Drugs that target monoaminergic transmission represent a first‐line treatment for major depression. Though a full understanding of the mechanisms that underlie antidepressant efficacy is lacking, evidence supports a role for enhanced excitatory transmission. This can occur through two non‐mutually exclusive mechanisms. The first involves increased function of excitatory neurons through relatively direct mechanisms such as enhanced dendritic arborization. Another mechanism involves reduced inhibitory function, which occurs with the rapid antidepressant ketamine. Consistent with this, GABAergic interneuron‐mediated cortical inhibition is linked to reduced gamma oscillatory power, a rhythm also diminished in depression. Remission of depressive symptoms correlates with restoration of gamma power. As a result of strong excitatory input, reliable GABA release, and fast firing, PV‐expressing neurons (PV neurons) represent critical pacemakers for synchronous oscillations. PV neurons also represent the predominant GABAergic population enveloped by perineuronal nets (PNNs), lattice‐like structures that localize glutamatergic input. Disruption of PNNs reduces PV excitability and enhances gamma activity. Studies suggest that monoamine reuptake inhibitors reduce integrity of the PNN. Mechanisms by which these inhibitors reduce PNN integrity, however, remain largely unexplored. A better understanding of these issues might encourage development of therapeutics that best up‐regulate PNN‐modulating proteases. We observe that the serotonin/norepinephrine reuptake inhibitor venlafaxine increases hippocampal matrix metalloproteinase (MMP)‐9 levels as determined by ELISA and concomitantly reduces PNN integrity in murine hippocampus as determined by analysis of sections following their staining with a fluorescent PNN‐binding lectin. Moreover, venlafaxine‐treated mice (30 mg/kg/day) show an increase in carbachol‐induced gamma power in ex vivo hippocampal slices as determined by local field potential recording and Matlab analyses. Studies with mice deficient in matrix metalloproteinase 9 (MMP‐9), a protease linked to PNN disruption in other settings, suggest that MMP‐9 contributes to venlafaxine‐enhanced gamma power. In conclusion, our results support the possibility that MMP‐9 activity contributes to antidepressant efficacy through effects on the PNN that may in turn enhance neuronal population dynamics involved in mood and/or memory. Cover Image for this issue: doi: .

Memory disruption in mild cognitive impairment (MCI) and Alzheimer's disease (AD) is poorly understood, particularly at early stages preceding neurodegeneration. In mouse models of AD, there are disruptions to sharp wave ripples (SWRs), hippocampal population events with a critical role in memory consolidation. However, the microcircuitry underlying these disruptions is underexplored. We tested whether a selective reduction in parvalbumin-expressing (PV) inhibitory interneuron activity underlies hyperactivity and SWR disruption. We employed the 5xFAD model of familial AD crossed with mouse lines labeling excitatory pyramidal cells (PCs) and inhibitory PV cells. We observed a 33% increase in frequency, 58% increase in amplitude, and 8% decrease in duration of SWRs in ex vivo slices from male and female three-month 5xFAD mice versus littermate controls. 5xFAD mice of the same age were impaired in a hippocampal-dependent memory task. Concurrent with SWR recordings, we performed calcium imaging, cell-attached, and whole-cell recordings of PC and PV cells within the CA1 region. PCs in 5xFAD mice participated in enlarged ensembles, with superficial PCs (sPCs) having a higher probability of spiking during SWRs. Both deep PCs (dPCs) and sPCs displayed an increased synaptic E/I ratio, suggesting a disinhibitory mechanism. In contrast, we observed a 46% spike rate reduction during SWRs in PV basket cells (PVBCs), while PV bistratified and axo-axonic cells were unimpaired. Excitatory synaptic drive to PVBCs was selectively reduced by 50%, resulting in decreased E/I ratio. Considering prior studies of intrinsic PV cell dysfunction in AD, these findings suggest alterations to the PC-PVBC microcircuit also contribute to impairment.

Repeated head impact exposure can cause memory and behavioral impairments. Here, we report that exposure to non-damaging, but high frequency, head impacts can alter brain function in mice through synaptic adaptation. High frequency head impact mice develop chronic cognitive impairments in the absence of traditional brain trauma pathology, and transcriptomic profiling of mouse and human chronic traumatic encephalopathy brain reveal that synapses are strongly affected by head impact. Electrophysiological analysis shows that high frequency head impacts cause chronic modification of the AMPA/NMDA ratio in neurons that underlie the changes to cognition. To demonstrate that synaptic adaptation is caused by head impact-induced glutamate release, we pretreated mice with memantine prior to head impact. Memantine prevents the development of the key transcriptomic and electrophysiological signatures of high frequency head impact, and averts cognitive dysfunction. These data reveal synapses as a target of high frequency head impact in human and mouse brain, and that this physiological adaptation in response to head impact is sufficient to induce chronic cognitive impairment in mice.

