Locus coeruleus: a new look at the blue spot.

The locus coeruleus (LC), or 'blue spot', is a small nucleus located deep in the brainstem that provides the far-reaching noradrenergic neurotransmitter system of the brain. This phylogenetically conserved nucleus has proved relatively intractable to full characterization, despite more than 60 years of concerted efforts by investigators. Recently, an array of powerful new neuroscience tools have provided unprecedented access to this elusive nucleus, revealing new levels of organization and function. We are currently at the threshold of major discoveries regarding how this tiny brainstem structure exerts such varied and significant influences over brain function and behaviour. All LC neurons receive inputs related to autonomic arousal, but distinct subpopulations of those neurons can encode specific cognitive processes, presumably through more specific inputs from the forebrain areas. This ability, combined with specific patterns of innervation of target areas and heterogeneity in receptor distributions, suggests that activation of the LC has more specific influences on target networks than had initially been imagined.

Brain Endothelial- and Epithelial-Specific Interferon Receptor Chain 1 Drives Virus-Induced Sickness Behavior and Cognitive Impairment.

Sickness behavior and cognitive dysfunction occur frequently by unknown mechanisms in virus-infected individuals with malignancies treated with type I interferons (IFNs) and in patients with autoimmune disorders. We found that during sickness behavior, single-stranded RNA viruses, double-stranded RNA ligands, and IFNs shared pathways involving engagement of melanoma differentiation-associated protein 5 (MDA5), retinoic acid-inducible gene 1 (RIG-I), and mitochondrial antiviral signaling protein (MAVS), and subsequently induced IFN responses specifically in brain endothelia and epithelia of mice. Behavioral alterations were specifically dependent on brain endothelial and epithelial IFN receptor chain 1 (IFNAR). Using gene profiling, we identified that the endothelia-derived chemokine ligand CXCL10 mediated behavioral changes through impairment of synaptic plasticity. These results identified brain endothelial and epithelial cells as natural gatekeepers for virus-induced sickness behavior, demonstrated tissue specific IFNAR engagement, and established the CXCL10-CXCR3 axis as target for the treatment of behavioral changes during virus infection and type I IFN therapy.

Olfactory Information Storage Engages Subcortical and Cortical Brain Regions That Support Valence Determination.

The olfactory bulb (OB) delivers sensory information to the piriform cortex (PC) and other components of the olfactory system. OB-PC synapses have been reported to express short-lasting forms of synaptic plasticity, whereas long-term potentiation (LTP) of the anterior PC (aPC) occurs predominantly by activating inputs from the prefrontal cortex. This suggests that brain regions outside the olfactory system may contribute to olfactory information processing and storage. Here, we compared functional magnetic resonance imaging BOLD responses triggered during 20 or 100 Hz stimulation of the OB. We detected BOLD signal increases in the anterior olfactory nucleus (AON), PC and entorhinal cortex, nucleus accumbens, dorsal striatum, ventral diagonal band of Broca, prelimbic-infralimbic cortex (PrL-IL), dorsal medial prefrontal cortex, and basolateral amygdala. Significantly stronger BOLD responses occurred in the PrL-IL, PC, and AON during 100 Hz compared with 20 Hz OB stimulation. LTP in the aPC was concomitantly induced by 100 Hz stimulation. Furthermore, 100 Hz stimulation triggered significant nuclear immediate early gene expression in aPC, AON, and PrL-IL. The involvement of the PrL-IL in this process is consistent with its putative involvement in modulating behavioral responses to odor experience. Furthermore, these results indicate that OB-mediated information storage by the aPC is embedded in a connectome that supports valence evaluation.

Frequency-dependency of the involvement of dopamine D1/D5 and beta-adrenergic receptors in hippocampal LTD triggered by locus coeruleus stimulation.

