John G. Howland

Long-term depression in the CNS

Long-term depression (LTD) in the CNS has been the subject of intense investigation as a process that may be involved in learning and memory and in various pathological conditions. Several mechanistically distinct forms of this type of synaptic plasticity have been identified and their molecular mechanisms are starting to be unravelled. Most studies have focused on forms of LTD that are triggered by synaptic activation of either NMDARs (N-methyl-D-aspartate receptors) or metabotropic glutamate receptors (mGluRs). Converging evidence supports a crucial role of LTD in some types of learning and memory and in situations in which cognitive demands require a flexible response. In addition, LTD may underlie the cognitive effects of acute stress, the addictive potential of some drugs of abuse and the elimination of synapses in neurodegenerative diseases.

Interaction between Perirhinal and Medial Prefrontal Cortex Is Required for Temporal Order But Not Recognition Memory for Objects in Rats

The present study investigated the roles of the perirhinal cortex, medial prefrontal cortex, and intrahemispheric interactions between them in recognition and temporal order memory for objects. Experiment 1 assessed the effects of bilateral microinfusions of the sodium channel blocker lidocaine into either the anterior perirhinal or medial prefrontal cortex immediately before memory testing in a familiarity discrimination task and a recency discrimination task, both of which involved spontaneous exploration of objects. Inactivation of the perirhinal cortex disrupted performance in both tasks, whereas inactivation of the medial prefrontal cortex disrupted performance in the recency, but not the familiarity, discrimination task. In a second experiment, the importance of intrahemispheric interactions between these structures in temporal order memory were assessed by comparing the effects of unilateral inactivation of either structure alone with those of crossed unilateral inactivation of both structures on the recency discrimination task. Crossed unilateral inactivation of both structures produced a significant impairment, whereas inactivation of either structure alone produced little or no impairment. Collectively, these findings suggest that the perirhinal cortex, but not the medial prefrontal cortex, contributes to retrieval of information necessary for long-term object recognition, whereas both structures, via intrahemispheric interactions between them, contribute to retrieval of information necessary for long-term object temporal order memory. These data are consistent with models in which attributed information is stored in posterior cortical sites and supports lower-order mnemonic functions (e.g., recognition memory) but can also be retrieved and further processed via interactions with the prefrontal cortex to support higher-order mnemonic functions (e.g., temporal order memory).

Hippocampal long-term depression mediates acute stress-induced spatial memory retrieval impairment

Acute stress impairs memory retrieval and facilitates the induction of long-term depression (LTD) in the hippocampal CA1 region of the adult rodent brain. However, whether such alterations in synaptic plasticity cause the behavioral effects of stress is not known. Here, we report that two selective inhibitors of the induction or expression of stress-enabled, N-methyl-d-aspartate receptor-dependent hippocampal LTD also block spatial memory retrieval impairments caused by acute stress. Additionally, we demonstrate that facilitating the induction of hippocampal LTD in vivo by blockade of glutamate transport mimics the behavioral effects of acute stress by impairing spatial memory retrieval. Thus, the present study demonstrates that hippocampal LTD is both necessary and sufficient to cause acute stress-induced impairment of spatial memory retrieval and provides a new perspective from which to consider the nature of cognitive deficits in disorders whose symptoms are aggravated by stress.

Chapter 8 Synaptic plasticity in learning and memory: Stress effects in the hippocampus

Synaptic plasticity has often been argued to play an important role in learning and memory. The discovery of long-term potentiation (LTP) and long-term depression (LTD), the two most widely cited cellular models of synaptic plasticity, significantly spurred research in this field. Although correlative evidence suggesting a role for synaptic changes such as those seen in LTP and LTD in learning and memory has been gained in a number of studies, definitive demonstrations of a specific role for either LTP or LTD in learning and memory are lacking. In this review, we discuss a number of recent advancements in the understanding of the mechanisms that mediate LTP and LTD in the rodent hippocampus and focus on the use of subunit-specific N-methyl-d-aspartate receptor antagonists and interference peptides as potential tools to study the role of synaptic plasticity in learning and memory. By using the modulation of synaptic plasticity and hippocampal-dependent learning and memory by acute stress as an example, we review a large body of convincing evidence indicating that alterations in synaptic plasticity underlie the changes in learning and memory produced by acute stress.