Hippocampal sharp wave ripples (SWRs) represent irregularly occurring synchronous neuronal population events that are observed during phases of rest and slow wave sleep. SWR activity that follows learning involves sequential replay of training-associated neuronal assemblies and is critical for systems level memory consolidation. SWRs are initiated by CA2 or CA3 pyramidal cells (PCs) and require initial excitation of CA1 PCs as well as participation of parvalbumin (PV) expressing fast spiking (FS) inhibitory interneurons. These interneurons are relatively unique in that they represent the major neuronal cell type known to be surrounded by perineuronal nets (PNNs), lattice like structures composed of a hyaluronin backbone that surround the cell soma and proximal dendrites. Though the function of the PNN is not completely understood, previous studies suggest it may serve to localize glutamatergic input to synaptic contacts and thus influence the activity of ensheathed cells. Noting that FS PV interneurons impact the activity of PCs thought to initiate SWRs, and that their activity is critical to ripple expression, we examine the effects of PNN integrity on SWR activity in the hippocampus. Extracellular recordings from the stratum radiatum of horizontal murine hippocampal hemisections demonstrate SWRs that occur spontaneously in CA1.As compared with vehicle, pre-treatment (120 min) of paired hemislices with hyaluronidase, which cleaves the hyaluronin backbone of the PNN, decreases PNN integrity and increases SWR frequency. Pre-treatment with chondroitinase, which cleaves PNN side chains, also increases SWR frequency. Together, these data contribute to an emerging appreciation of extracellular matrix as a regulator of neuronal plasticity and suggest that one function of mature perineuronal nets could be to modulate the frequency of SWR events. K E Y W O R D Schondrotinase, hippocampus, hyaluronidase, protease, PV interneuron

1 Memory disruption in mild cognitive impairment (MCI) and Alzheimer's disease (AD) is poorly 2 understood, particularly at early stages prior to neuronal or synaptic degeneration. In mouse models of 3 AD, there are observed disruptions to sharp wave ripples (SWRs), hippocampal population events with 4 a critical role in memory consolidation. However, the micro-circuitry underlying these disruptions are 5under-explored. We tested the hypothesis that a selective reduction in parvalbumin-expressing (PV) 6 inhibitory interneuron activity underlies hyperactivity and SWR disruption. We employed the 5xFAD 7 model of familial Alzheimer's disease crossed with mouse lines that selectively label excitatory pyramidal 8 cells (PCs) and inhibitory PV cells. We observed a 33% increase in frequency, 58% increase in amplitude, 9 and 8% decrease in duration of SWRs in acute slices from 3-month 5xFAD mice versus littermate 10 controls. 5xFAD mice of the same age were impaired in a task of hippocampal-dependent memory. 11Concurrent with SWR recordings, we performed calcium imaging, cell-attached, and whole-cell 12 recordings of PC and PV cells within the CA1 region. PCs in 5xFAD mice participated in enlarged 13 ensembles, with similar spiking activity, and increased synaptic E/I ratio, suggesting a disinhibitory 14 mechanism. In contrast, we observed a selective 46% spike rate reduction during SWRs in PV basket 15 cells (PVBCs), whereas PV bistratified and PV axo-axonic cells were unimpaired. Excitatory synaptic 16 drive to PVBCs was selectively reduced by 50%, resulting in decreased E/I ratio. Considering prior 17 studies of intrinsic PV cell dysfunction in AD, these findings suggest synaptic and network mechanisms 18 also play a prominent role. 19 Significance Statement 20We demonstrate that a specific sub-type of inhibitory neuron, PV-expressing basket cells, are 21 selectively impaired in a model of Alzheimer's disease during activity critical for the consolidation of 22 memory (i.e. SWRs). These results identify a cellular target for therapeutic intervention to restore aberrant 23 network activity in early amyloid pathology. While PV-expressing cells have previously been identified as 24 a potential therapeutic target, this study for the first time recognizes that other PV-expressing neuronal 25 sub-types, including bistratified and axo-axonic cells, are spared. It also represents the first attempt to 26 record synaptic and spiking activity during SWR events in early amyloid pathology, revealing that a 27 selective decrease in excitatory synaptic drive to PV basket cells likely underlies reduced function. 28