Patterned stimulation of the locus coeruleus (LC, 100 Hz), in conjunction with test-pulse stimulation of hippocampal afferents, results in input-specific long-term depression (LTD) of synaptic plasticity in the hippocampus. Effects are long-lasting and have been described in Schaffer-collateral-CA1 and perforant path-dentate gyrus synapses in behaving rats. To what extent LC-mediated hippocampal LTD (LC-LTD) is frequency-dependent is unclear. Here, we report that LC-LTD can be triggered by LC stimulation with 2 and 5 Hz akin to tonic activity, 10 Hz equivalent to phasic activity, and 100 Hz akin to high-phasic activity in the dentate gyrus (DG) of freely behaving rats. LC-LTD at both 2 and 100 Hz can be significantly prevented by an NMDA receptor antagonist. The LC releases both noradrenaline (NA) and dopamine (DA) from its hippocampal terminals and may also trigger hippocampal DA release by activating the ventral tegmental area (VTA). Unclear is whether both neurotransmitters contribute equally to hippocampal LTD triggered by LC stimulation (LC-LTD). Both DA D1/D5 receptors (D1/D5R) and beta-adrenergic receptors (ß-AR) are critically required for hippocampal LTD that is induced by patterned stimulation of hippocampal afferents, or is facilitated by spatial learning. We, therefore, explored to what extent these receptor subtypes mediate frequency-dependent hippocampal LC-LTD. LC-LTD elicited by 2, 5, and 10 Hz stimulation was unaffected by antagonism of ß-AR with propranolol, whereas LC-LTD induced by these frequencies was prevented by D1/D5R-antagonism using SCH23390. By contrast, LC-LTD evoked at 100 Hz was prevented by ß-AR-antagonism and only mildly affected by D1/D5R-antagonism. Taken together, these findings support that LC-LTD can be triggered by LC activity at a wide range of frequencies. Furthermore, the contribution of D1/D5R and ß-AR to hippocampal LTD that is triggered by LC activity is frequency-dependent and suggests that D1/D5R may be involved in LC-mediated hippocampal tonus.

Learning shifts the preferred theta phase of gamma oscillations in CA1.

Hippocampal neuronal oscillations reflect different cognitive processes and can therefore be used to dissect the role of hippocampal subfields in learning and memory. In particular, it has been suggested that encoding and retrieval is associated with slow gamma (25-55 Hz) and fast gamma (60-100 Hz) oscillations, respectively, which appear in a nested manner at specific phases of the ongoing theta oscillations (4-12 Hz). However, the relationship between memory demand and the theta phase of gamma oscillations remains unclear. Here, we assessed the theta phase preference of gamma oscillations in the CA1 region, at the starting and junction zones of a T-maze, while rats were learning an appetitive task. We found that the theta phase preference of slow gamma showed a ~180° phase shift when animals switched from novice to skilled performance during task acquisition. This phase-shift was not present at the junction zone, where animals chose a right or left turn within the T-maze, suggesting that a recall/decision process had already taken place at the starting zone. Our findings indicate that slow gamma oscillations support both encoding and retrieval, depending on the theta phase at which they occur. These properties are particularly evident prior to cognitive engagement in an acquired spatial task.

Hippocampal subfield-specific Homer1a expression is triggered by learning-facilitated long-term potentiation and long-term depression at medial perforant path synapses.

Learning about general aspects, or content details, of space results in differentiated neuronal information encoding within the proximodistal axis of the hippocampus. These processes are tightly linked to long-term potentiation (LTP) and long-term depression (LTD). Here, we explored the precise sites of encoding of synaptic plasticity in the hippocampus that are mediated by information throughput from the perforant path. We assessed nuclear Homer1a-expression that was triggered by electrophysiological induction of short and long forms of hippocampal synaptic plasticity, and compared it to Homer1a-expression that was triggered by LTP and LTD enabled by different forms of spatial learning. Plasticity responses were induced by patterned stimulation of the perforant path and were recorded in the dentate gyrus (DG) of freely behaving rats. We used fluorescence in situ hybridization to detect experience-dependent nuclear encoding of Homer1a in proximodistal hippocampal subfields. Induction of neither STP nor STD resulted in immediate early gene (IEG) encoding. Electrophysiological induction of robust LTP, or LTD, resulted in highly significant and widespread induction of nuclear Homer1a in all hippocampal subfields. LTP that was facilitated by novel spatial exploration triggered similar widespread Homer1a-expression. The coupling of synaptic depression with the exploration of a novel configuration of landmarks resulted in localized IEG expression in the proximal CA3 region and the lower (infrapyramidal) blade of the DG. Our findings support that synaptic plasticity induction via perforant path inputs promotes widespread hippocampal information encoding. Furthermore, novel spatial exploration promotes the selection of a hippocampal neuronal network by means of LTP that is distributed in an experience-dependent manner across all hippocampus subfields. This network may be modified during spatial content learning by LTD in specific hippocampal subfields. Thus, long-term plasticity-inducing events result in IEG expression that supports establishment and/or restructuring of neuronal networks that are necessary for long-term information storage.