Hippocampal long-term depression is required for the consolidation of spatial memory

Although NMDA receptor (NMDAR)-dependent long-term potentiation (LTP) and long-term depression (LTD) of glutamatergic transmission are candidate mechanisms for long-term spatial memory, the precise contributions of LTP and LTD remain poorly understood. Here, we report that LTP and LTD in the hippocampal CA1 region of freely moving adult rats were prevented by NMDAR 2A (GluN2A) and 2B subunit (GluN2B) preferential antagonists, respectively. These results strongly suggest that NMDAR subtype preferential antagonists are appropriate tools to probe the roles of LTP and LTD in spatial memory. Using a Morris water maze task, the LTP-blocking GluN2A antagonist had no significant effect on any aspect of performance, whereas the LTD-blocking GluN2B antagonist impaired spatial memory consolidation. Moreover, similar spatial memory deficits were induced by inhibiting the expression of LTD with intrahippocampal infusion of a short peptide that specifically interferes with AMPA receptor endocytosis. Taken together, our findings support a functional requirement of hippocampal CA1 LTD in the consolidation of long-term spatial memory.

Altered object-in-place recognition memory, prepulse inhibition, and locomotor activity in the offspring of rats exposed to a viral mimetic during pregnancy.

Infection during pregnancy (i.e., prenatal infection) increases the risk of psychiatric illnesses such as schizophrenia and autism in the adult offspring. The present experiments examined the effects of prenatal immune challenge on behavior in three paradigms relevant to these disorders: prepulse inhibition (PPI) of the acoustic startle response, locomotor responses to an unfamiliar environment and the N-methyl-d-aspartate antagonist MK-801, and three forms of recognition memory. Pregnant Long-Evans rats were exposed to the viral mimetic polyinosinic-polycytidylic acid (PolyI:C; 4 mg/kg, i.v.) on gestational day 15. Offspring were tested for PPI and locomotor activity before puberty (postnatal days (PNDs)35 and 36) and during young adulthood (PNDs 56 and 57). Four prepulse-pulse intervals (30, 50, 80, and 140 ms) were employed in the PPI test. Recognition memory testing was performed using three different spontaneous novelty recognition tests (object, object location, and object-in-place recognition) after PND 60. Regardless of sex, offspring of PolyI:C-treated dams showed disrupted PPI at 50-, 80-, and 140-ms prepulse-pulse intervals. In the prepubescent rats, we observed prepulse facilitation for the 30-ms prepulse-pulse interval trials that was selectively retained in the adult PolyI:C-treated offspring. Locomotor responses to MK-801 were significantly reduced before puberty, whereas responses to an unfamiliar environment were increased in young adulthood. Both male and female PolyI:C-treated offspring showed intact object and object location recognition memory, whereas male PolyI:C-treated offspring displayed significantly impaired object-in-place recognition memory. Females were unable to perform the object-in-place test. The present results demonstrate that prenatal immune challenge during mid/late gestation disrupts PPI and locomotor behavior. In addition, the selective impairment of object-in-place recognition memory suggests tasks that depend on prefrontal cortex may be particularly vulnerable following prenatal immune challenge.

Prenatal exposure to a viral mimetic alters behavioural flexibility in male, but not female, rats

