPFC interneuron populations, revealing persistent activity-induced reweighting of hippocampal recruitment across prefrontal inhibitory microcircuits. Ex vivo electrophysiology and computational modeling implicated weakened monosynaptic hippocampal drive onto vasoactive intestinal polypeptide (VIP)-expressing interneurons in this circuit reconfiguration. Prior vHPC input stimulation and the schizophrenia-associated Df(16)A+/- mutation, which also yielded reduced hippocampal input onto VIP interneurons, produced convergent alterations in task-related VIP interneuron activity associated with poorer SWM task learning. These findings implicate hippocampal input to VIP interneurons as a key locus of plasticity capable of reconfiguring inhibitory microcircuit activity linked to impaired working memory task learning. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=189 SRC="FIGDIR/small/665987v2_ufig1.gif" ALT="Figure 1"> View larger version (52K): org.highwire.dtl.DTLVardef@e26cb0org.highwire.dtl.DTLVardef@14d9d6borg.highwire.dtl.DTLVardef@9a0fc2org.highwire.dtl.DTLVardef@80afd1_HPS_FORMAT_FIGEXP M_FIG O_FLOATNOGraphical AbstractC_FLOATNO C_FIG

neuroscience↗

bioRxiv2022

Somatostatin peptide signaling dampens cortical circuits and promotes exploratory behavior

Somatostatin (SST) neurons in the prelimbic (PL) cortex mediate a variety of behavioral states. However, little is known about the actions of somatostatin peptide signaling in shaping cortical functioning and behavior. Here, we sought to characterize the unique physiological and behavioral roles of the SST peptide in the PL cortex. We employed a combination of ex vivo pharmacologic and optogenetic electrophysiology, in vivo calcium monitoring, and in vivo peptide pharmacology to explore the role of SST neuron and peptide signaling in the mouse PL cortex. Whole-cell slice electrophysiology was conducted in pyramidal and GABAergic neurons in the PL cortex of C57BL/6J and SST-IRES-Cre male and female mice to characterize the pharmacological mechanism of SST signaling. Fiber photometry of GCaMP6f fluorescent calcium signals from SST neurons was conducted to characterize the activity profile of SST neurons during exploration of an elevated plus maze (EPM) and open field test (OFT). We further used local delivery of both a broad SST receptor (SSTR) agonist and antagonist into bilateral PL cortex to test causal effects of SST administration and receptor blockade on these same exploratory behaviors. SSTR activation broadly hyperpolarized layer 2/3 pyramidal neurons in the PL cortex in both male and female mice ex vivo, an effect that was recapitulated with optogenetic stimulation of SST neurons, through both monosynaptic and polysynaptic GABA neuron-mediated mechanisms of action. This hyperpolarization was blocked by pre-application of the SSTR antagonist cyclo-somatostatin (cyclo-SST) and was non-reversible. SST neurons in PL were activated during EPM and OFT exploration, indicating task-related recruitment of these neurons. Lastly, in line with this exploration-related activity profile, SSTR agonist administration directly into the PL enhanced open arm exploration in the EPM, while in vivo administration of an antagonist had no effect. Together, this work describes a broad ability for SST peptide signaling to modulate microcircuits within the prefrontal cortex and related exploratory behaviors.

neuroscience↗