Preferential frequency-dependent induction of synaptic depression by the lateral perforant path and of synaptic potentiation by the medial perforant path inputs to the dentate gyrus.

The encoding of spatial representations is enabled by synaptic plasticity. The entorhinal cortex sends information to the hippocampus via the lateral (LPP) and medial perforant (MPP) paths that transfer egocentric item-related and allocentric spatial information, respectively. To what extent LPP and MPP information-relay results in different homosynaptic synaptic plasticity responses is unclear. We examined the frequency dependency (at 1, 5, 10, 50, 100, 200 Hz) of long-term potentiation (LTP) and long-term depression (LTD) at MPP and LPP synapses in the dentate gyrus (DG) of freely behaving adult rats. We report that whereas the MPP-DG synapses exhibit a predisposition toward the expression of LTP, LPP-DG synapses prefer to express synaptic depression. The divergence of synaptic plasticity responses is most prominent at afferent frequencies of 5, 100, Hz and 200 Hz. Priming with 10 or 50 Hz significantly modified the subsequent plasticity response in a frequency-dependent manner, but failed to change the preferred direction of change in synaptic strength of MPP and LPP synapses. Evaluation of the expression of GluN1, GluN2A, or GluN2B subunits of the NMDA receptor revealed equivalent expression in the outer and middle thirds of the molecular layer where LPP and MPP inputs convene, respectively, thus excluding NMDA receptors as a substrate for the frequency-dependent differences in bidirectional plasticity. These findings demonstrate that the LPP and MPP inputs to the DG enable differentiated and distinct forms of synaptic plasticity in response to the same afferent frequencies. Effects are extremely robust and resilient to metaplastic priming. These properties may support the functional differentiation of allocentric and item information provided to the DG by the MPP and LPP, respectively, that has been proposed by others. We propose that allocentric spatial information, conveyed by the MPP is encoded through hippocampal LTP in a designated synaptic network. This network is refined and optimized to include egocentric contextual information through LTD triggered by LPP inputs.

Orchestration of Hippocampal Information Encoding by the Piriform Cortex.

The hippocampus utilizes olfactospatial information to encode sensory experience by means of synaptic plasticity. Odor exposure is also a potent impetus for hippocampus-dependent memory retrieval. Here, we explored to what extent the piriform cortex directly impacts upon hippocampal information processing and storage. In behaving rats, test-pulse stimulation of the anterior piriform cortex (aPC) evoked field potentials in the dentate gyrus (DG). Patterned stimulation of the aPC triggered both long-term potentiation (LTP > 24 h) and short-term depression (STD), in a frequency-dependent manner. Dual stimulation of the aPC and perforant path demonstrated subordination of the aPC response, which was nonetheless completely distinct in profile to perforant path-induced DG plasticity. Correspondingly, patterned aPC stimulation resulted in somatic immediate early gene expression in the DG that did not overlap with responses elicited by perforant path stimulation. Our results support that the piriform cortex engages in specific control of hippocampal information processing and encoding. This process may underlie the unique role of olfactory cues in information encoding and retrieval of hippocampus-dependent associative memories.

Hippocampal Synaptic Plasticity, Spatial Memory, and Neurotransmitter Receptor Expression Are Profoundly Altered by Gradual Loss of Hearing Ability.