Current understanding of the etiology of neurodevelopmental disorders is limited; however, recent epidemiological studies demonstrate a strong correlation between prenatal infection during pregnancy and the development of schizophrenia in adult offspring. In particular, schizophrenia patients subjected to prenatal infection exhibit impairments in executive functions greater than schizophrenia patients not exposed to an infection while in utero. Acute prenatal treatment of rodents with the viral mimetic polyinosinic-polycytidylic acid (PolyI:C) induces behavioural and neuropathological alterations in the adult offspring similar to schizophrenia. However, impairments on tasks of executive function that involve the prefrontal cortex (PFC) have been rarely examined for the prenatal infection model. Hence, we investigated the effects of acute prenatal injection of PolyI:C (4.0 mg/kg, i.v., gestational day 15) on strategy set-shifting and reversal learning in an operant-based task. Our results show male, but not female, PolyI:C-treated adult offspring require more trials to reach criterion and perseverate during set-shifting. An opposite pattern was seen on the reversal day where the PolyI:C-treated male rats made fewer regressive errors. Females took more pre-training days and were slower to respond during the trials when compared to males regardless of prenatal treatment. The present findings validate the utility of the prenatal infection model for examining alterations of executive function, one of the most prominent cognitive symptoms of schizophrenia.

Converging effects of acute stress on spatial and recognition memory in rodents: a review of recent behavioural and pharmacological findings.

The heterogeneous effects of acute stress on learning and memory depend on numerous parameters related to the stressor, the time the stressor is experienced, and the nature of the stimuli or task examined. In the present review, we systematically summarize the rodent literature examining the effects of acute extrinsic stress on spatial and recognition memory. Converging evidence from a number of behavioural tasks suggests acute stress disrupts the retrieval of spatial and recognition memory regardless of whether the stress is experienced before or after learning. Few studies have attempted to discern whether these effects are due to specific failures in consolidation or retrieval of task relevant information. Recent studies demonstrate that diverse mechanisms related to activation of the hypothalamic-pituitary-adrenal axis and alterations in glutamatergic synaptic plasticity mediate the effects of acute stress on spatial and recognition memory. Taken together, these findings have significantly advanced our understanding of the neural mechanisms mediating learning and memory and may stimulate the search for novel therapeutics to treat stress-related psychiatric disorders.

Effects of acute stress and GluN2B-containing NMDA receptor antagonism on object and object–place recognition memory

The mechanisms underlying the complex effects of acute stress on memory are incompletely understood. Previous work suggests that the activation of N-methyl-d-aspartate (NMDA) receptors specifically containing GluN2B subunits may underlie the disruptions in spatial memory retrieval caused by acute stress (Wong et al., 2007 PNAS 104:11471). The present experiments were designed to assess whether a similar mechanism is involved in recognition memory. Recognition memory retrieval was assessed in Sprague-Dawley rats using an object recognition test and an object-place recognition test, both of which rely on patterns of spontaneous exploration. Exposure to acute stress for 30 min immediately before the test phase of either test disrupted memory retrieval. Administration of the GluN2B-selective antagonist Ro25-6981 (6 mg/kg; i.p.) enhanced memory in the object recognition test regardless of whether animals were exposed to acute stress. In the object-place test, Ro25-6981 had no effect on memory retrieval in the absence of stress but promoted memory following acute stress. These data highlight the specific contributions made by GluN2B-containing NMDA receptors to recognition memory for different types of stimuli.

Acute stress disrupts paired pulse facilitation and long‐term potentiation in rat dorsal hippocampus through activation of glucocorticoid receptors

Cognitive functions such as learning and memory are widely believed to depend on patterns of short‐ and long‐term synaptic plasticity. Factors, such as acute stress, which affect learning and memory, may do so by altering patterns of synaptic plasticity in distinct neural circuits. Numerous studies have examined the effects of acute stress on long‐term synaptic plasticity; however, few have examined its influence on short‐term plasticity. The present experiments directly assessed the effects of acute stress on short‐term synaptic plasticity as measured by paired pulse facilitation (PPF) of excitatory postsynaptic potentials recorded from rat dorsal hippocampus (dHip) in vivo. Long‐term potentiation (LTP) was also examined. Acute stress induced by exposure to an elevated platform impaired PPF and LTP in the dHip. Pretreatment of rats exposed to stress with mifepristone (RU38486; 10 mg kg−1) blocked the stress‐induced impairment of both PPF and LTP. These data demonstrate that activation of glucocorticoid receptors during acute stress disrupts normal patterns of both PPF and LTP in the dHip.