Sensory information comprises the substrate from which memories are created. Memories of spatial sensory experience are encoded by means of synaptic plasticity in the hippocampus. Hippocampal dependency on sensory information is highlighted by the fact that sudden and complete loss of a sensory modality results in an impairment of hippocampal function that persists for months. Effects are accompanied by extensive changes in the expression of neurotransmitter receptors in cortex and hippocampus, consistent with a substantial adaptive reorganization of cortical function. Whether gradual sensory loss affects hippocampal function is unclear. Progressive age-dependent hearing loss (presbycusis) is a risk factor for cognitive decline. Here, we scrutinized C57BL/6 mice that experience hereditary and cumulative deafness starting in young adulthood. We observed that 2-4 months postnatally, increases in the cortical and hippocampal expression of GluN2A and GluN2B subunits of the N-methyl-D-aspartate receptor occurred compared to control mice that lack sensory deficits. Furthermore, GABA and metabotropic glutamate receptor expression were significantly altered. Hippocampal synaptic plasticity was profoundly impaired and mice exhibited significant deficits in spatial memory. These data show that during cortical adaptation to cumulative loss of hearing, plasticity-related neurotransmitter expression is extensively altered in the cortex and hippocampus. Furthermore, cumulative sensory loss compromises hippocampal function.

Lipoprotein receptor loss in forebrain radial glia results in neurological deficits and severe seizures.

The Alzheimer disease-associated multifunctional low-density lipoprotein receptor-related protein-1 is expressed in the brain. Recent studies uncovered a role of this receptor for the appropriate functioning of neural stem cells, oligodendrocytes, and neurons. The constitutive knock-out (KO) of the receptor is embryonically lethal. To unravel the receptors' role in the developing brain we generated a mouse mutant by specifically targeting radial glia stem cells of the dorsal telencephalon. The low-density lipoprotein receptor-related protein-1 lineage-restricted KO female and male mice, in contrast to available models, developed a severe neurological phenotype with generalized seizures during early postnatal development. The mechanism leading to a buildup of hyperexcitability and emergence of seizures was traced to a failure in adequate astrocyte development and deteriorated postsynaptic density integrity. The detected impairments in the astrocytic lineage: precocious maturation, reactive gliosis, abolished tissue plasminogen activator uptake, and loss of functionality emphasize the importance of this glial cell type for synaptic signaling in the developing brain. Together, the obtained results highlight the relevance of astrocytic low-density lipoprotein receptor-related protein-1 for glutamatergic signaling in the context of neuron-glia interactions and stage this receptor as a contributing factor for epilepsy.

Cerebellar-hippocampal processing in passive perception of visuospatial change: An ego- and allocentric axis?

In addition to its role in visuospatial navigation and the generation of spatial representations, in recent years, the hippocampus has been proposed to support perceptual processes. This is especially the case where high-resolution details, in the form of fine-grained relationships between features such as angles between components of a visual scene, are involved. An unresolved question is how, in the visual domain, perspective-changes are differentiated from allocentric changes to these perceived feature relationships, both of which may be argued to involve the hippocampus. We conducted functional magnetic resonance imaging of the brain response (corroborated through separate event-related potential source-localization) in a passive visuospatial oddball-paradigm to examine to what extent the hippocampus and other brain regions process changes in perspective, or configuration of abstract, three-dimensional structures. We observed activation of the left superior parietal cortex during perspective shifts, and right anterior hippocampus in configuration-changes. Strikingly, we also found the cerebellum to differentiate between the two, in a way that appeared tightly coupled to hippocampal processing. These results point toward a relationship between the cerebellum and the hippocampus that occurs during perception of changes in visuospatial information that has previously only been reported with regard to visuospatial navigation.

Early Loss of Vision Results in Extensive Reorganization of Plasticity-Related Receptors and Alterations in Hippocampal Function That Extend Through Adulthood.

Although by adulthood cortical structures and their capacity for processing sensory information have become established and stabilized, under conditions of cortical injury, or sensory deprivation, rapid reorganization occurs. Little is known as to the impact of this kind of adaptation on cellular processes related to memory encoding. However, imaging studies in humans suggest that following loss or impairment of a sensory modality, not only cortical but also subcortical structures begin to reorganize. It is likely that these processes are supported by neurotransmitter receptors that enable synaptic and cortical plasticity. Here, we explored to what extent the expression of plasticity-related proteins (GABA-A, GABA-B, GluN1, GluN2A, GluN2B) is altered following early vision loss, and whether this impacts on hippocampal function. We observed that in the period of 2-4 months postnatally in CBA/J-mice that experience hereditary postnatal retinal degeneration, systematic changes of GABA-receptor and NMDA-receptor subunit expression occurred that emerged first in the hippocampus and developed later in the cortex, compared to control mice that had normal vision. Changes were accompanied by significant impairments in hippocampal long-term potentiation and hippocampus-dependent learning. These data indicate that during cortical adaptation to early loss of vision, hippocampal information processing is compromised, and this status impacts on the acquisition of spatial representations.

In the Piriform Cortex, the Primary Impetus for Information Encoding through Synaptic Plasticity Is Provided by Descending Rather than Ascending Olfactory Inputs.

Information encoding by means of persistent changes in synaptic strength supports long-term information storage and memory in structures such as the hippocampus. In the piriform cortex (PC), that engages in the processing of associative memory, only short-term synaptic plasticity has been described to date, both in vitro and in anesthetized rodents in vivo. Whether the PC maintains changes in synaptic strength for longer periods of time is unknown: Such a property would indicate that it can serve as a repository for long-term memories. Here, we report that in freely behaving animals, frequency-dependent synaptic plasticity does not occur in the anterior PC (aPC) following patterned stimulation of the olfactory bulb (OB). Naris closure changed action potential properties of aPC neurons and enabled expression of long-term potentiation (LTP) by OB stimulation, indicating that an intrinsic ability to express synaptic plasticity is present. Odor discrimination and categorization in the aPC is supported by descending inputs from the orbitofrontal cortex (OFC). Here, OFC stimulation resulted in LTP (>4 h), suggesting that this structure plays an important role in promoting information encoding through synaptic plasticity in the aPC. These persistent changes in synaptic strength are likely to comprise a means through which long-term memories are encoded and/or retained in the PC.

Less means more: The magnitude of synaptic plasticity along the hippocampal dorso-ventral axis is inversely related to the expression levels of plasticity-related neurotransmitter receptors.

The dorsoventral axis of the hippocampus exhibits functional differentiations with regard to (spatial Vs emotional) learning and information retention (rapid encoding Vs long-term storage), as well as its sensitivity to neuromodulation and information received from extrahippocampal structures. The mechanisms that underlie these differentiations remain unclear. Here, we explored neurotransmitter receptor expression along the dorsoventral hippocampal axis and compared hippocampal synaptic plasticity in the CA1 region of the dorsal (DH), intermediate (IH) and ventral hippocampi (VH). We observed a very distinct gradient of expression of the N-methyl-D-aspartate receptor GluN2B subunit in the Stratum radiatum (DH< IH< VH). A similar distribution gradient (DH< IH< VH) was evident in the hippocampus for GluN1, the metabotropic glutamate receptors mGlu1 and mGlu2/3, GABAB and the dopamine-D1 receptor. GABAA exhibited the opposite expression relationship (DH > IH > VH). Neurotransmitter release probability was lowest in DH. Surprisingly, identical afferent stimulation conditions resulted in hippocampal synaptic plasticity that was the most robust in the DH, compared with IH and VH. These data suggest that differences in hippocampal information processing and synaptic plasticity along the dorsoventral axis may relate to specific differences in the expression of plasticity-related neurotransmitter receptors. This gradient may support the fine-tuning and specificity of hippocampal synaptic encoding.

Novel encoding and updating of positional, or directional, spatial cues are processed by distinct hippocampal subfields: Evidence for parallel information processing and the "what" stream.

The specific roles of hippocampal subfields in spatial information processing and encoding are, as yet, unclear. The parallel map theory postulates that whereas the CA1 processes discrete environmental features (positional cues used to generate a "sketch map"), the dentate gyrus (DG) processes large navigation-relevant landmarks (directional cues used to generate a "bearing map"). Additionally, the two-streams hypothesis suggests that hippocampal subfields engage in differentiated processing of information from the "where" and the "what" streams. We investigated these hypotheses by analyzing the effect of exploration of discrete "positional" features and large "directional" spatial landmarks on hippocampal neuronal activity in rats. As an indicator of neuronal activity we measured the mRNA induction of the immediate early genes (IEGs), Arc and Homer1a. We observed an increase of this IEG mRNA in CA1 neurons of the distal neuronal compartment and in proximal CA3, after novel spatial exploration of discrete positional cues, whereas novel exploration of directional cues led to increases in IEG mRNA in the lower blade of the DG and in proximal CA3. Strikingly, the CA1 did not respond to directional cues and the DG did not respond to positional cues. Our data provide evidence for both the parallel map theory and the two-streams hypothesis and suggest a precise compartmentalization of the encoding and processing of "what" and "where" information occurs within the hippocampal subfields.

Intrinsic cellular and molecular properties of in vivo hippocampal synaptic plasticity are altered in the absence of key synaptic matrix molecules.

Hippocampal synaptic plasticity comprises a key cellular mechanism for information storage. In the hippocampus, both long-term potentiation (LTP) and long-term depression (LTD) are triggered by synaptic Ca2+ -elevations that are typically mediated by the opening of voltage-gated cation channels, such as N-methyl-d-aspartate receptors (NMDAR), in the postsynaptic density. The integrity of the post-synaptic density is ensured by the extracellular matrix (ECM). Here, we explored whether synaptic plasticity is affected in adult behaving mice that lack the ECM proteins brevican, neurocan, tenascin-C, and tenascin-R (KO). We observed that the profiles of synaptic potentiation and depression in the dentate gyrus (DG) were profoundly altered compared to plasticity profiles in wild-type littermates (WT). Specifically, synaptic depression was amplified in a frequency-dependent manner and although late-LTP (>24 hr) was expressed following strong afferent tetanization, the early component of LTP (<75 min post-tetanization) was absent. LTP (>4 hr) elicited by weaker tetanization was equivalent in WT and KO animals. Furthermore, this latter form of LTP was NMDAR-dependent in WT but not KO mice. Scrutiny of DG receptor expression revealed significantly lower levels of both the GluN2A and GluN2B subunits of the N-methyl-d-aspartate receptor, of the metabotropic glutamate receptor, mGlu5 and of the L-type calcium channel, Cav 1.3 in KO compared to WT animals. Homer 1a and of the P/Q-type calcium channel, Cav 1.2 were unchanged in KO mice. Taken together, findings suggest that in mice that lack multiple ECM proteins, synaptic plasticity is intact, but is fundamentally different.

The serotonergic 5-HT4 receptor: A unique modulator of hippocampal synaptic information processing and cognition.

Serotonin (5-hydroxytryptamine, 5-HT) contributes in multifarious ways to the regulation of brain function, spanning key aspects such as the sleep-wake cycle, appetite, mood and mental health. The 5-HT receptors comprise seven receptor families (5-HT1-7) that are further subdivided into 14 receptor subtypes. The role of the 5-HT receptor in the modulation of neuronal excitability has been well documented. Recently, however, it has become apparent that the 5-HT4 receptor may contribute significantly to cognition and regulates less ostensible aspects of brain function: it engages in metaplastic regulation of synaptic responsiveness in key brain structures such as the hippocampus, thereby specifically promoting persistent forms of synaptic plasticity, and influences the direction of change in synaptic strength in selected hippocampal subfields. This highly specific neuromodulatory control by the 5-HT4 receptor may in turn explain the reported role for this receptor in hippocampus-dependent cognition. In this review article, we describe the role of the 5-HT4 receptor in hippocampal function, and describe how this receptor plays a unique and highly specialised role in synaptic information storage and cognition.

ß-Adrenergic Control of Hippocampal Function: Subserving the Choreography of Synaptic Information Storage and Memory.

Noradrenaline (NA) is a key neuromodulator for the regulation of behavioral state and cognition. It supports learning by increasing arousal and vigilance, whereby new experiences are "earmarked" for encoding. Within the hippocampus, experience-dependent information storage occurs by means of synaptic plasticity. Furthermore, novel spatial, contextual, or associative learning drives changes in synaptic strength, reflected by the strengthening of long-term potentiation (LTP) or long-term depression (LTD). NA acting on ß-adrenergic receptors (ß-AR) is a key determinant as to whether new experiences result in persistent hippocampal synaptic plasticity. This can even dictate the direction of change of synaptic strength.The different hippocampal subfields play different roles in encoding components of a spatial representation through LTP and LTD. Strikingly, the sensitivity of synaptic plasticity in these subfields to ß-adrenergic control is very distinct (dentate gyrus > CA3 > CA1). Moreover, NA released from the locus coeruleus that acts on ß-AR leads to hippocampal LTD and an enhancement of LTD-related memory processing. We propose that NA acting on hippocampal ß-AR, that is graded according to the novelty or saliency of the experience, determines the content and persistency of synaptic information storage in the hippocampal subfields and therefore of spatial memories.

mGlu5 acts as a switch for opposing forms of synaptic plasticity at mossy fiber-CA3 and commissural associational-CA3 synapses.

Within the hippocampus, different kinds of spatial experience determine the direction of change of synaptic weights. Synaptic plasticity resulting from such experience may enable memory encoding. The CA3 region is very striking in this regard: due to the distinct molecular properties of the mossy fiber (MF) and associational-commissural (AC) synapses, it is believed that they enable working memory and pattern completion. The question arises, however, as to how information reaching these synapses results in differentiated encoding. Given its crucial role in enabling persistent synaptic plasticity in other hippocampal subfields, we speculated that the metabotropic glutamate receptor mGlu5 may regulate information encoding at MF and AC synapses. Here, we show that antagonism of mGlu5 inhibits LTP, but not LTD at MF synapses of freely behaving adult rats. Conversely, mGlu5 antagonism prevents LTD but not LTP at AC-CA3 synapses. This suggests that, under conditions in which mGlu5 is activated, LTP may be preferentially induced at MF synapses, whereas LTD is favored at AC synapses. To assess this possibility, we applied 50 Hz stimulation that should generate postsynaptic activity that corresponds to θm, the activation threshold that lies between LTP and LTD. MGlu5 activation had no effect on AC responses but potentiated MF synapses. These data suggest that mGlu5 serves as a switch that alters signal-to-noise ratios during information encoding in the CA3 region. This mechanism supports highly tuned and differentiated information storage in CA3 synapses.

The requirement of BDNF for hippocampal synaptic plasticity is experience-dependent.

Brain-derived neurotrophic factor (BDNF) supports neuronal survival, growth, and differentiation and has been implicated in forms of hippocampus-dependent learning. In vitro, a specific role in hippocampal synaptic plasticity has been described, although not all experience-dependent forms of synaptic plasticity critically depend on BDNF. Synaptic plasticity is likely to enable long-term synaptic information storage and memory, and the induction of persistent (>24 h) forms, such as long-term potentiation (LTP) and long-term depression (LTD) is tightly associated with learning specific aspects of a spatial representation. Whether BDNF is required for persistent (>24 h) forms of LTP and LTD, and how it contributes to synaptic plasticity in the freely behaving rodent has never been explored. We examined LTP, LTD, and related forms of learning in the CA1 region of freely dependent mice that have a partial knockdown of BDNF (BDNF(+/-) ). We show that whereas early-LTD (<90min) requires BDNF, short-term depression (<45 min) does not. Furthermore, BDNF is required for LTP that is induced by mild, but not strong short afferent stimulation protocols. Object-place learning triggers LTD in the CA1 region of mice. We observed that object-place memory was impaired and the object-place exploration failed to induce LTD in BDNF(+/-) mice. Furthermore, spatial reference memory, that is believed to be enabled by LTP, was also impaired. Taken together, these data indicate that BDNF is required for specific, but not all, forms of hippocampal-dependent information storage and memory. Thus, very robust forms of synaptic plasticity may circumvent the need for BDNF, rather it may play a specific role in the optimization of weaker forms of plasticity. The finding that both learning-facilitated LTD and spatial reference memory are both impaired in BDNF(+/-) mice, suggests moreover, that it is critically required for the physiological encoding of hippocampus-dependent memory. © 2015 The Authors Hippocampus Published by Wiley Periodicals, Inc.